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Sample records for elicits cyclooxygenase-2-driven prostaglandin

  1. Prostaglandin-dependent modulation of dopaminergic neurotransmission elicits inflammation-induced aversion in mice

    PubMed Central

    Fritz, Michael; Klawonn, Anna M.; Nilsson, Anna; Singh, Anand Kumar; Zajdel, Joanna; Björk Wilhelms, Daniel; Lazarus, Michael; Löfberg, Andreas; Jaarola, Maarit; Örtegren Kugelberg, Unn; Billiar, Timothy R.; Hackam, David J.; Sodhi, Chhinder P.; Breyer, Matthew D.; Jakobsson, Johan; Schwaninger, Markus; Schütz, Günther; Rodriguez Parkitna, Jan; Saper, Clifford B.; Blomqvist, Anders; Engblom, David

    2015-01-01

    Systemic inflammation causes malaise and general feelings of discomfort. This fundamental aspect of the sickness response reduces the quality of life for people suffering from chronic inflammatory diseases and is a nuisance during mild infections like common colds or the flu. To investigate how inflammation is perceived as unpleasant and causes negative affect, we used a behavioral test in which mice avoid an environment that they have learned to associate with inflammation-induced discomfort. Using a combination of cell-type–specific gene deletions, pharmacology, and chemogenetics, we found that systemic inflammation triggered aversion through MyD88-dependent activation of the brain endothelium followed by COX1-mediated cerebral prostaglandin E2 (PGE2) synthesis. Further, we showed that inflammation-induced PGE2 targeted EP1 receptors on striatal dopamine D1 receptor–expressing neurons and that this signaling sequence induced aversion through GABA-mediated inhibition of dopaminergic cells. Finally, we demonstrated that inflammation-induced aversion was not an indirect consequence of fever or anorexia but that it constituted an independent inflammatory symptom triggered by a unique molecular mechanism. Collectively, these findings demonstrate that PGE2-mediated modulation of the dopaminergic motivational circuitry is a key mechanism underlying the negative affect induced by inflammation. PMID:26690700

  2. Prostaglandin E2 requirement for transforming growth factor beta 1 inhibition of elicited macrophage 14 kDa phospholipase A2 release.

    PubMed Central

    McCord, M.; Bolognese, B.; Marshall, L. A.

    1995-01-01

    1. Cultured elicited-peritoneal macrophages release a soluble type II 14 kDa phospholipase A2 (PLA2) over time, reaching a plateau by 20-24 h of incubation and maintaining these levels over 72 h. Prostaglandin E2 (PGE2) is also produced but does not plateau until 48-72 h. 2. Transforming growth factor beta 1 (TGF beta 1) reduces cellular 14 kDa PLA2 and its subsequent release by approximately half, but does not alter PGE2 production. Co-incubation of TGF beta 1 with indomethacin interfered, in a concentration-dependent manner, with the ability of TGF beta 1 to reduce cellular 14 kDa PLA2 and its subsequent release over 24 h. The regulation of TGF beta 1 was not specific to indomethacin since other non-steroidal anti-inflammatory drugs had the same effect. This suggested that cyclooxygenase activity was essential for TGF beta 1 to exert its effect and indeed, the addition of exogenous PGE2 restored the TGF beta 1 action. 3. PGE2 alone exerted a concentration-dependent negative feedback action on elicited-macrophage 14 kDa PLA2 release. The inhibitory concentration (IC50 = approximately 180 ng PGE2 ml-1) approximated the PGE2 levels measured in the 24 h macrophage conditioned media (85-140 ng PGE2 ml-1) where PLA2 release began to plateau. Further, incubation of cells with indomethacin over 48 h resulted in the enhancement of 14 kDa PLA2 activity compared to that released from untreated cells. Forskolin failed to inhibit 14 kDa PLA2 release, suggesting PGE2 was not acting through an increase in adenylate cyclase. 4. Taken together, the data are consistent with the immunosuppressive aspects reported for both mediators during inflammation and demonstrates the requirement of PGE2 for TGF beta 1 action on the elicited macrophage. Images Figure 3 PMID:8590973

  3. Inhibition of experimental autoimmune tubulointerstitial nephritis in Brown-Norway rats by (15S)-15-methyl prostaglandin E1. Analysis of the effect of prostaglandin E1 on the induction of the humoral immune response and the elicitation of humorally mediated inflammation.

    PubMed Central

    Ulich, T. R.; Ni, R. X.

    1986-01-01

    Brown-Norway (BN) rats develop tubulointerstitial nephritis (TIN) after immunization with bovine tubular basement membrane (TBM) and adjuvants. Daily subcutaneous injections (either on Days 0-7 or Days 0-14) of (15S)-15-methyl prostaglandin E1 (M-PGE1) at a dose of 1 mg/kg/day markedly inhibited or completely abrogated the development of both the acute polymorphonuclear (Day 10) and the subsequent mononuclear (Day 14) inflammatory phases of BN rat TIN. Circulating anti-TBM antibody in Days 0-7 M-PGE1-treated rats was moderately diminished on Day 8 after immunization but not on Day 14. Circulating anti-TBM antibody in Days 0-14 M-PGE1-treated rats was only slightly diminished on Day 14. In experiments to test the effect of M-PGE1 on the elicitation phase of humorally mediated inflammation, M-PGE1 inhibited the acute inflammatory response observed 6 hours after intradermal injection of particulate TBM into TBM-sensitized BN rats. The inflammation in these skin tests was demonstrated by passive transfer experiments to be humorally mediated. The inhibition of acute humorally mediated intradermal inflammation was not attributable to neutropenia, because M-PGE1 caused a significant neutrophilia as demonstrated by peripheral blood smears. Although the inhibition of TIN in Days 0-14 M-PGE1-treated rats may have been due, in part, to dysfunction of the elicitation phase of humorally mediated inflammation, the inhibition of TIN in Days 0-7 M-PGE1-treated rats was more likely secondary to the diminished induction of either humoral or cellular immunity. Images Figure 5 Figure 6 Figure 7 PMID:3740216

  4. Prostaglandins and prostaglandin receptor antagonism in migraine.

    PubMed

    Antonova, Maria

    2013-05-01

    Human models of headache may contribute to understanding of prostaglandins' role in migraine pathogenesis. The current thesis investigated the migraine triggering effect of prostaglandin E2 (PGE2) in migraine patients without aura, the efficacy of a novel EP4 receptor antagonist, BGC20-1531, in prevention of PGE2-induced headache and the ability of prostaglandin F2α (PGF2α) to trigger headache without any vasodilatation in healthy volunteers. All studies were designed as double-blind, placebo-controlled, cross-over experiments, where PGE2/PGF2α or saline were infused over 20-25 min. In the study with EP4 receptor antagonist healthy volunteers were pre-treated with two different doses of BGC20-1531 or placebo followed by PGE2 infusion over 25 min. The headache data were collected during the whole study day, whereas the possible vascular changes were measured during the in-hospital phase of 1.5 h. The infusion of PGE2 caused the immediate migraine-like attacks and vasodilatation of the middle cerebral artery in migraine patients without aura. The highly specific and potent EP4 receptor antagonist, BGC20-1531, was not able to attenuate PGE2-induced headache and vasodilatation of both intra- and extra-cerebral arteries. The intravenous infusion of PGF2α did not induce headache or statistically significant vasoconstriction of cerebral arteries in healthy volunteers. Novel data on PGE2-provoked immediate migraine-like attacks suggest that PGE2 may be one of the important final products in the pathogenesis of migraine. The lack of efficacy of EP4 receptor antagonist suggests that a single receptor blockade is not sufficient to block PGE2 responses, hence EP2 receptor should be investigated as a potential drug target for the treatment of migraine. The absence of headache during the PGF2α infusion demonstrates that vasodilating properties are necessary for the induction of headache and migraine. PMID:23673269

  5. Bimatoprost and prostaglandin F(2 alpha) selectively stimulate intracellular calcium signaling in different cat iris sphincter cells.

    PubMed

    Spada, Clayton S; Krauss, Achim H-P; Woodward, David F; Chen, June; Protzman, Charles E; Nieves, Amelia L; Wheeler, Larry A; Scott, David F; Sachs, George

    2005-01-01

    Bimatoprost is a synthetic analog of prostaglandin F(2 alpha) ethanolamide (prostamide F(2 alpha)), and shares a pharmacological profile consistent with that of the prostamides. Like prostaglandin F(2 alpha) carboxylic acid, bimatoprost potently lowers intraocular pressure in dogs, primates and humans. In order to distinguish its mechanism of action from prostaglandin F(2 alpha), fluorescence confocal microscopy was used to examine the effects of bimatoprost, prostaglandin F(2 alpha) and 17-phenyl prostaglandin F(2 alpha) on calcium signaling in resident cells of digested cat iris sphincter, a tissue which exhibits contractile responses to both agonists. Constant superfusion conditions obviated effective conversion of bimatoprost. Serial challenge with 100 nM bimatoprost and prostaglandin F(2 alpha) consistently evoked responses in different cells within the same tissue preparation, whereas prostaglandin F(2 alpha) and 17-phenyl prostaglandin F(2 alpha) elicited signaling responses in the same cells. Bimatoprost-sensitive cells were consistently re-stimulated with bimatoprost only, and prostaglandin F(2 alpha) sensitive cells could only be re-stimulated with prostaglandin F(2 alpha). The selective stimulation of different cells in the same cat iris sphincter preparation by bimatoprost and prostaglandin F(2 alpha), along with the complete absence of observed instances in which the same cells respond to both agonists, strongly suggests the involvement of distinct receptors for prostaglandin F(2 alpha) and bimatoprost. Further, prostaglandin F(2 alpha) but not bimatoprost potently stimulated calcium signaling in isolated human embryonic kidney cells stably transfected with the feline- and human-prostaglandin F(2 alpha) FP-receptor and in human dermal fibroblast cells, and only prostaglandin F(2 alpha) competed with radioligand binding in HEK-feFP cells. These studies provide further evidence for the existence of a bimatoprost-sensitive receptor that is distinct from

  6. Prostaglandin E3 metabolism and cancer

    PubMed Central

    Yang, Peiying; Jiang, Yan; Fischer, Susan M.

    2015-01-01

    The anticancer activity of n-3 fatty acids, especially those derived from fish, such as eicosapentaenoic acid (EPA) and docosahexaenoic acid) (DHA), has been studied for centuries. While there is a growing body of evidence that EPA and DHA may influence cancer initiation and development through targeting multiple events of tumor development, the underlying mechanisms responsible for these activities are still not fully understood. A number of studies have suggested that the anticancer activities of EPA and DHA are associated with their effects on eicosanoid metabolism by which they inhibit prostaglandin E2 (PGE2) production. In contrast to DHA, EPA can function as a substrate for cyclooxygenases (COXs) to synthesize unique 3-series prostaglandin compounds, especially PGE3. With advance technology in mass spectrometry, there is renewed interest in studying the role of PGE3 in EPA elicited anti-proliferative activity in various cancers, with some promising results. Here, we summarize the regulation of PGE3 synthesis in cancer cells and its role in EPA elicited anticancer activity. The development of PGE3 and its metabolites as potential biomarkers for future clinical evaluation of EPA and fish oil in cancer care is discussed. PMID:24657656

  7. Prostaglandins: pharmacology and clinical application.

    PubMed

    Karim, S M; Hillier, K

    1974-01-01

    Prostaglandin research has been 1 of the most stimulating features of biomedical investigation in the past decade. Interest developed at a time of expanding knowledge of hormonal and neurohormonal behavior and research work received a tremendous impetus in the early 1960s with the elucidation in Sweden of the chemical structures of prostaglandins, followed by the discovery of their biosynthetic pathways. The original findings of large amounts of prostaglandin in the male accessory genital glands and their secretions, and subsequent discovery in the menstrual and amniotic fluids linked these substances with human production. As a result of further investigation, clinical applications of prostaglandins for the induction of labor and termination of early unwanted pregnancies have been developed. Apart from the functions of the prostaglandins in the reproductive area, they have been shown to have a widespread distribution in the body and produce many different pharmacological effects. Prostaglandins are thought to be involved in the regulation of blood pressure and through their vascular effects have therapeutic potential in the treatment of hypertension and peripheral vascular disease. Through their bronchodilator effect, some prostaglandins may become useful in the treatment of asthma. PMID:4611742

  8. Misidentification of prostamides as prostaglandins.

    PubMed

    Glass, Michelle; Hong, Jiwon; Sato, Timothy A; Mitchell, Murray D

    2005-07-01

    Prostaglandins and endogenous cannabinoid metabolites share the same lipid backbone with differing polar head groups at exactly the position through which a large molecule is attached to provide antigenicity and thus raise antisera. Hence, we hypothesized that antisera raised against prostaglandins linked to a large molecule such as BSA at the carboxyl functional group would also recognize endogenous cannabinoid metabolites and lead to highly misleading interpretations of data. We found major cross-reactivity of commercial antisera raised to prostaglandins with endocannabinoid metabolites. Furthermore, in a well-characterized cell line (WISH) or primary amnion tissue explants, endocannabinoid treatment led to increased production of endocannabinoid metabolites as opposed to primary prostaglandins. This was apparent only after separation of products by thin-layer chromatography, because they measured as prostaglandins by radioimmunoassay. These findings have major implications for our interpretation of data in situations in which these prostaglandin-like molecules are formed, and they stress the need for chromatographic or spectrometric confirmation of prostaglandin production detected by antibody-based methods. PMID:15863842

  9. Prostaglandins, bioassay and inflammation

    PubMed Central

    Flower, R J

    2006-01-01

    The formation of the British Pharmacological Society coincided almost exactly with a series of ground-breaking studies that ushered in an entirely new field of research – that of lipid mediator pharmacology. For many years following their chemical characterisation, lipids were considered only to be of dietary or structural importance. From the 1930s, all this changed – slowly at first and then more dramatically in the 1970s and 1980s with the emergence of the prostaglandins (PGs), the first intercellular mediators to be clearly derived from lipids, in a dynamic on-demand system. The PGs exhibit a wide range of biological activities that are still being evaluated and their properties underlie the action of one of the world's all-time favourite medicines, aspirin, as well as its more modern congeners. This paper traces the development of the PG field, with particular emphasis on the skilful utilisation of the twin techniques of bioassay and analytical chemistry by U.K. and Swedish scientists, and the intellectual interplay between them that led to the award of a joint Nobel Prize to the principal researchers in the PG field, half a century after the first discovery of these astonishingly versatile mediators. PMID:16402103

  10. Lipopolysaccharide induces macrophage migration via prostaglandin D(2) and prostaglandin E(2).

    PubMed

    Tajima, Tsuyoshi; Murata, Takahisa; Aritake, Kosuke; Urade, Yoshihiro; Hirai, Hiroyuki; Nakamura, Masataka; Ozaki, Hiroshi; Hori, Masatoshi

    2008-08-01

    Lipopolysaccharide (LPS) produces prostaglandins (PGs) concomitant to eliciting macrophage migration. We evaluated the role of PGs in initiating the migration of macrophages, especially focusing on PGD(2) and PGE(2). In RAW264.7 macrophages, cyclooxygenase (COX)-2 inhibitor, CAY10404 [3-(4-methylsulphonylphenyl)-4-phenyl-5-trifluoromethylisoxazole], completely inhibited LPS-mediated migration at 4 h (early phase) but only partially inhibited the migration at 8 h (late phase), suggesting the presence of PG-dependent and -independent pathways. In the early phase, LPS up-regulated mRNA expressions of COX-2, hematopoietic PGD synthase (H-PGDS), and microsomal-PGE synthase 1, increasing PGD(2) and PGE(2) substantially. The chemoattractant receptor-homologous molecule expressed on Th2 lymphocytes (CRTH2) agonist, DK-PGD(2) (13-14-dihydro-15-keto-PGD(2)), and the EP4 agonist, ONO-AE1-329 (16-{3-methoxymethyl}phenyl-omega-tetranor-3,7-dithia-prostaglandin E(1)), but not selective agonists of D prostanoid receptor, E prostanoid receptor (EP) 2, or EP3, stimulated random migration (chemokinesis). In peritoneal macrophages from CRTH2-deficient and H-PGDS-deficient mice, LPS-mediated migration was significantly inhibited at either early or late phases of the migration. The H-PGDS inhibitor, HQL-79 [4-(diphenylmethoxy)-1-[3-(1H-tetrazol-5-yl)propyl-piperidine

  11. Anorectic activity of prostaglandin precursors.

    PubMed Central

    Doggett, N S; Jawaharlal, K

    1977-01-01

    1 Intraperitoneal and intragastric (i.g.) administration of prostaglandin precursors arachidonic (2 mg, 15 mg/kg, i.p; 30 mg/kg i.g.), linolenic (100 mg/kg i.p.; 200 mg/kg, i.g.) and linoleic (15, 100 mg/kg, i.p.; 100 mg/kg, i.g.) acids to 22 h food-deprived rats inhibits food intake. 2 This anorexia is similar to that induced by prostaglandin F2alpha (1 mg/kg, i.p.). 3 At anorectic doses these fatty acids do not cause pyrexia, in fact arachidonic acid causes hypothermia. 4 Prior treatment with indomethacin (15 mg/kg) and paracetamol (50 mg/kg) specifically reverses the anorexia and the behavioural satiety induced by the three fatty acids, while not affecting prostaglandin F2alpha-induced suppression of food intake. 5 Results of the present experiments suggest that both physiological and pharmacological modification of appetite could be brought about through an effect on prostaglandin generating systems. PMID:890209

  12. Ludic Elicitation: Using Games for Knowledge Elicitation

    ERIC Educational Resources Information Center

    Cao, Yan

    2014-01-01

    Knowledge elicitation from human beings is important for many fields, such as decision support systems, risk communication, and customer preference studying. Traditional approaches include observations, questionnaires, structured and semi-structured interviews, and group discussions. Many publications have been studying different techniques for a…

  13. Prostaglandin D2 toxicity in primary neurons is mediated through its bioactive cyclopentenone metabolites

    PubMed Central

    Liu, Hao; Li, Wenjin; Rose, Marie E.; Pascoe, Jordan L.; Miller, Tricia M.; Ahmad, Muzamil; Poloyac, Samuel M.; Hickey, Robert W.; Graham, Steven H.

    2014-01-01

    Prostaglandin D2 (PGD2) is the most abundant prostaglandin in brain but its effect on neuronal cell death is complex and not completely understood. PGD2 may modulate neuronal cell death via activation of DP receptors or its metabolism to the cyclopentenone prostaglandins (CyPGs) PGJ2, Δ12-PGJ2 and 15-deoxy-Δ12,14-PGJ2, inducing cell death independently of prostaglandin receptors. This study aims to elucidate the effect of PGD2 on neuronal cell death and its underlying mechanisms. PGD2 dose-dependently induced cell death in rat primary neuron-enriched cultures in concentrations of ≥ 10 μM, and this effect was not reversed by treatment with either DP1 or DP2 receptor antagonists. Antioxidants N-acetylcysteine (NAC) and glutathione which contain sulfhydryl groups that can bind to CyPGs, but not ascorbate or tocopherol, attenuated PGD2-induced cell death. Conversion of PGD2 to CyPGs was detected in neuronal culture medium; treatment with these CyPG metabolites alone exhibited effects similar to those of PGD2, including apoptotic neuronal cell death and accumulation of ubiquitinated proteins. Disruption of lipocalin-type prostaglandin D synthase (L-PGDS) protected neurons against hypoxia. These results support the hypothesis that PGD2 elicits its cytotoxic effects through its bioactive CyPG metabolites rather than DP receptor activation in primary neuronal culture. PMID:23973622

  14. Comparison between the in vivo rate of metabolism of prostaglandin I2 and its blood-pressure-lowering response after intravenous administration in the rat.

    PubMed

    Pace-Asciak, C R; Rosenthal, A; Domazet, Z

    1979-07-27

    Intravenous bolus injection of prostaglandin I2 in the Inactin-anaesthetised rat produces a slow dose-dependant vasodepression which reaches maximum approximately 15 s. after injection. Administration of 9 beta-[3H1]-prostaglandin I2 by the same route followed by serial arterial sampling and TLC analysis revealed a slow conversion into one less polar metabolite starting after 20 s and reaching 40% by two minutes in the circulation. These experiments indicate that prostaglandin I2 survives pulmonary transit for a sufficiently long time to elicit a biological action. Thus its continuous systemic vascular synthesis could play an important role in the control of hypertension. PMID:383157

  15. The Enteropathy of Prostaglandin Deficiency

    PubMed Central

    Adler, David H.; Phillips, John A.; Cogan, Joy D.; Iverson, Tina M.; Stein, Jeffrey A.; Brenner, David A.; Morrow, Jason D.; Boutaud, Olivier; Oates, John A.

    2009-01-01

    Purpose Small intestinal ulcers are frequent complications of therapy with non-steroidal anti-inflammatory drugs (NSAIDs). We present here a genetic deficiency of eicosanoid biosynthesis that illuminates the mechanism of NSAID-induced ulcers of the small intestine. Methods Eicosanoids and metabolites were measured by isotope-dilution with mass spectrometry. cDNA was obtained by reverse transcription and sequenced following amplification with RT-PCR. Results We investigated the cause of chronic recurrent small intestinal ulcers, small bowel perforations, and gastrointestinal blood loss in a 45 year old male who was not taking any cyclooxygenase inhibitor. Prostaglandin metabolites in urine were significantly depressed. Serum thromboxane B2 (TxB2) production was 4.6% of normal controls (p<0.006) and serum 12-HETE was 1.3% of controls (p<0.005). Optical platelet aggregation with simultaneous monitoring of ATP release demonstrated absent granule secretion in response to ADP and a blunted aggregation response to ADP and collagen, but normal response to arachidonic acid (AA). LTB4 biosynthesis by ionophore activated leukocytes was only 3% of controls and urinary LTE4 was undetectable. These findings suggested deficient AA release from membrane phospholipids by cytosolic phospholipase A2-α (cPLA2-α) which regulates cyclooxygenase and lipoxygenase mediated eicosanoid production by catalyzing the release of their substrate, AA. Sequencing of cPLA2-α cDNA demonstrated 2 heterozygous non-synonymous single base pair mutations: Ser111Pro (S111P) and Arg485His (R485H), as well as a known SNP: Lys651Arg (K651R). Conclusion Characterization of this cPLA2-α deficiency provides support for the importance of prostaglandins in protecting small intestinal integrity, and indicates that loss of prostaglandin biosynthesis is sufficient to produce small intestinal ulcers. PMID:19148786

  16. The current status of prostaglandins as abortifacients.

    PubMed

    Brenner, W E

    1975-10-01

    The present use and potential uses of prostaglandins as abortifacients are summarized. Pertinent history, chemistry, prostaglandins' possible role in physiologic and pathologic processes and pharmacologic actions are discussed. The results of natural prostaglandins and their analogues by systemic and intrauterine administration for the purposes of postcoital contraception, menstrual regulation, first- and second-trimester abortion, preoperative dilation of the cervix, and delivery of patients with death in utero are presented. The only approved method of induction of abortion with prostaglandins, prostaglandin F2alpha by the intra-amniotic route for the induction of midtrimester abortion, is evaluated and compared to other methods of midtrimester abortion. It was concluded that: (1) the present use of prostaglandins is an important addition to the obstetrician's armamentarium, (2) more effective and/or convenient methods that are useful in patients over a wider gestational age appear to have been defined, and (3) the routine use of prostaglandins for postcoital contraception, menstrual regulation, and first-trimester abortion will require the development of analogues that are more specific as to their abortifacient actions than the natural prostaglandins and/or the development of improved delivery systems. PMID:810025

  17. Prostaglandin ethanolamides attenuate damage in a human explant colitis model.

    PubMed

    Nicotra, Lauren L; Vu, Megan; Harvey, Benjamin S; Smid, Scott D

    2013-01-01

    Endocannabinoids are protective in animal colitis models. As endocannabinoids also form novel prostaglandin ethanolamides (prostamides) via COX-2, we investigated the effects of prostamides and other COX-2 mediators on tissue damage in an ex vivo human mucosal explant colitis model. Healthy human colonic mucosae were incubated with pro-inflammatory cytokines TNF-α and IL-1β to elicit colitis-like tissue damage. The PGF-ethanolamide analogue, bimatoprost decreased colitis scores which were reversed by a prostamide-specific antagonist AGN 211334, but not the FP receptor antagonist AL-8810. PGF-ethanolamide and PGE-ethanolamide also reduced cytokine-evoked epithelial damage. Anandamide was protective in the explant colitis model; however COX-2 inhibition did not alter its effects, associated with a lack of COX-2 induction in explant mucosal tissue. These findings support an anti-inflammatory role for prostamides and endocannabinoids in the human colon. PMID:23380599

  18. Effects of prostaglandins and prostaglandin synthetase inhibitors on acutely obstructed kidneys in the dog.

    PubMed

    Zwergel, U; Zwergel, T; Ziegler, M

    1991-01-01

    An intact canine model was developed to study the effects of prostaglandins (PG) and prostaglandin synthetase inhibitors on acutely obstructed kidneys. Totally implanted nephrostomy tubes were placed to measure renal pelvic pressure. Complete ureteral obstruction was obtained with a Fogarty balloon catheter inflated in the distal ureter; by this method renal pelvic pressure reached 40-50 mm Hg. Renal pelvic pressure was reduced after intravenous indomethacin and dipyrone administration, whereas blood pressure showed no major changes. Exogenous prostaglandins had both immediate and contrary effects: PGE2 caused a significant decrease, whereas PGF2 alpha caused a significant increase in renal pelvic and blood pressure. The reduced rise in renal pelvic pressure appears to be the main reason for the analgesic effects of prostaglandin synthetase inhibitors. The efficiency of these drugs in the treatment of renal colic is supported by this study, that of prostaglandins cannot be proved. PMID:1792708

  19. Synthesis of prostaglandin E2, thromboxane B2 and prostaglandin catabolism in gastritis and gastric ulcer.

    PubMed Central

    Hawkey, C J

    1986-01-01

    Because endogenous prostaglandins may protect the gastric mucosa a study was conducted to determine factors influencing the synthesis of immunoreactive prostaglandin (iPG) E2 and thromboxane (iTx) B2 as measured by radioimmunoassay and prostaglandin catabolism measured radiometrically, in human gastric mucosa. Gastric mucosa was obtained at endoscopy. Synthesis of iPE2 and iTxB2 was inhibited in vitro by indomethacin; iTxB2 synthesis was also selectively inhibited by the thromboxane synthesis inhibitor dazmegrel. Prostaglandin catabolism was inhibited by carbenoxolone. Multivariate analysis showed that synthesis of iPGE2 from endogenous precursor during homogenisation was decreased in patients on non-steroidal anti-inflammatory drugs. Mucosal inflammation was associated with significantly increased synthesis of iPGE2 and decreased prostaglandin catabolism. There were no differences between the mucosa of patients with or without gastric ulcers, nor between the ulcer rim and mucosa 5 cm away. Age, sex, smoking history and ingestion of antisecretory drugs appeared to exert no influence. In this study gastritis was the major influence on prostaglandin synthesis. It seems unlikely that prostaglandin deficiency is a strong predisposing factor for gastric ulceration. PMID:3468053

  20. [Prostaglandins in gynecology and obstetrics].

    PubMed

    Klausch, B; Kyank, H

    1972-06-01

    A review of early research (up through 1970) on prostaglandins (PGs) is presented. Their chemical structure and classification based on their ring-structure is detailed as well as various analytic methods of mammalian tissues and body fluids. For clinical use PGE1 and 2, PGF2alpha and PGA1 are the most significant ones because of their properties. PGs have many physiological activities encompassing many organ systems. Their pharmacological actions include: 1) stimulation of nonvascular smooth muscle; 2) peripheral vasodilation (excluding PGFs which cause vasoconstriction); 3) inhibition of lipolysis; 4) inhibition of platelet aggregation; 5) inhibition of gastric peristalsis and gastric juice secretion; 6) bronchodilation; and 7) inhibition of spontaneous CNS activity. The level of PGEs in semen is closely related to the degree of fertility; normally fertile men have 55 mcg PGE/ml and never less than 11 mcg/ml. Current studies are under way on the effect of PGE in artificial insemination of sperm of subfertile men. PGF2alpha and PGE2 stimulate menstruation and uterine contraction; other PGs inhibit uterine contraction. PGs from semen have a role in sperm transport and possibly act on fallopian tube motility aiding sperm capacitation, and ovum retention and transport. Early trials with PGs point to a possible action as an abortifacient, as a once-a-month contraceptive, or a postconception contraceptive agent. PGF2alpha is found in variable concentrations in maternal blood during contraction of the pregnant uterus; levels increase as labor progresses. PGs have been used for labor induction, for induction of abortion and in mole pregnancy. Given as a constant intravenous infusion they produce regular contractions leading to natural expulsion of the fetus and causing very few side effects in the woman with no adverse effects on the fetus. PGs' action compares favorably with that of oxytocin and is preferable for labor induction in certain pregnancy complications. PGE1

  1. Effects of in vivo administration of epidermal growth factor (EGF) on uterine contractility, prostaglandin production and timing of parturition in rats.

    PubMed

    Ribeiro, M L; Farina, M; Aisemberg, J; Franchi, A

    2003-10-01

    Prostaglandins synthesized by cyclooxygenases elicit uterine contractions during labour. Nitric oxide synthases (NOS) produce nitric oxide (NO), which maintains uterine quiescence during pregnancy. Epidermal growth factor (EGF) interacts with prostaglandins and NO in many biological systems. The aim of this work was to study the effect of the in vivo administration of EGF on uterine contractility, prostaglandin production and timing of parturition in rats. EGF was injected into the uterine lumen of pregnant rats on day 20, 21 or 22 of gestation. Intra-uterine administration of 500 ng EGF on day 21 of gestation delayed parturition for 18 h compared with control rats. Administration of EGF was able to: (i) reduce cyclooxygenase expression in the uterus (determined by western blot analysis) and production of prostaglandins by the uterus (evaluated by conversion of [(14)C]arachidonate to labelled prostaglandins); (ii) decrease prostaglandin concentrations in amniotic fluid (radioimmunoassay); (iii) increase NO production (evaluated by conversion of [(14)C]arginine into [(14)C]citrulline); (iv) increase serum progesterone concentrations to more than control concentrations (P<0.05; radioimmunoassay); and (v) reduce the amplitude of the uterine contractions. The overall effect was a delay in the onset of delivery. This in vivo effect raises the question of whether exogenous EGF plays a role in the initiation of parturition. PMID:14525528

  2. Unconsciously elicited perceptual prior

    PubMed Central

    Chang, Raymond; Baria, Alexis T.; Flounders, Matthew W.; He, Biyu J.

    2016-01-01

    Increasing evidence over the past decade suggests that vision is not simply a passive, feed-forward process in which cortical areas relay progressively more abstract information to those higher up in the visual hierarchy, but rather an inferential process with top-down processes actively guiding and shaping perception. However, one major question that persists is whether such processes can be influenced by unconsciously perceived stimuli. Recent psychophysics and neuroimaging studies have revealed that while consciously perceived stimuli elicit stronger responses in higher visual and frontoparietal areas than those that fail to reach conscious awareness, the latter can still drive high-level brain and behavioral responses. We investigated whether unconscious processing of a masked natural image could facilitate subsequent conscious recognition of its degraded counterpart (a black-and-white “Mooney” image) presented many seconds later. We found that this is indeed the case, suggesting that conscious vision may be influenced by priors established by unconscious processing of a fleeting image.

  3. Identification and Characterization of Novel Microsomal Prostaglandin E Synthase-1 Inhibitors for Analgesia.

    PubMed

    Chandrasekhar, Srinivasan; Harvey, Anita K; Yu, Xiao-Peng; Chambers, Mark G; Oskins, Jennifer L; Lin, Chaohua; Seng, Thomas W; Thibodeaux, Stefan J; Norman, Bryan H; Hughes, Norman E; Schiffler, Matthew A; Fisher, Matthew J

    2016-03-01

    Prostaglandin (PG) E2 plays a critical role in eliciting inflammation. Nonsteroidal anti-inflammatory drugs and selective inhibitors of cyclooxygenase, which block PGE2 production, have been used as key agents in treating inflammation and pain associated with arthritis and other conditions. However, these agents have significant side effects such as gastrointestinal bleeding and myocardial infarction, since they also block the production of prostanoids that are critical for other normal physiologic functions. Microsomal prostaglandin E2 synthase-1 is a membrane-bound terminal enzyme in the prostanoid pathway, which acts downstream of cyclooxygenase 2 and is responsible for PGE2 production during inflammation. Thus, inhibition of this enzyme would be expected to block PGE2 production without inhibiting other prostanoids and would provide analgesic efficacy without the side effects. In this report, we describe novel microsomal prostaglandin E2 synthase-1 inhibitors that are potent in blocking PGE2 production and are efficacious in a guinea pig monoiodoacetate model of arthralgia. These molecules may be useful in treating the signs and symptoms associated with arthritis. PMID:26740668

  4. Prostaglandins and their receptors in insect biology

    Technology Transfer Automated Retrieval System (TEKTRAN)

    We treat the biological significance of prostaglandins (PGs) and their known receptors in insect biology. PGs and related eicosanoids are oxygenated derivatives of arachidonic acid (AA) and two other C20 polyunsaturated fatty acids. PGs are mostly appreciated in the context of biomedicine, but a gr...

  5. Prostaglandin I2 and prostaglandin E2 modulate human intrarenal artery contractility through prostaglandin E2-EP4, prostacyclin-IP, and thromboxane A2-TP receptors.

    PubMed

    Eskildsen, Morten P; Hansen, Pernille B L; Stubbe, Jane; Toft, Anja; Walter, Steen; Marcussen, Niels; Rasmussen, Lars M; Vanhoutte, Paul M; Jensen, Boye L

    2014-09-01

    Cyclooxygenase inhibitors decrease renal blood flow in settings with decreased effective circulating volume. The present study examined the hypothesis that prostaglandins, prostaglandin E2 (PGE2) and prostacyclin (PGI2), induce relaxation of human intrarenal arteries through PGE2-EP and PGI2-IP receptors. Intrarenal arteries were microdissected from human nephrectomy samples (n=53, median diameter ≈362 μm, 88% viable, 76% relaxed in response to acetylcholine). Rings were suspended in myographs to record force development. In vessels with K(+)-induced tension (EC70: -log [mol/L]=1.36±0.03), PGE2 and PGI2 induced concentration-dependent relaxation (-log EC50: PGE2=7.1±0.3 and PGI2=7.7). The response to PGE2 displayed endothelium dependence and desensitization. Relaxation by PGE2 was mimicked by an EP4 receptor agonist (CAY10598, EC50=6.7±0.2). The relaxation after PGI2 was abolished by an IP receptor antagonist (BR5064, 10(-8) mol/L). Pretreatment of quiescent arteries with PGE2 for 5 minutes (10(-6) mol/L) led to a significant right shift of the concentration-response to norepinephrine (EC50 from 6.6±0.1-5.9±0.1). In intrarenal arteries with K(+)-induced tone, PGE2 and PGI2 at 10(-5) mol/L elicited increased tension. This was abolished by thromboxane receptor (TP) antagonist (S18886, 10(-6) mol/L). A TP agonist (U46619, n=6) evoked tension (EC50=8.1±0.2) that was inhibited by S18886. Polymerase chain reaction and immunoblotting showed EP4, IP, and TP receptors in intrarenal arteries. In conclusion, PGE2 and PGI2 may protect renal perfusion by activating cognate IP and EP4 receptors associated with smooth muscle cells and endothelium in human intrarenal arteries and contribute to increased renal vascular resistance at high pathological concentrations mediated by noncognate TP receptor. PMID:24914192

  6. Minor changes in gene expression in the mouse preoptic hypothalamic region by inflammation-induced prostaglandin E2.

    PubMed

    Vasilache, A M; Kugelberg, U; Blomqvist, A; Nilsberth, C

    2013-07-01

    We investigated to what extent inflammation-induced prostaglandin E2 (PGE2 ) regulates gene expression in the central nervous system. Wild-type mice and mice with deletion of the gene encoding microsomal prostaglandin E synthase-1 (mPGES-1), which cannot produce inflammation-induced PGE2 , were subjected to peripheral injection of bacterial wall lipopolysaccharide (LPS) and killed after 5 h. The median and medial preoptic nuclei, which are rich in prostaglandin E receptors, were isolated by laser capture microdissection (LCM), and subjected to whole genome microarray analysis. Although the immune stimulus induced robust transcriptional changes in the brain, as seen by a quantitative reverse transcriptase-polymerase chain reaction (qRT-PCR) on selected genes, only small PGE2 -dependent gene expression changes were observed in the gene array analysis and, for only two genes, a pronounced differential expression between LPS-treated wild-type and mPGES-1 knockout mice could be verified by qRT-PCR. These were Hspa1a and Hspa1b, encoding heat shock proteins, which showed a two- to three-fold higher expression in wild-type mice than in knockout mice after immune challenge. However, the induced expression of these genes was found to be secondary to increased body temperature because they were induced also by cage exchange stress, which did not elicit PGE2 synthesis, and thus were not induced per se by PGE2 -elicited transcriptional events. Our findings suggest that inflammation-induced PGE2 has little effect on gene expression in the preoptic region, and that centrally elicited disease symptoms, although PGE2 -dependent, occur as a result of regulation of neuronal excitability that is a consequence of intracellular, transcriptional-independent signalling cascades. Our findings also imply that the profound changes in gene expression in the brain that are elicited by peripheral inflammation occur independently of PGE2 via a yet unidentified mechanism. PMID:23631667

  7. Prostaglandins and mechanisms of preterm birth.

    PubMed

    Challis, John R G; Sloboda, Deborah M; Alfaidy, Nadia; Lye, Steven J; Gibb, William; Patel, Fal A; Whittle, Wendy L; Newnham, John P

    2002-07-01

    Increased uterine contractility at term and preterm results first from activation and then stimulation of the myometrium. Activation can be provoked by mechanical stretch of the uterus, and by an endocrine pathway resulting from increased activity of the fetal hypothalamic-pituitary-adrenal axis. In sheep fetuses, increased cortisol output during pregnancy regulates expression of prostaglandin synthase type 2 (PGHS-2) in the placenta in an oestrogen-independent manner, resulting in increased concentrations of prostaglandin E2 (PGE2) in the fetal circulation. Later increases in maternal uterine expression of PGHS-2 require increases in oestrogen and lead to increased concentrations of PGF(2alpha) in the maternal circulation. Thus, regulation of PGHS-2 at term is differentially controlled in fetal (trophoblast) and maternal (uterine epithelium) tissue. This difference may reflect expression of glucocorticoid receptor but not oestrogen receptor (ER) in placental trophoblast cells. In women, cortisol also contributes to increased prostaglandin production in fetal tissues through upregulation of PGHS-2 (amnion and chorion) and downregulation of 15-OH prostaglandin dehydrogenase (PGDH; chorion trophoblasts). The effect of cortisol on expression of PGDH in the chorion reverses a tonic stimulatory effect of progesterone, potentially through a paracrine or autocrine action. In membranes, cortisol may be derived from cortisone through activity of 11beta-hydroxysteroid dehydrogenase (11beta-HSD) type 1, in addition to secretion from the maternal or fetal adrenal glands. In placenta, 11beta-HSD-2 oxidase activity predominates and expression of this enzyme is reduced with hypoxaemia and in placentae from pre-eclamptic pregnancies. In these circumstances, increased concentrations of maternal cortisol may cross into the fetal compartment, contributing to growth restriction and programming later life disease. PMID:12090913

  8. The Role of Prostaglandins in Allergic Lung Inflammation and Asthma

    PubMed Central

    Claar, Dru; Hartert, Tina V.; Peebles, R. Stokes

    2015-01-01

    Prostaglandins are products of the cyclooxygenase pathway of arachidonic acid metabolism. There are five primary prostaglandins, PGD2, PGE2, PGF2, PGI2, and thromboxane B2, all of which signal through distinct seven transmembrane, G-protein coupled receptors. Some prostaglandins may counteract the actions of others, or even the same prostaglandin may have opposing physiologic or immunologic effects, depending on the specific receptor through which it signals. In this review, we will examine the effects of cyclooxygenase activity and the various prostaglandins on allergic airway inflammation and physiology that is associated with asthma. We also highlight the potential therapeutic benefit of targeting prostaglandins in allergic lung inflammation and asthma based on basic science, animal model, and human studies. PMID:25541289

  9. UVB light upregulates prostaglandin synthases and prostaglandin receptors in mouse keratinocytes

    SciTech Connect

    Black, Adrienne T.; Gray, Joshua P.; Shakarjian, Michael P.; Mishin, Vladimir; Laskin, Debra L.; Heck, Diane E.; Laskin, Jeffrey D.

    2008-10-01

    Prostaglandins belong to a class of cyclic lipid-derived mediators synthesized from arachidonic acid via COX-1, COX-2 and various prostaglandin synthases. Members of this family include prostaglandins such as PGE{sub 2}, PGF{sub 2{alpha}}, PGD{sub 2} and PGI{sub 2} (prostacyclin) as well as thromboxane. In the present studies we analyzed the effects of UVB on prostaglandin production and prostaglandin synthase expression in primary cultures of undifferentiated and calcium-differentiated mouse keratinocytes. Both cell types were found to constitutively synthesize PGE{sub 2}, PGD{sub 2} and the PGD{sub 2} metabolite PGJ{sub 2}. Twenty-four hours after treatment with UVB (25 mJ/cm{sup 2}), production of PGE{sub 2} and PGJ{sub 2} increased, while PGD{sub 2} production decreased. This was associated with increased expression of COX-2 mRNA and protein. UVB (2.5-25 mJ/cm{sup 2}) also caused marked increases in mRNA expression for the prostanoid synthases PGDS, mPGES-1, mPGES-2, PGFS and PGIS, as well as expression of receptors for PGE{sub 2} (EP1 and EP2), PGD{sub 2} (DP and CRTH2) and prostacyclin (IP). UVB was more effective in inducing COX-2 and DP in differentiated cells and EP1 and IP in undifferentiated cells. UVB readily activated keratinocyte PI-3-kinase (PI3K)/Akt, JNK and p38 MAP signaling pathways which are known to regulate COX-2 expression. While inhibition of PI3K suppressed UVB-induced mPGES-1 and CRTH2 expression, JNK inhibition suppressed mPGES-1, PGIS, EP2 and CRTH2, and p38 kinase inhibition only suppressed EP1 and EP2. These data indicate that UVB modulates expression of prostaglandin synthases and receptors by distinct mechanisms. Moreover, both the capacity of keratinocytes to generate prostaglandins and their ability to respond to these lipid mediators are stimulated by exposure to UVB.

  10. Diverse Roles of Prostaglandins in Blastocyst Implantation

    PubMed Central

    2014-01-01

    Prostaglandins (PGs), derivatives of arachidonic acid, play an indispensable role in embryo implantation. PGs have been reported to participate in the increase in vascular permeability, stromal decidualization, blastocyst growth and development, leukocyte recruitment, embryo transport, trophoblast invasion, and extracellular matrix remodeling during implantation. Deranged PGs syntheses and actions will result in implantation failure. This review summarizes up-to-date literatures on the role of PGs in blastocyst implantation which could provide a broad perspective to guide further research in this field. PMID:24616654

  11. Prostaglandin E1 in hand angiography

    SciTech Connect

    Levy, J.M.; Joseph, R.B.; Bodell, L.S.; Nykamp, P.W.; Hessel, S.J.

    1983-11-01

    Prostaglandin E1 (PG1) is a rapid, potent vasodilator which, when infused into the arterial system in low doses by bolus injection, has no significant systemic effects and has a relatively long duration of action. Sixty-three hand angiograms were done on 55 patients, comparing PGE1 to tolazoline and to angiograms done with no vasodilation. There was no significant difference between PGE1 and tolazoline in digital artery opacification; however, venous opacification was very significantly better with PGE1. PGE1 should be a drug of choice in hand angiography.

  12. Endogenous prostaglandin in guinea pig taenia coli.

    PubMed

    Yamaguchi, T; Hitzig, B; Coburn, R F

    1976-01-01

    Prostaglandin (PGE) is synthesized in the guinea pig taenia coli. A low threshold concentration for an effect of exogenous PGE1 or PGE2 on spontaneous mechanical activity was demonstrated. The PG synthetase inhibitors aspirin, indomethacin, and 5,8,11,14-eicosatetraynoic acid, at concentrations that inhibited PGE efflux, had effects on spontaneous mechanical activity, membrane potential, membrane resistance, and evoked and spontaneous action potentials (single and double sucrose-gap methods) that were consistent with an action due to inhibition of membrane PGE concentration. The threshold concentration of indomethacin, which inhibited PGE efflux, was the same as the concentration that inhibited spontaneous mechanical activity. Pretreatment with ouabain (10(-6)-10(-5) g/ml) or elevated extracellular K+ (29 and 126 mM) made the guinea pig taenia coli entirely refractory to exogenous PGE1 or PGE2; the mechanical effects of the three prostaglandin synthetase inhibitors also were absent in the presence of elevated K+ or ouabain. The data are consistent with a hypothesis that, under conditions of our experiments, endogenous PGE has an effect on resting tension and spontaneous mechanical activity and on properties of the surface membrane of the guinea pig taenia coli. PMID:1251900

  13. Sickness: From the focus on cytokines, prostaglandins, and complement factors to the perspectives of neurons.

    PubMed

    Poon, David Chun-Hei; Ho, Yuen-Shan; Chiu, Kin; Wong, Hoi-Lam; Chang, Raymond Chuen-Chung

    2015-10-01

    Systemic inflammation leads to a variety of physiological (e.g. fever) and behavioral (e.g. anorexia, immobility, social withdrawal, depressed mood, disturbed sleep) responses that are collectively known as sickness. While these phenomena have been studied for the past few decades, the neurobiological mechanisms by which sickness occurs remain unclear. In this review, we first revisit how the body senses and responds to infections and injuries by eliciting systemic inflammation. Next, we focus on how peripheral inflammatory molecules such as cytokines, prostaglandins, and activated complement factors communicate with the brain to trigger neuroinflammation and sickness. Since depression also involves inflammation, we further elaborate on the interrelationship between sickness and depression. Finally, we discuss how immune activation can modulate neurons in the brain, and suggest future perspectives to help unravel how changes in neuronal functions relate to sickness responses. PMID:26363665

  14. Identification and pharmacological characterization of the prostaglandin FP receptor and FP receptor variant complexes

    PubMed Central

    Liang, Y; Woodward, D F; Guzman, V M; Li, C; Scott, D F; Wang, J W; Wheeler, L A; Garst, M E; Landsverk, K; Sachs, G; Krauss, A H-P; Cornell, C; Martos, J; Pettit, S; Fliri, H

    2008-01-01

    Background and purpose: A prostamide analogue, bimatoprost, has been shown to be effective in reducing intraocular pressure, but its precise mechanism of action remains unclear. Hence, to elucidate the molecular mechanisms of this effect of bimatoprost, we focused on pharmacologically characterizing prostaglandin FP receptor (FP) and FP receptor variant (altFP) complexes. Experimental approach: FP receptor mRNA variants were identified by reverse transcription-polymerase chain reaction. The FP-altFP4 heterodimers were established in HEK293/EBNA cells co-expressing FP and altFP4 receptor variants. A fluorometric imaging plate reader was used to study Ca2+ mobilization. Upregulation of cysteine-rich angiogenic protein 61 (Cyr61) mRNA was measured by Northern blot analysis, and phosphorylation of myosin light chain (MLC) by western analysis. Key results: Six splicing variants of FP receptor mRNA were identified in human ocular tissues. Immunoprecipitation confirmed that the FP receptor is dimerized with altFP4 receptors in HEK293/EBNA cells co-expressing FP and altFP4 receptors. In the studies of the kinetic profile for Ca2+ mobilization, prostaglandin F2α (PGF2α) elicited a rapid increase in intracellular Ca2+ followed by a steady state phase. In contrast, bimatoprost elicited an immediate increase in intracellular Ca2+ followed by a second phase. The prostamide antagonist, AGN211335, selectively and dose-dependently inhibited the bimatoprost-initiated second phase of Ca2+ mobilization, Cyr61 mRNA upregulation and MLC phosphorylation, but did not block the action of PGF2α. Conclusion and implications: Bimatoprost lacks effects on the FP receptor but may interact with the FP-altFP receptor heterodimer to induce alterations in second messenger signalling. Hence, FP-altFP complexes may represent the underlying basis of bimatoprost pharmacology. PMID:18587449

  15. Suppression of newborn natural killer cell activity by prostaglandin E2

    SciTech Connect

    Milch, P.O.; Salvatore, W.; Luft, B.; Baker, D.A.

    1988-10-01

    The effect of prostaglandin E2 on natural killer cell activity of cord blood was examined. Natural killer cell activity, determined by chromium 51 release, was significantly reduced after prostaglandin E2 (1 microgram/ml) treatment. Prostaglandin E2 has been found to enhance the cellular spread of herpesvirus. Thus prostaglandins may enhance viral infections indirectly by suppressing natural killer cell activity.

  16. Clinical applications of prostaglandins in Obstetrics and Gynaecology.

    PubMed

    Karim, S M

    1982-10-01

    Although a number of potential practical uses of prostaglandins have been identified, these compounds have so far found clinical applications mainly in Obstetrics and Gynaecology. It is almost 15 years since a prostaglandin was first used for the induction of term labour and prostaglandin E2 is now commercially available for this purpose in many countries. For the termination of second trimester pregnancy, prostaglandins have almost completely replaced other methods previously in use. Other areas where prostaglandins are routinely used or where their uses are being developed, include menstrual induction, preevacuation dilatation of the cervix in the first trimester, termination of pregnancy in cases of missed abortion, intrauterine fetal death and other types of abnormal pregnancies, control of post-partum haemorrhage, treatment of post-partum or post surgical urine retention and ripening of the cervix prior to induction of labour at term. In early studies, prostaglandins E2 and F2 alpha were used for all the applications listed above. In order to increase efficacy and reduce side effects, a number of synthetic analogues were later evaluated for application in selected areas. Those with modification in the 15 and 16 positions of PGE2 and PGF2 alpha molecules have undergone extensive clinical trials and some of these analogues are now in routine use. The current status of the practical applications of prostaglandins in Obstetrics and Gynaecology is reviewed. PMID:6299163

  17. Reversible Conjunctival Pigmentation Associated With Prostaglandin Use.

    PubMed

    Choi, Daniel Y; Chang, Robert T; Yegnashankaran, Krishnan; Friedman, Neil J

    2016-01-01

    A 54-year-old Indian male with a diagnosis of ocular hypertension was started on a prostaglandin analog (PGA) in both eyes to lower intraocular pressure. Six years later, he developed progressively increasing bilateral limbal conjunctival hyperpigmentation. Travoprost was discontinued and replaced with brinzolamide and over the next year, the patient's conjunctival pigmentation improved significantly in both the eyes. This case report documents with slit-lamp photography the first case of conjunctival pigmentation associated with PGA use that has been shown to have reversal with discontinuation of the PGA. Because of the widespread use of PGAs, and the evolving nature of the conjunctival pigmentation, clinicians should be aware of this reversible condition when considering biopsy or removal of conjunctival melanocytic lesions. PMID:25967530

  18. Prostaglandins: a report on early clinical studies

    PubMed Central

    Hinman, J. W.

    1970-01-01

    The prostaglandins are a unique group of pharmacologically active lipids which are widely distributed in mammalian tissues and body fluids. The chemistry of this family of compounds has been established in elegant detail. Research quantities of these highly active natural compounds were obtained by enzymatic bioconversion of essential fatty acids and now studies devoted to the elucidation of their physiological roles and their clinical potential are progressing rapidly. Fields of greatest current interest in clinical medicine include renal-cardiovascular research, induction of labour and therapeutic abortion, control of the reproductive cycle (including fertility control), bronchodilation, enhancement of nasal patency and antisecretory activity. Results available to date are too preliminary for many conclusions to be drawn, but are sufficiently encouraging to assure continued and expanding efforts in several fields. PMID:4098885

  19. Prostaglandin dehydrogenase and the initiation of labor.

    PubMed

    Challis, J R; Patel, F A; Pomini, F

    1999-01-01

    In summary, these studies have suggested that prostaglandin dehydrogenase may have a central role to play in the mechanisms which determine biologically active prostaglandin concentrations within human fetal membranes and placenta at the time of labor, at term or preterm. Moreover, our studies indicate that the regulation of PGDH may by multifactorial (figure 3). In certain regions of the membranes, we suggest that PGDH expression may be influenced by levels of anti-inflammatory and pro-inflammatory cytokines. In other regions of the membranes, we suggest that PGDH may be regulated at a transcriptional level by competing activities of progesterone and cortisol. The action of progesterone could be effected through systemically-derived steroid, or by locally synthesized steroid, acting in a paracrine and/or autocrine fashion. The effects of cortisol in placenta must be due to glucocorticoid derived from the maternal or fetal compartment, since the placenta lacks the hydroxylases required for endogenous cortisol production. However, metabolism of cortisol by 11 beta-HSD-2 reduces the potency of this glucocorticoid in placental tissue. In chorion however, cortisol may be formed locally, from cortisone, in addition to its being derived from the maternal circulation and/or from the amniotic fluid. Our current studies do not allow us to delineate whether the effects of progesterone and cortisol on PGDH are exerted through the glucocorticoid receptor (GR) or progesterone receptor (PR) or both. It is possible that through pregnancy, PGDH activity is maintained by progesterone acting either through low levels of PR in membranes, or, more likely, acting through GR. At term, elevated levels of cortisol compete with and displace progesterone from GR, resulting in inhibition of PGDH transcription and activity. In this way, local withdrawal of progesterone action would be effected within human intrauterine tissues, without requiring changes in systemic, circulating progesterone

  20. Eliciting expert knowledge in conservation science.

    PubMed

    Martin, Tara G; Burgman, Mark A; Fidler, Fiona; Kuhnert, Petra M; Low-Choy, Samantha; McBride, Marissa; Mengersen, Kerrie

    2012-02-01

    Expert knowledge is used widely in the science and practice of conservation because of the complexity of problems, relative lack of data, and the imminent nature of many conservation decisions. Expert knowledge is substantive information on a particular topic that is not widely known by others. An expert is someone who holds this knowledge and who is often deferred to in its interpretation. We refer to predictions by experts of what may happen in a particular context as expert judgments. In general, an expert-elicitation approach consists of five steps: deciding how information will be used, determining what to elicit, designing the elicitation process, performing the elicitation, and translating the elicited information into quantitative statements that can be used in a model or directly to make decisions. This last step is known as encoding. Some of the considerations in eliciting expert knowledge include determining how to work with multiple experts and how to combine multiple judgments, minimizing bias in the elicited information, and verifying the accuracy of expert information. We highlight structured elicitation techniques that, if adopted, will improve the accuracy and information content of expert judgment and ensure uncertainty is captured accurately. We suggest four aspects of an expert elicitation exercise be examined to determine its comprehensiveness and effectiveness: study design and context, elicitation design, elicitation method, and elicitation output. Just as the reliability of empirical data depends on the rigor with which it was acquired so too does that of expert knowledge. PMID:22280323

  1. Effects of Prostaglandin Analogues on Aqueous Humor Outflow Pathways

    PubMed Central

    Winkler, Nelson S.

    2014-01-01

    Abstract Elevated intraocular pressure (IOP) is the most prevalent risk factor for glaucoma. All treatments, whether surgical or pharmaceutical, are aimed at lowering IOP. Prostaglandin analogues are a first line therapy for glaucoma due to their ability to reduce IOP, once-daily dosing, efficacy, and minimal side-effect profile. Whereas prostaglandin analogues have been known to alter aqueous humor outflow through the unconventional (uveoscleral) pathway, more recent evidence suggests their action also occurs through the conventional (trabecular) pathway. Understanding how prostaglandin analogues successfully lower IOP is important, as this information may lead to the discovery of new molecular targets for future therapeutic intervention. This review explores the current understanding of prostaglandin analogue biology as it pertains to IOP reduction and improved aqueous humor outflow facility. PMID:24359106

  2. Angiotensin II induced release of prostaglandins from rat uterus.

    PubMed

    Campos, G A; Guerra, F A; Israel, E J

    1983-08-01

    The effect of Angiotensin II (A-II) on 6-keto-prostaglandin F1 (6-keto-PGF1 alpha) and prostaglandin F (PGF) production by the rat uterus was studied using a novel superfusion technique. The method of superfusion used allows prostaglandin synthesis in the myometrium and endometrium to be measured independently while their anatomical relationship is undisturbed. Prostaglandins were measured by radioimmunoassay. In uterine horns from castrated, estrogen treated rats, A-II (10(-6)M) stimulated the production rate of 6-keto-PGF1 alpha in the myometrium nd PGF in the endometrium. Sterile horns and pregnant horns coexisting in the same animals showed different responses when superfused with culture medium containing A-II (10(-6)M). In the sterile horns A-II failed to stimulate prostaglandin synthesis whereas in the pregnant horns there was a significant increase in the production rate of both 6-keto-PGF1 alpha and PGF in the decidua (endometrium) and of 6-keto-PGF1 alpha in the myometrium. Our results suggests that the effect of A-II on prostaglandin synthesis by the rat uterus appears to be dependent of the hormonal milieu of the experimental animal. Estrogen stimulated A-II induced PG synthesis. Progesterone inhibited the synthesis of PGs caused by A-II in non-decidualized uterus but stimulated the release of PG in the decidualized uterus. The apparent differential effect of A-II in stimulating prostaglandin synthesis in the whole uterus indicates that there are different pathways for prostaglandin production in both the endometrium and myometrium. PMID:6689628

  3. Simulated microgravity upregulates an endothelial vasoconstrictor prostaglandin.

    PubMed

    Sangha, D S; Han, S; Purdy, R E

    2001-08-01

    Endothelial nitric oxide contributes to the vascular hyporesponsiveness to norepinephrine (NE) observed in carotid arteries from rats exposed to simulated microgravity. The goal of the present study was to determine whether a cyclooxygenase product of arachidonic acid also influences vascular responsiveness in this setting. Microgravity was simulated in rats by hindlimb unweighting (HU). After 20 days of HU, carotid arteries were isolated from control and HU-treated rats, and vascular rings were mounted in tissue baths for the measurement of isometric contraction. Two cyclooxygenase inhibitors, indomethacin and ibuprofen, and the selective thromboxane A(2) prostanoid-receptor antagonist, SQ-29548, had no effect on the contraction to NE in control vessels but markedly reduced contraction to NE in HU vessels. When the endothelium was removed, indomethacin no longer had any effect on the NE-induced contraction in HU vessels. In endothelium-intact vessels in the presence of indomethacin, the addition of the nitric oxide synthase inhibitor, N(G)-L-nitro-arginine methyl ester, to the medium bathing HU vessels increased the contraction to NE to the level of that of the control vessels. These results indicate that HU treatment induced two endothelial changes in carotid artery that opposed each other. Nitric oxide activity was increased and was responsible for the vascular hyporesponsiveness to NE. The activity of a vasoconstrictor prostaglandin was also increased, and attenuated the vasodilating effect of nitric oxide. PMID:11457795

  4. Simulated microgravity upregulates an endothelial vasoconstrictor prostaglandin

    NASA Technical Reports Server (NTRS)

    Sangha, D. S.; Han, S.; Purdy, R. E.

    2001-01-01

    Endothelial nitric oxide contributes to the vascular hyporesponsiveness to norepinephrine (NE) observed in carotid arteries from rats exposed to simulated microgravity. The goal of the present study was to determine whether a cyclooxygenase product of arachidonic acid also influences vascular responsiveness in this setting. Microgravity was simulated in rats by hindlimb unweighting (HU). After 20 days of HU, carotid arteries were isolated from control and HU-treated rats, and vascular rings were mounted in tissue baths for the measurement of isometric contraction. Two cyclooxygenase inhibitors, indomethacin and ibuprofen, and the selective thromboxane A(2) prostanoid-receptor antagonist, SQ-29548, had no effect on the contraction to NE in control vessels but markedly reduced contraction to NE in HU vessels. When the endothelium was removed, indomethacin no longer had any effect on the NE-induced contraction in HU vessels. In endothelium-intact vessels in the presence of indomethacin, the addition of the nitric oxide synthase inhibitor, N(G)-L-nitro-arginine methyl ester, to the medium bathing HU vessels increased the contraction to NE to the level of that of the control vessels. These results indicate that HU treatment induced two endothelial changes in carotid artery that opposed each other. Nitric oxide activity was increased and was responsible for the vascular hyporesponsiveness to NE. The activity of a vasoconstrictor prostaglandin was also increased, and attenuated the vasodilating effect of nitric oxide.

  5. Evidence against a physiological role of prostaglandins in the regulation of noradrenaline release in the cat spleen.

    PubMed Central

    Dubocovich, M L; Langer, S Z

    1975-01-01

    1. The effects of prostaglandins E2 (PGE2) and indomethacin on responses and on noradrenaline overflow elicited by nerve stimulation were studied in the perfused cat's spleen, at different calcium concentrations in the perfusion medium: 0-26, 0-65 and 2-6 mve stimulation and in the overflow of the transmitter. PGE2 was more effective in reducing transmitter overflow at 5 than at 30 Hz. 3. Indomethacin, 14-0 muM, prevented the release of PGE-like material in the venous effluent of the spleen elicited by either nerve stimulation or by exogenous noradrenaline. 4. During exposure to 14-0 muM indomethacin there was no increase in responses to nerve stimulation or in the overflow of noradrenaline elicited by nerve stimulation at 5 or at 30 Hz. 5. Similar results to those obtained with exogenous PGE2 and with indomethacin in the presence of 2-6 mM calcium, were observed when the experiments were carried out in the presence of either 0-65 or 0-26 mM calcium. 6. In the presence of the alpha-adrenoceptor blocking agents, phenoxybenzamine (2-9 muM) or phentolamine (3-1 muM), the increase in transmitter overflow obtained during stimulation was 6-5 and 8-3-fold respectively. 7. Since inhibition of the synthesis of PGE did not increase transmitter overflow during nerve stimulation, it appears that the proposed negative feed-back mechanism mediated by endogenous prostaglandins does not play an important physiological role in the regulation of adrenergic neurotransmission in the cat spleen. In this tissue the major endogenous negative feed-back regulatory mechanism is triggered by the neurotransmitter through the activation of prejunctional alpha-adrenoceptors. PMID:171381

  6. Sulforaphane Inhibits Prostaglandin E2 Synthesis by Suppressing Microsomal Prostaglandin E Synthase 1

    PubMed Central

    Zhou, Jiping; Joplin, Denise G.; Cross, Janet V.; Templeton, Dennis J.

    2012-01-01

    Sulforaphane (SFN) is a dietary cancer preventive with incompletely characterized mechanism(s) of cancer prevention. Since prostaglandin E2 (PGE2) promotes cancer progression, we hypothesized that SFN may block PGE2 synthesis in cancer cells. We found that SFN indeed blocked PGE2 production in human A549 cancer cells not by inhibiting COX-2, but rather by suppressing the expression of microsomal prostaglandin E synthase (mPGES-1), the enzyme that directly synthesizes PGE2. We identified the Hypoxia Inducible Factor 1 alpha (HIF-1α) as the target of SFN-mediated mPGES-1 suppression. SFN suppressed HIF-1α protein expression and the presence of HIF-1α at the mPGES-1 promoter, resulting in reduced transcription of mPGES-1. Finally, SFN also reduced expression of mPGES-1 and PGE2 production in A549 xenograft tumors in mice. Together, these results point to the HIF-1α, mPGES-1 and PGE2 axis as a potential mediator of the anti-cancer effects of SFN, and illustrate the potential of SFN for therapeutic control of cancer and inflammation. Harmful side effects in patients taking agents that target the more upstream COX-2 enzyme render the downstream target mPGES-1 a significant target for anti-inflammatory therapy. Thus, SFN could prove to be an important therapeutic approach to both cancer and inflammation. PMID:23166763

  7. Impotence evaluated by the use of prostaglandin E1

    SciTech Connect

    Hwang, T.I.; Yang, C.R.; Wang, S.J.; Chang, C.L.; Tzai, T.S.; Chang, C.H.; Wu, H.C.

    1989-06-01

    We screened 80 patients at our hospital for the differential diagnosis of impotence using intracavernous injection of prostaglandin E1 (20 micrograms). The rate of positive response was 78.8 per cent (63 patients). Neither systemic reactions nor priapism occurred. However, a considerable incidence (23.8 per cent, 19 of 80 patients) of tolerable injection pain was encountered. The 133-xenon penile washout study was conducted routinely in impotent men for hemodynamic evaluation of penile vascularity. In 80 patients a positive correlation between the response of intracavernous prostaglandin E1 injection and the result of the washout study was found (r equals 0.381, p less than 0.0002). We selected 14 subjects randomly to receive additional intravenous infusions of prostaglandin E1 (6 ampules, 120 micrograms total) for 3 days, after which another 133-xenon washout study was done. The washout studies before and after intravenous prostaglandin E1 infusion were compared, and 10 patients (71.4 per cent) appeared to obtain improvement in half-time clearance and penile blood flow. However, only 3 patients noticed improvement subjectively. We suggest that prostaglandin E1 could be a desirable alternative for the diagnosis and treatment of impotence.

  8. Is brain prostaglandin synthesis involved in responses to cold?

    PubMed Central

    Cranston, W I; Hellon, R F; Mitchell, D

    1975-01-01

    1. Experiments with rats have suggested that prostaglandin synthesis in the C.N.S. may mediate thermoregulatory reactions to cold. This possibility was investigated in cats using two types of experiment. 2. In one series of experiments, c.s.f. collected from the cisterna magna of conscious cats exposed to a cold and a hot environment was assayed for prostaglandin-like activity. During cold exposure there was a slight increase in activity which persisted after return to neutral ambient temperature. There was no correlation between prostaglandin-like activity and rectal temperature. During the heat exposure there was no demonstrable change in activity. 3. In the second series, conscious cats were exposed to cold conditions and given intravenous injections of salicylate, paracetamol, or indomethacin, all of which inhibit prostaglandin synthesis. Indomethacin salicylate nor paracetamol caused any significant change in rectal temperature. 4. The results do not support a role for C.N.S. prostaglandin synthesis in thermoregulatory reactions to cold in cats. PMID:1177099

  9. Prostaglandins and Their Receptors in Insect Biology

    PubMed Central

    Stanley, David; Kim, Yonggyun

    2011-01-01

    We treat the biological significance of prostaglandins (PGs) and their known receptors in insect biology. PGs and related eicosanoids are oxygenated derivatives of arachidonic acid (AA) and two other C20 polyunsaturated fatty acids. PGs are mostly appreciated in the context of biomedicine, but a growing body of literature indicates the biological significance of these compounds extends throughout the animal kingdom, and possibly beyond. The actions of most PGs are mediated by specific receptors. Biomedical research has discovered a great deal of knowledge about PG receptors in mammals, including their structures, pharmacology, molecular biology and cellular locations. Studies of PG receptors in insects lag behind the biomedical background, however, recent results hold the promise of accelerated research in this area. A PG receptor has been identified in a class of lepidopteran hemocytes and experimentally linked to the release of prophenoloxidase. PGs act in several crucial areas of insect biology. In reproduction, a specific PG, PGE2, releases oviposition behavior in most crickets and a few other insect species; PGs also mediate events in egg development in some species, which may represent all insects. PGs play major roles in modulating fluid secretion in Malpighian tubules, rectum and salivary glands, although, again, this has been studied in only a few insect species that may represent the Class. Insect immunity is a very complex defense system. PGs and other eicosanoids mediate a large number of immune reactions to infection and invasion. We conclude that research into PGs and their receptors in insects will lead to important advances in our understanding of insect biology. PMID:22654840

  10. Many Putative Endocrine Disruptors Inhibit Prostaglandin Synthesis

    PubMed Central

    Kristensen, David M.; Skalkam, Maria L.; Audouze, Karine; Lesné, Laurianne; Desdoits-Lethimonier, Christele; Frederiksen, Hanne; Brunak, Søren; Skakkebæk, Niels E.; Jégou, Bernard; Hansen, Jacob B.; Junker, Steffen; Leffers, Henrik

    2011-01-01

    Background Prostaglandins (PGs) play key roles in development and maintenance of homeostasis of the adult body. Despite these important roles, it remains unclear whether the PG pathway is a target for endocrine disruption. However, several known endocrine-disrupting compounds (EDCs) share a high degree of structural similarity with mild analgesics. Objectives and Methods Using cell-based transfection and transduction experiments, mass spectrometry, and organotypic assays together with molecular modeling, we investigated whether inhibition of the PG pathway by known EDCs could be a novel point of endocrine disruption. Results We found that many known EDCs inhibit the PG pathway in a mouse Sertoli cell line and in human primary mast cells. The EDCs also reduced PG synthesis in ex vivo rat testis, and this reduction was correlated with a reduced testosterone production. The inhibition of PG synthesis occurred without involvement of canonical PG receptors or the peroxisome proliferator–activated receptors (PPARs), which have previously been described as targets of EDCs. Instead, our results suggest that the compounds may bind directly into the active site of the cyclooxygenase (COX) enzymes, thereby obstructing the conversion of arachidonic acid to PG precursors without interfering with the expression of the COX enzymes. A common feature of the PG inhibitory EDCs is the presence of aromatic groups that may stabilize binding in the hydrophobic active site of the COX enzymes. Conclusion Our findings suggest a hitherto unknown mode of action by EDCs through inhibition of the PG pathway and suggest new avenues to investigate effects of EDCs on reproductive and immunological disorders that have become increasingly common in recent decades. PMID:21081300

  11. Endotoxin elicits ambivalent social behaviors.

    PubMed

    Yee, Jason R; Prendergast, Brian J

    2012-07-01

    The acute phase response to infection is reliably accompanied by decreases in social investigation; however, social behavior is commonly assayed in inescapable environments using unfamiliar social stimuli. In this experiment, male Wistar rats were raised from weaning with 2 familiar, same-sex conspecifics. In adulthood, rats were implanted with radiotelemetry devices that permitted localization in space, and were challenged with LPS treatments (150 μg/kg, i.p.) in a novel, semi-natural arena which afforded the treated (Focal) animal exclusive control of social exposure, and the ability to avoid social interactions. LPS reliably elicited thermoregulatory responses (transient hypothermia and fever) during the scotophase following injection, but did not yield changes in the proportion of time spent engaged in social interactions: both LPS- and saline-treated rats spent approximately 10% of the night with their familiar cagemates. Injection treatments markedly altered the spatial distribution of activity: LPS-treated rats exhibited significant increases in the amount of time spent as far as possible from their cagemates. The data suggest that sickness responses to LPS may give rise to a transient state of social ambivalence-characterized by a persistent motivation to engage in social contact, but also by increased avoidance of social environments. Selective maintenance of social motivation illustrates plasticity in the expression of sickness behaviors and may be adaptive in social species. PMID:22172640

  12. Expression of prostaglandin E synthases in the bovine oviduct.

    PubMed

    Gauvreau, D; Moisan, V; Roy, M; Fortier, M A; Bilodeau, J-F

    2010-01-01

    The oviduct is a specialized organ responsible for the storage and the transport of male and female gametes. It also provides an optimal environment for final gamete maturation, fertilization, and early embryo development. Prostaglandin (PG) E(2) is involved in many female reproductive functions, including ovulation, fertilization, implantation, and parturition. However, the control of its synthesis in the oviduct is not fully understood. Cyclooxygenases (COXs) are involved in the first step of the transformation of arachidonic acid to PGH(2.) The prostaglandin E synthases (PGESs) constitute a family of enzymes that catalyze the conversion of PGH(2) to PGE(2), the terminal step in the formation of this bioactive prostaglandin. Quantitative real-time PCR was used to determine the expression of COX-1, COX-2, microsomal prostaglandin E synthase-1 (mPGES-1), microsomal prostaglandin E synthase-2 (mPGES-2), and cytosolic prostaglandin E synthase (cPGES) mRNA in various sections of the oviduct, both ipsilateral and contralateral (to the ovary on which ovulation occurred) at various stages of the estrous cycle. Furthermore, protein expression and localization of cPGES, mPGES-1, and mPGES-2 were determined by Western blot and immunohistochemistry. All three PGESs were detected at both mRNA and protein levels in the oviduct. These PGESs were mostly concentrated in the oviductal epithelial layer and primarily expressed in the ampulla section of the oviduct and to a lesser extent in the isthmus and the isthmic-ampullary junction. The mPGES-1 protein was highly expressed in the contralateral oviduct, which contrasted with mPGES-2 mostly expressed in the ipsilateral oviduct. This is apparently the first report documenting that the three PGESs involved in PGE(2) production were present in the Bos taurus oviduct. PMID:19875162

  13. 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

  14. Suppression of Alzheimer-Associated Inflammation by Microglial Prostaglandin-E2 EP4 Receptor Signaling

    PubMed Central

    Woodling, Nathaniel S.; Wang, Qian; Priyam, Prachi G.; Larkin, Paul; Shi, Ju; Johansson, Jenny U.; Zagol-Ikapitte, Irene; Boutaud, Olivier

    2014-01-01

    A persistent and nonresolving inflammatory response to accumulating Aβ peptide species is a cardinal feature in the development of Alzheimer's disease (AD). In response to accumulating Aβ peptide species, microglia, the innate immune cells of the brain, generate a toxic inflammatory response that accelerates synaptic and neuronal injury. Many proinflammatory signaling pathways are linked to progression of neurodegeneration. However, endogenous anti-inflammatory pathways capable of suppressing Aβ-induced inflammation represent a relatively unexplored area. Here we report that signaling through the prostaglandin-E2 (PGE2) EP4 receptor potently suppresses microglial inflammatory responses to Aβ42 peptides. In cultured microglial cells, EP4 stimulation attenuated levels of Aβ42-induced inflammatory factors and potentiated phagocytosis of Aβ42. Microarray analysis demonstrated that EP4 stimulation broadly opposed Aβ42-driven gene expression changes in microglia, with enrichment for targets of IRF1, IRF7, and NF-κB transcription factors. In vivo, conditional deletion of microglial EP4 in APPSwe-PS1ΔE9 (APP-PS1) mice conversely increased inflammatory gene expression, oxidative protein modification, and Aβ deposition in brain at early stages of pathology, but not at later stages, suggesting an early anti-inflammatory function of microglial EP4 signaling in the APP-PS1 model. Finally, EP4 receptor levels decreased significantly in human cortex with progression from normal to AD states, suggesting that early loss of this beneficial signaling system in preclinical AD development may contribute to subsequent progression of pathology. PMID:24760848

  15. [Receptors involved in the mechanism of action of topical prostaglandines].

    PubMed

    Neacsu, Alina Mihaela

    2009-01-01

    Hypotensive effect to prostaglandins analogs (latanoprost, travoprost, tafluprost) means to increase uveoscleral outflow by action to FP receptors who generated extracellular matrix changes and intermuscular spaces changes. Syntetic prostamides analogs (bimatoprost) have a particulary action with a receptors most and intensive studied. The bimatoprost effect is the consequences to preferated stimulations on the specific receptors who have action only the tissue with prostaglandins activity is important to specify what the bimatoprost have dual effect: to uveoscleral outflow and classic outflow by increase hidraulic conductivity. PMID:19697832

  16. Characterization of the interaction between the prostaglandin D2 DP1 receptor and the intracellular L-prostaglandin D synthase.

    PubMed

    Binda, Chantal; Parent, Jean-Luc

    2015-01-01

    Identification of G protein-coupled receptor (GPCR)-interacting proteins is an intense subject of current research. However, confirmation and characterization of identified interactions can be difficult with GPCRs, especially at the endogenous level. Here, we describe how we characterized the interaction between the prostaglandin D2 DP1 receptor and the intracellular L-type prostaglandin D synthase by in vitro pull-down assays using purified recombinant GST- and His-tagged proteins, by co-immunoprecipitation of overexpressed Flag- and HA-tagged proteins, and by co-immunoprecipitation of endogenous proteins. PMID:25304348

  17. Gastroprotective activity of ent-beyerene derivatives in mice: Effects on gastric secretion, endogenous prostaglandins and non-protein sulfhydryls.

    PubMed

    Parra, Teresa; Benites, Julio; Ruiz, Lina M; Sepulveda, Beatriz; Simirgiotis, Mario; Areche, Carlos

    2015-07-15

    Seventeen compounds (2-18) synthetized from the diterpenoid ent-beyer-15-en-18-ol (1) isolated from aerial part of Baccharis tola were tested for their gastroprotective activity on the model of HCl/EtOH-induced gastric lesions in mice. Furthermore cytotoxicity test toward fibroblasts and AGS cells were performed. The results showed that compound 1 (ED50=50 mg/kg), 2, 6 and 13 were the most active regarding gastroprotective activity. Compounds 8-10 and 17-18 showed the lowest cytotoxicity toward fibroblasts and AGS cells. Regarding to mode of gastroprotective action, the effect elicited by 6 (50 mg/kg) was reversed by Indomethacin but not by N-ethylmaleimide, N(G)-nitro-L-arginine methyl ester or ruthenium red, which suggests that prostaglandins are involved in the mode of gastroprotective action of 6. PMID:26009162

  18. Ketoprofen S(+) enantiomer inhibits prostaglandin production and cell growth in 3T6 fibroblast cultures.

    PubMed

    Sánchez, T; Moreno, J J

    1999-04-01

    The ketoprofen S(+) enantiomer inhibits with great stereoselectivity both prostaglandin H synthase isoenzymes. Thus, the biological effects of ketoprofen on inflammation are due almost entirely to the S(+) isomer. Here, we report that the S(+) enantiomer, at doses that inhibit prostaglandin synthesis, is effective in reducing DNA synthesis and 3T6 fibroblast growth. Our data suggest that prostaglandins are involved in the control of 3T6 fibroblast growth and that the effect of the ketoprofen S(+) enantiomer on 3T6 proliferation is correlated with its effects on prostaglandin H synthase and prostaglandin production. PMID:10323281

  19. Reducing prostaglandin E2 production to raise cancer immunogenicity

    PubMed Central

    Zelenay, Santiago; Reis e Sousa, Caetano

    2016-01-01

    ABSTRACT Cyclooxygenases (COX), commonly upregulated in numerous cancers, generate prostaglandin E2 (PGE2), which has been implicated in key aspects of malignant growth including proliferation, invasion and angiogenesis. Recently, we showed that production of PGE2 by cancer cells dominantly enables progressive tumor growth via immune escape and that cyclooxygenase inhibitors synergize with immunotherapy to enhance tumor eradication.

  20. Reducing prostaglandin E2 production to raise cancer immunogenicity.

    PubMed

    Zelenay, Santiago; Reis E Sousa, Caetano

    2016-05-01

    Cyclooxygenases (COX), commonly upregulated in numerous cancers, generate prostaglandin E2 (PGE2), which has been implicated in key aspects of malignant growth including proliferation, invasion and angiogenesis. Recently, we showed that production of PGE2 by cancer cells dominantly enables progressive tumor growth via immune escape and that cyclooxygenase inhibitors synergize with immunotherapy to enhance tumor eradication. PMID:27467936

  1. Bioassay-guided isolation of an anti-ulcer diterpenoid from Croton reflexifolius: role of nitric oxide, prostaglandins and sulfhydryls.

    PubMed

    Reyes-Trejo, Benito; Sánchez-Mendoza, María Elena; Becerra-García, Anabel Ariana; Cedillo-Portugal, Ernestina; Castillo-Henkel, Carlos; Arrieta, Jesús

    2008-07-01

    Croton reflexifolius H. B. K (Euphorbiaceae) is a very common medicinal plant in the Huastecan region of Mexico that, according to local folk medicine, is considered useful in the treatment of gastritis and gastric ulcer. We have aimed to test the validity of this practice by using the experimental model of an ethanol-induced gastric ulcer in male Wistar rats. The results showed that C. reflexifolius had gastroprotector activity, that the hexane extract had the highest protective activity (64.38+/-7.72%), and that polyalthic acid isolated from this extract was the main active gastroprotector agent. Rats treated orally with polyalthic acid showed a gastroprotective effect similar to that elicited by carbenoxolone. As with carbenoxolone, the effect elicited by polyalthic acid was attenuated by pretreatment with either N(G)-nitro-L-arginine methyl ester (70 mgkg(-1), i.p.), a nitric oxide (NO) synthase inhibitor, or N-ethylmaleimide (10 mgkg(-1), s.c.), a blocker of sulfhydryl groups. This suggested that the gastroprotective mechanism of this diterpenoid involved the participation of both NO and endogenous sulfhydryl groups. Contrary to carbenoxolone, the gastroprotective effect of polyalthic acid was not affected by the inhibition of prostaglandin synthesis with indometacin (10 mgkg(-1), s. c.). In conclusion, Croton reflexifolius contains compounds with gastroprotector activity. Polyalthic acid, which was isolated from this plant, was the main compound with gastroprotector activity, having effectiveness similar to that found with the use of carbenoxolone. Whereas NO and sulfhydryl groups were involved in the mechanisms of gastroprotective action of polyalthic acid, prostaglandins were not. PMID:18549681

  2. Prostaglandin ethanolamides (prostamides): in vitro pharmacology and metabolism.

    PubMed

    Matias, I; Chen, J; De Petrocellis, L; Bisogno, T; Ligresti, A; Fezza, F; Krauss, A H-P; Shi, L; Protzman, C E; Li, C; Liang, Y; Nieves, A L; Kedzie, K M; Burk, R M; Di Marzo, V; Woodward, D F

    2004-05-01

    We investigated whether prostaglandin ethanolamides (prostamides) E(2), F(2alpha), and D(2) exert some of their effects by 1) activating prostanoid receptors either per se or after conversion into the corresponding prostaglandins; 2) interacting with proteins for the inactivation of the endocannabinoid N-arachidonoylethanolamide (AEA), for example fatty acid amide hydrolase (FAAH), thereby enhancing AEA endogenous levels; or 3) activating the vanilloid receptor type-1 (TRPV1). Prostamides potently stimulated cat iris contraction with potency approaching that of the corresponding prostaglandins. However, prostamides D(2), E(2), and F(2alpha) exhibited no meaningful interaction with the cat recombinant FP receptor, nor with human recombinant DP, EP(1-4), FP, IP, and TP prostanoid receptors. Prostamide F(2alpha) was also very weak or inactive in a panel of bioassays specific for the various prostanoid receptors. None of the prostamides inhibited AEA enzymatic hydrolysis by FAAH in cell homogenates, or AEA cellular uptake in intact cells. Furthermore, less than 3% of the compounds were hydrolyzed to the corresponding prostaglandins when incubated for 4 h with homogenates of rat brain, lung, or liver, and cat iris or ciliary body. Very little temperature-dependent uptake of prostamides was observed after incubation with rat brain synaptosomes or RBL-2H3 cells. We suggest that prostamides' most prominent pharmacological actions are not due to transformation into prostaglandins, activation of prostanoid receptors, enhancement of AEA levels, or gating of TRPV1 receptors, but possibly to interaction with novel receptors that seem to be functional in the cat iris. PMID:14757851

  3. [Medical treatments and practices. What should be done when a prostaglandin proves ineffective?].

    PubMed

    Nordmann, J-P

    2005-06-01

    Prostaglandin analogs are very frequently used as first-line therapy in the treatment of glaucoma. In some cases, they may be ineffective or insufficient or they may induce side effects. The absence of an ocular pressure-lowering effect of a prostaglandin is in general a class effect. Thus a switch to another prostaglandin will probably not be more effective. In such cases, it may be better to use another therapeutic class. On the other hand, the side effects of prostaglandin are more often directly related to the chemical structure of the drug used and may not occur with another prostaglandin. Consequently, considering the dramatic effect of prostaglandin on ocular pressure compared to other drugs, when one prostaglandin causes side effects, it may be useful to try another one before changing the drug family. PMID:16208240

  4. Influence of prostaglandins and adrenoceptor agonists on contractile activity in the human cervix at term.

    PubMed

    Bryman, I; Norström, A; Lindblom, B

    1986-04-01

    The influence of prostaglandins as well as adrenoceptor agonists and antagonists on contractile activity of isolated cervical smooth muscle from term pregnant women was studied. Prostaglandin E2 had an inhibitory effect at extremely low concentrations. Inhibition also was induced by prostaglandin F2 alpha, prostaglandin I2, and 6-keto-prostaglandin F1 alpha, but at considerably higher concentrations. Contractions evoked by noradrenaline or phenylephrine were blocked by the alpha-adrenoceptor antagonist phenoxybenzamine. The beta-adrenoceptor agonist terbutaline acted as an inhibitor, whereas isoprenaline in most cases stimulated contractile activity. The inhibitory action of prostaglandins and especially the high sensitivity to prostaglandin E2 point to a physiologic role of these compounds for cervical dilatation and retraction. A predominance of alpha-adrenoceptors might be of importance for the maintenance of cervical competence during pregnancy. PMID:2870450

  5. Long-term assessment of prostaglandin analogs and timolol fixed combinations vs prostaglandin analogs monotherapy

    PubMed Central

    Liu, Ai-Wei; Gan, Lin-Yang; Yao, Xiang; Zhou, Jian

    2016-01-01

    AIM To draw a Meta-analysis over the comparison of the intraocular pressure (IOP)-lowering efficacy and safety between the commonly used fixed-combinations of prostaglandin analogs and 0.5% timolol with prostaglandin analogs (PGAs) monotherapy. METHODS After searching the published reports from MEDLINE, EMBASE, the Cochrane Library, all randomized controlled clinical trials (RCTs) comparing the fixed combination of PGAs/timolol therapy (FCs) and PGAs monotherapy with treatment duration at least 6mo were included. The efficacy outcomes were mean diurnal IOP, percentage of participants whose IOP were lower than 18 mm Hg, incidence of visual field change, while the safety outcomes included corneal side effects, hyperemia and eye irritation. The analysis was carried out in RevMan version 5.3 software. RESULTS After six-month medical intervention, the mean diurnal IOP of FCs was lower than PGAs (MD -1.14, 95% CI -1.82 to -0.46, P=0.001); the percentage of target IOP achieving between FCs and PGAs showed no significant difference (RR 1.18, 95% CI 0.97 to 1.43, P=0.10). No statistically significant differences of the incidence of hyperemia (RR 0.67, 95% CI 0.45 to 1.01, P=0.06) and eye irritation (RR 1.20, 95% CI 0.95 to 1.51, P=0.12) between the FCs and PGAs monotherapy were detected. Only one research involved in corneal events, result of this trial revealed no difference between two intervention groups regarding corneal effects (central endothelial cell density, MD -0.20, 95% CI -0.72 to 0.32, P=0.45; central corneal thickness, MD -0.01, 95% CI -0.02 to 0.00, P=0.23). The evaluation of visual field change was not performed due to the limited duration of the trials included in this Meta-analysis. CONCLUSION The long-term efficacy of the FCs overweighed the PGAs monotherapy in lowering IOP, but in the incidence of hyperemia and eye irritation syndromes, the differences are not statically significant. More RCTs with detailed and authentic data over the assessments of

  6. The expression of prostaglandin-E2 and its receptor in the oviduct of Chinese brown frog (Rana dybowskii).

    PubMed

    Hu, Ruiqi; Xi, Liqin; Cao, Qing; Yang, Rui; Liu, Yuning; Sheng, Xia; Han, Yingying; Yuan, Zhengrong; Guo, Yan; Weng, Qiang; Xu, Meiyu

    2016-07-01

    The Chinese brown frog (Rana dybowskii) has one special physiological phenomenon, which is that its oviduct expands prior to hibernation rather than in the breeding period. In this study, we investigated the immunolocalization and expression levels of prostaglandin-E2 (PGE2), cyclooxygenase (COX)-1 and COX-2, as well as one of its receptor subtypes 4 (EP4) in the oviduct of Rana dybowskii during the pre-hibernation and breeding period. PGE2, COX-1, COX-2 and EP4 have been observed in glandular and epithelial cells in the breeding period, whereas only in the epithelial cells during the pre-hibernation. Consistently, the protein levels of COX-2 and EP4 were higher in the pre-hibernation as compared to the breeding period, but the diversity of COX-1 was not obvious. In addition, oviductal PGE2 concentration was also significantly higher in the pre-hibernation. These results suggested that prostaglandin-E2 may play an important autocrine or paracrine role in oviductal cell proliferation and differentiation of Rana dybowskii during pre-hibernation. PMID:27246901

  7. Metabolic fate of radiolabeled prostaglandin D2 in a normal human male volunteer

    SciTech Connect

    Liston, T.E.; Roberts, L.J. 2d.

    1985-10-25

    50 microCi of (TH)prostaglandin D2 tracer (100 Ci/mmol) was infused intravenously into a normal human male volunteer. 75% of the infused radioactivity was excreted into the urine within 5 h. This urine was added to urine obtained from two mastocytosis patients with marked overproduction of prostaglandin D2. Radiolabeled prostaglandin D2 urinary metabolites were chromatographically isolated and purified and subsequently identified by gas chromatography-mass spectrometry. 25 metabolites were identified. 23 of these compounds comprising 37% of the recovered radioactivity had prostaglandin F-ring structures, and only two metabolites comprising 2.7% of the recovered radioactivity retained the prostaglandin D-ring structure. The single most abundant metabolite identified was 9,11-dihydroxy-15-oxo-2,3,18,19-tetranorprost-5-ene-1,20-dioic acid which was isolated in a tricyclic form as a result of formation of a lower side chain hemiketal followed by lactonization of the terminal carboxyl and the hemiketal hydroxyl. Different isomeric forms of several prostaglandin F-ring metabolites were identified. An isomer of prostaglandin F2 alpha was also excreted intact into the urine as a metabolite of prostaglandin D2. 15 PGF-ring compounds were treated with n-butylboronic acid and 13 failed to form a boronate derivative, suggesting that the orientation of the hydroxyl group at C-11 in these 13 metabolites is beta. This study documents that prostaglandin D2 is metabolized to prostaglandin F-ring metabolites in vivo in humans. These results also bring into question the accuracy of quantifying prostaglandin F2 alpha metabolites as a specific index of endogenous prostaglandin F2 alpha biosynthesis, as well as quantifying urinary prostaglandin F2 alpha as an accurate index of renal production of prostaglandin F2 alpha.

  8. Identification of the Major Prostaglandin Glycerol Ester Hydrolase in Human Cancer Cells*

    PubMed Central

    Manna, Joseph D.; Wepy, James A.; Hsu, Ku-Lung; Chang, Jae Won; Cravatt, Benjamin F.; Marnett, Lawrence J.

    2014-01-01

    Prostaglandin glycerol esters (PG-Gs) are produced as a result of the oxygenation of the endocannabinoid, 2-arachidonoylglycerol, by cyclooxygenase 2. Understanding the role that PG-Gs play in a biological setting has been difficult because of their sensitivity to enzymatic hydrolysis. By comparing PG-G hydrolysis across human cancer cell lines to serine hydrolase activities determined by activity-based protein profiling, we identified lysophospholipase A2 (LYPLA2) as a major enzyme responsible for PG-G hydrolysis. The principal role played by LYPLA2 in PGE2-G hydrolysis was confirmed by siRNA knockdown. Purified recombinant LYPLA2 hydrolyzed PG-Gs in the following order of activity: PGE2-G > PGF2α-G > PGD2-G; LYPLA2 hydrolyzed 1- but not 2-arachidonoylglycerol or arachidonoylethanolamide. Chemical inhibition of LYPLA2 in the mouse macrophage-like cell line, RAW264.7, elicited an increase in PG-G production. Our data indicate that LYPLA2 serves as a major PG-G hydrolase in human cells. Perturbation of this enzyme should enable selective modulation of PG-Gs without alterations in endocannabinoids, thereby providing a means to decipher the unique functions of PG-Gs in biology and disease. PMID:25301951

  9. Epidermal growth factor modulation of prostaglandins and nitrite biosynthesis in rat fetal membranes.

    PubMed

    Ribeiro, M L; Ogando, D; Farina, M; Franchi, A

    2004-01-01

    The production of prostaglandins (PGs) and nitric oxide (NO) by amnion tissue may play a significant role in parturition. It is thought that epidermal growth factor (EGF) may be one of the fetal signals that governs the initiation of labor. The aim of the present study was to investigate the effect of EGF in vivo on the PGs and nitrite production of rat fetal membranes. We have evaluated the regulation of PGs and nitrite production in rat fetal membranes ex vivo. The intra-uterine administration of EGF 500 ng in day 21 of pregnancy induced increases in PGE(2) (P<0.001) and PGF(2alpha) (P<0.01) compared to the control fetal membranes from pregnant rats on day 22. Also, this dose of EGF diminished nitrate production significantly (P<0.01). We found that fetal membranes at term (days 18-22 of gestation) expressed EGF-R. The NO donor, nitroprussiate 300 and 600 microM, elicited an inhibitory effect on the PGE(2) and PGF(2alpha) stimulated synthesis. On the other hand, indomethacin 10(-6) and 10(-7)M, a non-selective cyclooxygenase inhibitor, reverted the inhibitory effect exerted by EGF. Hence, rat fetal membranes were found to express epidermal growth factor receptors and, under the effect of EGF, PGs and nitrites production pathways interact probably to prevent a toxic effect caused by an exacerbated synthesis of these mediators. PMID:14643177

  10. Solute concentration affects bradykinin-mediated increases in renal prostaglandin E2

    SciTech Connect

    Zenser, T.V.; Davis, E.S.; Rapp, N.S.; Davis, B.B.

    1981-12-01

    The effects of solute concentration on the bradykinin-mediated increase in inner medullary slice prostaglandin E2 (PGE2) synthesis were investigated. PG content was determined by specific RIA. Bradykinin stimulation was prevented by the addition of the following solutes to Krebs buffer: 1.0 M urea, 0.5 or 1.0 M NaCl, 0.5 or 1.0 M mannitol, 1.0 M urea plus 0.5 M NaCl, or 1.0 M mannitol plus 0.5 M NaCl. By contrast, basal PGE2 synthesis was increased by 1.0 M mannitol or by 1.0 M mannitol plus 0.5 M NaCl, but decreased by 1.0 M urea. Urea elicited a concentration-dependent, reversible inhibition of bradykinin stimulation, with 0.01 M urea being the lowest effective concentration. By contrast, basal PGE2 synthesis was only reduced at a urea concentration greater than 0.6 M. Arachidonic acid-mediated increases in both PGE2 and PGF2 alpha synthesis were not prevented by 1.0 M urea. The latter suggests that neither PG endoperoxide synthetase nor PG endoperoxide E isomerase are inhibited by urea. The data indicate that different hypertonic solutions have different effects on basal PG production, but all inhibit bradykinin stimulation.

  11. Prostaglandin uptake and metabolism by the perfused rat liver

    PubMed Central

    Dawson, W.; Jessup, Sheila J.; McDonald-Gibson, Wendy; Ramwell, P. W.; Shaw, Jane E.

    1970-01-01

    1. The prostaglandins are C20 unsaturated fatty acids which exhibit diverse physiological effects of short duration. We have investigated the speed of removal of PGE1 and PGF1α from the circulating blood and their subsequent metabolism by the isolated perfused rat liver. 2. Following either a single injection of radiolabelled PGE1 or PGF1α into the hepatic artery or portal vein, or recirculation of prostaglandins through the liver for 2·5 h, the distribution of radioactivity within extracts of bile, blood and liver was determined. The nature of the radioactive products of meta-bolism was inferred by comparison of the distribution of radioactivity after injecting carbon and tritium labelled standards, and by thin-layer chromatography, gas-liquid chromatography, ultraviolet and bioassay analysis. 3. A single injection of 1-14C PGE1 indicated that the liver could efficiently remove 89-95% of circulating PGE1 on a single passage. Biliary excretion was excluded as a major route for elimination of unchanged PGE1, because only 0·3-0·8% of the injected radioactivity was detected in the bile. During recirculation of 1-14C PGE1, 11-19% of the injected radioactivity was detected as exchanged 14CO2. The radioactivity detected within liver was identified with further fragments resulting from decarboxylation of PGE1, which were incorporated into fatty acids and then phospholipids. 4. Studies with 5,6-3H PGE1, and comparison with the results obtained using 1-14C PGE1, revealed a 30-fold increase in the percentage of radioactivity excreted into the bile, suggesting that biliary excretion may be a major route for elimination of compounds smaller than C20 prostaglandin. Evidence that the cyclopentane ring was intact was inferred by formation of a PGB compound on treatment with alkali; similar biliary excretion of 9-3H PGF1α also occurred. In addition, the increased radioactivity detected within the liver (37%) and blood (43%) after a single injection of 5,6-3H PGE1 had the

  12. Studies on the metabolism of prostaglandin D/sub 2/ in humans

    SciTech Connect

    Liston, T.E.

    1985-01-01

    Fifty ..mu..Ci of (/sup 3/H)-prostaglandin D/sub 2/ tracer (100 Ci/mMole) was infused intravenously into a normal human male volunteer. Seventy-five percent of the infused radioactivity was excreted into the urine within 5 hours. This urine was added to urine obtained from two mastocytosis patients with marked overproduction of prostaglandin D/sub 2/. Twenty-five radiolabelled prostaglandin D/sub 2/ urinary metabolites were chromatographically isolated and purified and subsequently identified by gas chromatography-mass spectrometry. Twenty-three of these metabolites, comprising 37% of the recovered radioactivity, had prostaglandin F-ring structures, and only 2 metabolites, comprising 2.7% of the recovered radioactivity retained the prostaglandin D-ring structure. The single most abundant metabolite identified was 9,11-dihydroxy-15-oxo-2,3,18,19-tetranorprost-5-energy-1,20-dioic acid which was isolated in a tricyclic form. Different isomeric forms of several prostaglandin F-ring metabolites were identified. To further investigate the metabolism of prostaglandin D/sub 2/, in vitro studies examining the metabolic transformation of prostaglandin D/sub 2/ by human liver were conducted. This study documents that prostaglandin D/sub 2/ is metabolized to PGF-ring metabolites in vivo in humans, and is converted to a structurally new prostaglandin, 9/sub ..cap alpha../, 11/sub ..beta../-PGF/sub 2/ in vitro by a cytosolic NADPH-dependent 11-Ketoreductase in the human liver.

  13. Metabolism of prostaglandin F2 alpha in Zellweger syndrome. Peroxisomal beta-oxidation is a major importance for in vivo degradation of prostaglandins in humans.

    PubMed Central

    Diczfalusy, U; Kase, B F; Alexson, S E; Björkhem, I

    1991-01-01

    We have recently shown in vitro that the peroxisomal fraction of a rat liver homogenate has the highest capacity to beta-oxidize prostaglandins. In order to evaluate the relative importance of peroxisomes for this conversion also in vivo, we administered [3H]prostaglandin F2 alpha to an infant suffering from Zellweger syndrome, a congenital disorder characterized by the absence of intact peroxisomes. As a control, labeled compound was administered to two healthy volunteers. Urine was collected, fractionated on a SEP-PAK C18 cartridge, and subjected to reversed-phase high-performance liquid chromatography. The Zellweger patient was found to excrete prostaglandin metabolites considerably less polar than those of the control subjects. The major urinary metabolite in the control subjects was practically absent in the urine from the Zellweger patient. The major urinary prostaglandin F2 alpha metabolite from the Zellweger patient was identified as an omega-oxidized C20-prostaglandin, 9,11-dihydroxy-15-oxoprost-5-ene-1,20-dioic acid. The major urinary prostaglandin F2 alpha metabolite from the control subjects had chromatographic properties of a tetranor (C16) prostaglandin, in accordance with earlier published data. The present results, in combination with our previous in vitro data, indicate that peroxisomal beta-oxidation is of major importance for in vivo chain shortening of prostaglandins. PMID:1885782

  14. Stereoscopy Amplifies Emotions Elicited by Facial Expressions

    PubMed Central

    Kätsyri, Jari; Häkkinen, Jukka

    2015-01-01

    Mediated facial expressions do not elicit emotions as strongly as real-life facial expressions, possibly due to the low fidelity of pictorial presentations in typical mediation technologies. In the present study, we investigated the extent to which stereoscopy amplifies emotions elicited by images of neutral, angry, and happy facial expressions. The emotional self-reports of positive and negative valence (which were evaluated separately) and arousal of 40 participants were recorded. The magnitude of perceived depth in the stereoscopic images was manipulated by varying the camera base at 15, 40, 65, 90, and 115 mm. The analyses controlled for participants’ gender, gender match, emotional empathy, and trait alexithymia. The results indicated that stereoscopy significantly amplified the negative valence and arousal elicited by angry expressions at the most natural (65 mm) camera base, whereas stereoscopy amplified the positive valence elicited by happy expressions in both the narrowed and most natural (15–65 mm) base conditions. Overall, the results indicate that stereoscopy amplifies the emotions elicited by mediated emotional facial expressions when the depth geometry is close to natural. The findings highlight the sensitivity of the visual system to depth and its effect on emotions. PMID:27551358

  15. Strategies for Eliciting HIV-1 Inhibitory Antibodies

    PubMed Central

    Tomaras, Georgia D.; Haynes, Barton F.

    2012-01-01

    Purpose of review Major roadblocks persist in the development of vaccines that elicit potent neutralizing antibodies targeting diverse HIV-1 strains, similar to known broadly neutralizing HIV-1 human monoclonal antibodies. Alternatively, other types of anti-HIV-1 envelope antibodies that may not neutralize HIV-1 in traditional neutralization assays but have other anti-HIV-1 activities (hereafter termed HIV-1 inhibitory antibodies) can be elicited by current vaccine strategies, and numerous studies are exploring their roles in preventing HIV-1 acquisition. We review examples of strategies for eliciting potentially protective HIV-1 inhibitory antibodies. Recent Findings Heterologous prime-boost strategies can yield anti-HIV immune responses; although only one (canarypox prime, Env protein boost) has been tested and shown positive results in an efficacy trial (RV144). Although the immune correlates of protection are as yet undefined, the reduced rate of acquisition without a significant effect on initial viral loads or CD4+ T cell counts, have raised the hypothesis of an RV144 vaccine-elicited transient protective B cell response. Summary In light of the RV144 trial, there is a critical need to define the entire functional spectrum of anti-HIV-1 antibodies, how easily each can be elicited, and how effective different types of antibody effector mechanisms can be in prevention of HIV-1 transmission. PMID:20978384

  16. Stereoscopy Amplifies Emotions Elicited by Facial Expressions.

    PubMed

    Hakala, Jussi; Kätsyri, Jari; Häkkinen, Jukka

    2015-12-01

    Mediated facial expressions do not elicit emotions as strongly as real-life facial expressions, possibly due to the low fidelity of pictorial presentations in typical mediation technologies. In the present study, we investigated the extent to which stereoscopy amplifies emotions elicited by images of neutral, angry, and happy facial expressions. The emotional self-reports of positive and negative valence (which were evaluated separately) and arousal of 40 participants were recorded. The magnitude of perceived depth in the stereoscopic images was manipulated by varying the camera base at 15, 40, 65, 90, and 115 mm. The analyses controlled for participants' gender, gender match, emotional empathy, and trait alexithymia. The results indicated that stereoscopy significantly amplified the negative valence and arousal elicited by angry expressions at the most natural (65 mm) camera base, whereas stereoscopy amplified the positive valence elicited by happy expressions in both the narrowed and most natural (15-65 mm) base conditions. Overall, the results indicate that stereoscopy amplifies the emotions elicited by mediated emotional facial expressions when the depth geometry is close to natural. The findings highlight the sensitivity of the visual system to depth and its effect on emotions. PMID:27551358

  17. Rational elicitation of cold-sensitive phenotypes.

    PubMed

    Baliga, Chetana; Majhi, Sandipan; Mondal, Kajari; Bhattacharjee, Antara; VijayRaghavan, K; Varadarajan, Raghavan

    2016-05-01

    Cold-sensitive phenotypes have helped us understand macromolecular assembly and biological phenomena, yet few attempts have been made to understand the basis of cold sensitivity or to elicit it by design. We report a method for rational design of cold-sensitive phenotypes. The method involves generation of partial loss-of-function mutants, at either buried or functional sites, coupled with selective overexpression strategies. The only essential input is amino acid sequence, although available structural information can be used as well. The method has been used to elicit cold-sensitive mutants of a variety of proteins, both monomeric and dimeric, and in multiple organisms, namely Escherichia coli, Saccharomyces cerevisiae, and Drosophila melanogaster This simple, yet effective technique of inducing cold sensitivity eliminates the need for complex mutations and provides a plausible molecular mechanism for eliciting cold-sensitive phenotypes. PMID:27091994

  18. Cytoprotective effect of prostaglandin E2 in irradiated rat ileum

    SciTech Connect

    Tomas-de la Vega, J.E.; Banner, B.F.; Hubbard, M.; Boston, D.L.; Thomas, C.W.; Straus, A.K.; Roseman, D.L.

    1984-01-01

    Radiation injury to the gastrointestinal tract is an infrequent but major clinical problem. Results of previous studies have shown that prostaglandins provide cytoprotection of the gastrointestinal mucosa against a variety of noxious agents, although, prior to this study, the protection against radiation exposure had not been documented. Exteriorized segment of Sprague-Dawley rat ileum was radiated with 10 and 15 Gy (/sup 137/Cs). One group of rats was pretreated with prostaglandin E2 one hour before and 24 hours after radiation injury. The rats were sacrificed three and five days following radiation injury. Morphometric measurement of mucosal thickness, villous height, crypt of Lieberkuehn height and number of mitoses per square millimeter swath of tissue were analyzed. Also, /sup 125/IUdR and /sup 3/HTdR were injected in a group of rats radiated with 15 Gy (/sup 137/Cs). /sup 125/IUdR counts per minute per milligram of dry weight and /sup 3/HTdR labeled cells were counted and analyzed. The morphometric measurements and radioactive labeled tissue counts suggest that prostaglandin E2 has a cytoprotective effect upon irradiated rat ileum. Speculations about the possible mechanism and usefulness of this observation are included.

  19. Evaluation of the role of prostaglandins E and F in acalculous gallbladder disease

    SciTech Connect

    Deshpande, Y.G.; Kaminski, D.L.; Thomas, L.

    1986-03-01

    Prostaglandins have been shown to play a role in gallbladder disease. This study was performed to evaluate prostaglandin E and F production by human gallbladder mucosal cells and muscle tissue from patients undergoing cholecystectomy for acalculous gallbladder disease. These results were compared to values produced by gall bladders removed from patients with no known gallbladder disease. Five patient underwent cholecystectomy for acute and five for chronic acalculous cholecystitis. Gallbladder mucosal cells were separated from muscle wall by submucosal injection of EDTA and shaking in tissue culture media. Prostaglandin levels were measured in mucosal cell and muscle tissue homogenate by radioimmunoassay (ng/mg homogenate protein). Homogenate prostaglandin E concentrations were significantly increased in mucosa and muscle tissue in gall bladders from patients with acute acalculous cholecystitis. Chronic acalculous gallbladder disease was not associated with changes in prostaglandin formation when compared to values produced by gall bladders from asymptomatic patients. Acute acalculous cholecystitis may be a prostaglandin mediated disorder.

  20. Attenuation of Ischemic Liver Injury by Prostaglandin E1 Analogue, Misoprostol, and Prostaglandin I2 Analogue, OP-41483

    PubMed Central

    Totsuka, Eishi; Todo, Satoru; Zhu, Yue; Ishizaki, Naoki; Kawashima, Yoshiyuki; Jin, Maeng Bong; Urakami, Atsushi; Shimamura, Tsuyoshi; Starzl, Thomas E

    2010-01-01

    Background Prostaglandin has been reported to have protective effects against liver injury. Use of this agent in clinical settings, however, is limited because of drug-related side effects. This study investigated whether misoprostol, prostaglandin E1 analogue, and OP-41483, prostaglandin I2 analogue, which have fewer adverse effects with a longer half-life, attenuate ischemic liver damage. Study Design Thirty beagle dogs underwent 2 hours of hepatic vascular exclusion using venovenous bypass. Misoprostol was administered intravenously for 30 minutes before ischemia and for 3 hours after reperfusion. OP-41483 was administered intraportally for 30 minutes before ischemia (2 μg/kg/min) and for 3 hours after reperfusion (0.5 μg/kg/min). Animals were divided into five groups: untreated control group (n = 10); high-dose misoprostol (total 100 μg/kg) group (MP-H, n = 5); middle-dose misoprostol (50 μg/kg) group (MP-M, n = 5); low-dose misoprostol (25 μg/kg) group (MP-L, n = 5); and OP-41483 group (OP, n = 5). Animal survival, hepatic tissue blood flow (HTBF), liver function, and histology were analyzed. Results Two-week animal survival rates were 30% in control, 60% in MP-H, 100% in MP-M, 80% in MP-L, and 100% in OP. The treatments with prostaglandin analogues improved HTBF, and attenuated liver enzyme release, adenine nucleotrides degradation, and histologic abnormalities. In contrast to the MP-H animals that exhibited unstable cardiovascular systems, the MP-M, MP-L, and OP animals experienced only transient hypotension. Conclusions These results indicate that misoprostol and OP-41483 prevent ischemic liver damage, although careful dose adjustment of misoprostol is required to obtain the best protection with minimal side effects. PMID:9740185

  1. Mechanical stimulation of skeletal muscle cells mitigates glucocorticoid-induced decreases in prostaglandin production and prostaglandin synthase activity

    NASA Technical Reports Server (NTRS)

    Chromiak, J. A.; Vandenburgh, H. H.

    1994-01-01

    The glucocorticoid dexamethasone (Dex) induces a decline in protein synthesis and protein content in tissue cultured, avian skeletal muscle cells, and this atrophy is attenuated by repetitive mechanical stretch. Since the prostaglandin synthesis inhibitor indomethacin mitigated this stretch attenuation of muscle atrophy, the effects of Dex and mechanical stretch on prostaglandin production and prostaglandin H synthase (PGHS) activity were examined. In static cultures, 10(-8) M Dex reduced PGF2 alpha production 55-65% and PGE2 production 84-90% after 24-72 h of incubation. Repetitive 10% stretch-relaxations of non-Dex-treated cultures increased PGF2 alpha efflux 41% at 24 h and 276% at 72 h, and increased PGE2 production 51% at 24 h and 236% at 72 h. Mechanical stimulation of Dex-treated cultures increased PGF2 alpha production 162% after 24 h, returning PGF2 alpha efflux to the level of non-Dex-treated cultures. At 72 h, stretch increased PGF2 alpha efflux 65% in Dex-treated cultures. Mechanical stimulation of Dex-treated cultures also increased PGE2 production at 24 h, but not at 72 h. Dex reduced PGHS activity in the muscle cultures by 70% after 8-24 h of incubation, and mechanical stimulation of the Dex-treated cultures increased PGHS activity by 98% after 24 h. Repetitive mechanical stimulation attenuates the catabolic effects of Dex on cultured skeletal muscle cells in part by mitigating the Dex-induced declines in PGHS activity and prostaglandin production.

  2. Prostaglandins, endotoxin and lipid A on body temperature in rats.

    PubMed Central

    Feldberg, W; Saxena, P N

    1975-01-01

    1. In unanaesthetized restrained rats kept at an ambient temperature of 21-23degrees C, rectal temperature was continuously monitored and the temperature effects of injections of prostaglandins, endotoxin from Salmonella abortus equi, lipid A, and antipyretics were examined. 2. Fever occurred when prostaglandin E1, E2, F1alpha or F2alpha (PGE1, PGE2, PGF1alpha, PGF2alpha) was injected into the cerebral ventricles in doses of 200 ng and 2 mug. PGE2 was the most potent prostaglandin followed in descending order by PGE1, PGF2alpha, and PGF1alpha. The fever produced by 2 mug of PGE1 and PGE2 was short and followed by a fall in temperature to below the pre-injection level. 3. I.V. injections of endotoxin and lipid A in doses of 3 or 10 mug usually caused a long lasting fall in temperature, but when injected into the cerebral ventricles in doses of 400 ng or 1 mug, they produced long lasting fevers. 4. Injected I.V. or I.P., indomethacin and paracetamol had a hypothermic action of their own. Indomethacin was more potent than paracetamol and both were more potent than injected I.P. 5. I.V. and I.P. injections of indomethacin and paracetamol did not reverse the hypothermia in response to I.V. endotoxin or lipid A, but the fever responses to their injection into the cerebral ventricles were prevented and abolished by the antipyretics. 6. It is concluded that in rats endotoxin and lipid A, or the endogenous pyrogens produced by them, do not readily pass through the blood-brain barrier into the brain tissue. If they do reach brain tissue, as when injected into the cerebral ventricles, they stimulate synthesis and release of prostaglandin in rats as they do in other species, and thereby produce fever. The hypothermia in response to I.V. endotoxin or lipid A, on the other hand, is thought to be independent of prostaglandin synthesis and to result from a direct toxic action on the skin vessels. PMID:1177107

  3. The use of prostaglandins and their analogues for abortion.

    PubMed

    Bygdeman, M

    1984-12-01

    In general, termination of second trimester pregnancy is associated with three to five times higher morbidity and mortality risks than termination during the first trimester. The procedures mainly used are extra- or intra-amniotic administration of solutions such as hypertonic saline, ethacridine lactate, PGF2 alpha and PGE2. In comparison with these procedures, the use of prostaglandin analogues may offer important advantages, the most important one being the possibility of using non-invasive routes of administration. The continuous development of new analogues has now resulted in compounds that are highly effective in stimulating uterine contractility and are associated with a low frequency of side-effects; these compounds are suitable for both vaginal and intramuscular administration and are applicable for termination of pregnancy during both the early and late parts of the second trimester. The most widely used method for termination of first trimester pregnancy is vacuum aspiration. It is a highly effective procedure and the overall complication rate is low. One problem with vacuum aspiration is the mechanical dilatation of the cervical canal which is necessary from at least the 8th week and onwards. Pretreatment with laminaria tents or with prostaglandin analogues eliminates or reduces the need for mechanical dilatation and significantly facilitates the procedure. Pretreatment with prostaglandin analogues also reduces the risk of both operative and postoperative complications. The prostaglandins also offer a possibility as a non-surgical procedure for termination of very early pregnancy. Both vaginal and intramuscular administration of the latest generation of PG analogues have been shown in several studies to be equally as effective as vacuum aspiration if the treatment is restricted to the first three weeks following the first missed menstrual period. Gastrointestinal side-effects are still a problem although of significantly less importance than if natural

  4. Prostaglandin E2 and Prostaglandin F2α Differentially Modulate Matrix Metabolism of Human Nucleus Pulposus Cells

    PubMed Central

    Vo, Nam V.; Sowa, Gwendolyn A.; Kang, James D.; Seidel, Christopher; Studer, Rebecca K.

    2016-01-01

    Prostaglandin (PG) actions on disc metabolism are unclear even though certain PGs are highly expressed by disc cells under inflammatory conditions and nonsteroidal anti-inflammatory drugs (NSAIDs) are frequently used to block PG production to treat back pain. Hence this study aimed to (1) quantify gene expression of arachidonic acid cascade components responsible for PG synthesis and (2) examine the effects of key PGs on disc matrix homeostasis. Microarray analysis revealed that inflammatory stress increases expression of synthases and receptors for prostaglandin E2 (PGE2) and prostaglandin F2α (PGF2α), resulting in elevated PGE2 and PGF2α production in conditioned media of disc cells. PGE2 diminished disc cell proteoglycan synthesis, in a dose-dependent manner. Semiquantitative RT-PCR revealed differential effects of PGE2 and PGF2α on disc cell expression of key matrix structural genes, aggrecan, versican, collagens type I and II. PGE2 and PGF2α also decreased message for the anabolic factor, IGF-1. PGE2 decreased mRNA expression for the anti-catabolic factor TIMP-1 while PGF2α increased mRNAs for catabolic factors MMP-1 and MMP-3. Thus, PGE2 and PGF2α may have an overall negative impact on disc matrix homeostasis, and the use of NSAIDs may impact disc metabolism as well as treat back pain. PMID:20839316

  5. Synthesis of prostaglandins by conjugate addition and alkylation of a directed enolate ion. 4,5-allenyl prostaglandins

    SciTech Connect

    Patterson, J.W. )

    1990-09-28

    Over the previous two decades many elegant syntheses of prostaglandins, which in more sophisticated forms, allow the stereospecific introduction of the various asymmetric carbons have been accomplished. However, among these approaches the cuprate addition/enolate alkylation of suitable cyclopentenone {sup 2} stands out because of brevity and convergence. The recent reports by Noyori{sup 3} and Corey{sup 4} and their colleagues have reduced to practice the conversion of 4-alkoxycyclopentenones to prostaglandin E{sub 2} (PGE{sub 2}) by conjugate addition of an organocopper derivative of the lower side chain followed by alkylation of the resulting carbanion with methyl 7-halohept-2-enoate. The subject of this paper is application of the Tardella tin enolate alkylation developed by Noyori to the synthesis of 4, 5-allenic prostaglandins, a pharmacologically important class of compounds. The authors results demonstrate that the tandem alkylation of an enone precursor with a cuprate reagent followed by alkylation of the corresponding tin enolate with bromide reagent is a viable synthetic method for 4,5-didehydro-PGE{sub 2}. Because the optically active forms of 1 and the vinyl iodide precursor of the PGE{sub 2} lower side chain have been employed to produce a single enantiomer of PGE{sub 2}, the extension of the methodology described here to the synthesis of single enantiomers of 4a awaits only the preparation of the separate enantiomers of allene 14.

  6. Co-oxidation of 2-bromohydroquinone by renal prostaglandin synthase. Modulation of prostaglandin synthesis by 2-bromohydroquinone and glutathione.

    PubMed

    Lau, S S; Monks, T J

    1987-01-01

    Homogenates from rat renal papillae, a rich source of the prostaglandin (PG) H synthase system (PHS), metabolized [14C]2-bromohydroquinone, in the presence of arachidonic acid, to products which are covalently bound to protein. The co-oxidation of 2-bromohydroquinone caused a concentration-dependent stimulation in 6-keto-PGF1 alpha, thromboxane B2, PGF2 alpha, PGE2, and PGD2 formation. Glutathione (1 mM) caused a decrease in prostaglandin formation and inhibited the arachidonic acid-supported covalent binding of [14C]2-bromohydroquinone with the concomitant formation of [14C]2-bromohydroquinone-glutathione conjugates, oxidized glutathione, and an increase in the recovery of [14C]2-bromohydroquinone. NADPH also inhibited [14C]2-bromohydroquinone covalent binding, probably by reduction of the semiquinone radical back to the hydroquinone. Indomethacin and aspirin, inhibitors of the cyclooxygenase component of PHS, and propylthiouracil and methimazole, inhibitors of the hydroperoxidase component of PHS, inhibited the arachidonic acid-supported covalent binding of [14C]2-bromohydroquinone by 94%, 52%, 78%, and 79% respectively. These data suggest that 1) renal PHS may play a role in activating the nephrotoxin, 2-bromohydroquinone, and that 2) xenobiotic metabolism and its subsequent effects on glutathione levels can modulate renal prostaglandin synthesis. PMID:2893705

  7. Eliciting User Requirements Using Appreciative Inquiry

    ERIC Educational Resources Information Center

    Gonzales, Carol Kernitzki

    2010-01-01

    Many software development projects fail because they do not meet the needs of users, are over-budget, and abandoned. To address this problem, the user requirements elicitation process was modified based on principles of Appreciative Inquiry. Appreciative Inquiry, commonly used in organizational development, aims to build organizations, processes,…

  8. LinkIT: a ludic elicitation game for eliciting risk perceptions.

    PubMed

    Cao, Yan; McGill, William L

    2013-06-01

    The mental models approach, a leading strategy to develop risk communications, involves a time- and labor-intensive interview process and a lengthy questionnaire to elicit group-level risk perceptions. We propose that a similarity ratings approach for structural knowledge elicitation can be adopted to assist the risk mental models approach. The LinkIT game, inspired by games with a purpose (GWAP) technology, is a ludic elicitation tool designed to elicit group understanding of the relations between risk factors in a more enjoyable and productive manner when compared to traditional approaches. That is, consistent with the idea of ludic elicitation, LinkIT was designed to make the elicitation process fun and enjoyable in the hopes of increasing participation and data quality in risk studies. Like the mental models approach, the group mental model obtained via the LinkIT game can hence be generated and represented in a form of influence diagrams. In order to examine the external validity of LinkIT, we conducted a study to compare its performance with respect to a more conventional questionnaire-driven approach. Data analysis results conclude that the two group mental models elicited from the two approaches are similar to an extent. Yet, LinkIT was more productive and enjoyable than the questionnaire. However, participants commented that the current game has some usability concerns. This presentation summarizes the design and evaluation of the LinkIT game and suggests areas for future work. PMID:23078149

  9. An evaluation of vulvomucosal injections of prostaglandins for induction of parturition in swine

    PubMed Central

    Friendship, Robert M.; Templeton, Catherine L.; Deckert, Anne E.

    1990-01-01

    Two trials were performed to evaluate the efficacy of prostaglandins administered via the vulvomucosal route at one-half the recommended dosage in comparison to prostaglandins injected intramuscularly (IM) at the standard dosage. In trial 1, sows on three commercial swine farms were given prostaglandin F2α at a dosage of 10 mg IM (n = 110) or 5 mg prostaglandin F2α using a vulvomucosal injection (n = 94). The numbers of sows farrowing within 36 h postinjection were 92 (84%) and 83 (88%), respectively. In trial 2, sows on four commercial swine operations were induced to farrow by means of one of three treatments: cloprostenol 175 μg IM (n = 71); cloprostenol 87.5 μg vulvomucosally (n = 57); or prostaglandin F2α 5 mg vulvomucosally (n = 96). The numbers of sows farrowing within 36 h postinduction were 69 (97%), 53 (93%), and 91 (94%), respectively. Vulvomucosal injections of prostaglandin F2α and cloprostenol at one-half the dosage appeared to be as effective as intramuscular injections of prostaglandin F2α and cloprostenol at the recommended level. There were fewer sows demonstrating restless behavior following the injection of lower dosages of prostaglandin F2α vulvomucosally, compared to sows given the recommended dosage of prostaglandin F2α IM. PMID:17423605

  10. Prostaglandin D2 induces the production of human beta-defensin-3 in human keratinocytes.

    PubMed

    Kanda, Naoko; Ishikawa, Takeko; Watanabe, Shinichi

    2010-04-01

    The antimicrobial peptide human beta-defensin-3 (hBD-3) is produced by epidermal keratinocytes and protects the skin from infections. This peptide induces the release of a lipid mediator, prostaglandin D(2) from dermal mast cells. Prostaglandin D(2) binds to cell-surface G protein-coupled receptors, D prostanoid receptor, and chemoattractant receptor-homologous molecule expressed on T helper cell type 2 (CRTH2). Both receptors are detected on epidermal keratinocytes. It is reported that prostaglandin D(2) is involved in cutaneous allergy, however, its role in antimicrobial defense is unknown. We examined the in vitro effects of prostaglandin D(2) on hBD-3 production in normal human keratinocytes. Prostaglandin D(2) enhanced hBD-3 secretion and mRNA expression in human keratinocytes. Prostaglandin D(2)-induced hBD-3 production was suppressed by the CRTH2 antagonist ramatroban and by antisense oligonucleotides against c-Jun and c-Fos, components of a transcription factor, activator protein-1 (AP-1). Prostaglandin D(2) enhanced the transcriptional activity and DNA binding of AP-1, expression, phosphorylation, and DNA binding of c-Fos proteins in keratinocytes. Prostaglandin D(2)-induced hBD-3 production, AP-1 activity, and c-Fos expression and phosphorylation were suppressed by U0126, PP2, and pertussis toxin, which are inhibitors of mitogen-activated protein kinase kinase (MEK), src, and G(i) proteins, respectively. The phosphorylation of extracellular signal-regulated kinase (ERK), downstream kinase of MEK, was induced by prostaglandin D(2), and suppressed by ramatroban, pertussis toxin, PP2, and U0126. These results suggest that prostaglandin D(2) induces hBD-3 production in human keratinocytes by activating AP-1 through the expression and phosphorylation of c-Fos via the CRTH2/G(i)/src/MEK/ERK pathway. Prostaglandin D(2) may promote cutaneous antimicrobial activity via hBD-3. PMID:19925780

  11. Prostaglandin synthesis inhibitors block alcohol-induced fetal hypoplasia.

    PubMed

    Pennington, S; Allen, Z; Runion, J; Farmer, P; Rowland, L; Kalmus, G

    1985-01-01

    Alcohol-induced growth retardation is a fetal effect consistently associated with maternal ethanol consumption. In humans, those infants whose mothers consume even a limited amount of ethanol during pregnancy have a significant incidence of growth inhibition. The molecular mechanism responsible for this growth deficiency is unknown, and prevention depends on maternal abstinence during pregnancy. The data reported here suggest that ethanol-mediated increases in tissue prostaglandin (PG) E levels (PGE1 plus PGE2) are correlated with the growth retardation. Further, simultaneous administration of PG synthesis inhibitors with the alcohol blocks the rise in tissue PG levels and protects against the alcohol-induced hypoplasia. PMID:3904508

  12. Prostaglandin E2 stimulates the production of interleukin-6 by neonatal mouse parietal bones.

    PubMed

    Holt, I; Davie, M W; Braidman, I P; Marshall, M J

    1994-04-01

    The pleiotropic cytokine interleukin-6 (IL-6) is thought to be involved in bone homeostasis. A number of bone resorbing agents have been shown to induce the release of IL-6 from bone. We wished to determine whether prostaglandin E2 (PGE2), which is a mediator of bone resorption, can elicit the production of IL-6. IL-6 was measured by the proliferative response of B9 hybridoma cells and could be completely neutralised by an anti-IL-6 antibody. Parietal bones from neonatal mice were maintained in culture in the presence of indomethacin (10(-6) M) with or without PGE2. The time course and dose-response to PGE2 of IL-6 production were determined. After 6 h in culture, 10(-8) M PGE2 produced significantly more IL-6 than the controls (P < 0.005). PGE2 (10(-6) M) stimulated the production of a mean of 12.8 ng/ml IL-6 over 6 h. Preincubating bones with indomethacin for 20 h prior to a 6 h culture with indomethacin led to a lowering of the production of IL-6 (mean 1.8 ng/ml) compared to bones cultured without the preincubation period (5.8 ng/ml). When the indomethacin preincubation period was used, a significant increase in IL-6 production was found with 10(-9) M PGE2 (P < 0.005), and 10(-6) M PGE2 caused the production of 39.9 ng/ml IL-6 over 6 h. Stripping endocranial and ectocranial membranes from bones demonstrated the membranes to be the major site of IL-6 production. However, intact bones were required for maximal stimulated IL-6 production. PMID:8061551

  13. Prostaglandin E2 regulates angiogenesis via activation of fibroblast growth factor receptor-1.

    PubMed

    Finetti, Federica; Solito, Raffaella; Morbidelli, Lucia; Giachetti, Antonio; Ziche, Marina; Donnini, Sandra

    2008-01-25

    Prostaglandin E(2) (PGE(2)) behaves as a mitogen in epithelial tumor cells as well as in many other cell types. We investigated the actions of PGE(2) on microvascular endothelial cells (capillary venular endothelial cells) with the purpose of delineating the signaling pathway leading to the acquisition of the angiogenic phenotype and to new vessel formation. PGE(2) (100 nM) produced activation of the fibroblast growth factor receptor 1 (FGFR-1), as measured by its phosphorylation, but not of vascular endothelial growth factor receptor 2. PGE(2) stimulated the EP3 subtype receptor, as deduced by abrogation of EP3 Galpha(i) subunit activity through pertussis toxin. Consistent with this result, in human umbilical venular endothelial cells missing the EP3 receptor, PGE(2) did not phosphorylate FGFR-1. Upon binding to its receptor, PGE(2) initiated an autocrine/paracrine signaling cascade involving the intracellular activation of c-Src, activation of matrix metalloproteinase (predominantly MMP2), which in turn caused the mobilization of membrane-anchored fibroblast growth factor-2 (FGF-2). In fact, in cells unable to release FGF-2 the transfection with both FGFR-1 and EP3 did not result in FGFR-1 phosphorylation in response to PGE(2). Relevance for the FGF2-FGFR-1 system was highlighted by confocal analysis, showing receptor internalization after cell exposure to the prostanoid. ERK1/2 appeared to be the distal signal involved, its phosphorylation being sensitive to either cSrc inhibitor or FGFR-1 blocker. Finally, PGE(2) stimulated cell migration and capillary formation in aortic rings, which were severely reduced by inhibitors of signaling molecules or by receptor antagonist. In conclusion, this study provides evidence for the involvement of FGFR-1 through FGF2 in eliciting PGE(2) angiogenic responses. This signaling pattern is similar to the autocrine-paracrine mechanism which operates in endothelial cells to support neovascular growth. PMID:18042549

  14. Prostaglandin (PG)E2 exhibits anti-fibrotic activity in vocal fold fibroblasts

    PubMed Central

    Zhou, Hang; Felsen, Diane; Sandulache, Vlad C.; Amin, Milan R.; Kraus, Dennis H.; Branski, Ryan C.

    2011-01-01

    Objectives/Hypothesis Prostaglandin (PG)E2 has been implicated in a variety of disease processes. It has been described as antifibrotic in the lower airway, yet scar-inducing in the skin. We seek to describe the effects of PGE2 on vocal fold fibroblasts and its interactions with TGF-β1. In addition, we describe a novel organotypic model, a critical step in the development of therapeutic trials. Study Design In vitro, ex vivo Level of Evidence N/A Methods Collagen secretion by human vocal fold fibroblasts (HVFF) was assayed in response to TGF-β1, PGE2, and specific EP receptor agonists. Basal HVFF migratory rate was also quantified in response to PGE2. TGF-β1 induced COX-2 mRNA expression/PGE2 secretion. Excised vocal folds were subjected to exogenous IL-1β; PGE2 secretion into the supernatant was then assayed. Results TGF-β1-induced collagen secretion was blunted in a dose-dependent manner in response to PGE2. This effect appears to be mediated primarily through the EP1 and EP2 receptors. TGF-β1 induced COX-2 mRNA expression and PGE2 secretion. In our organ culture model, IL-1β stimulated PGE2 secretion in a dose-dependent manner. Conclusions PGE2 is anti-fibrotic; this finding suggests that the upper airway response to this inflammatory mediator differs significantly from the lower airway. These data have important clinical implications for a variety of pathological processes. Furthermore, exogenous TGF-β1 elicits induction of COX-2, suggesting inherent complexity regarding these processes and PGE2, signaling specifically. In addition, our organ culture model may prove useful as a means to quantify biological phenomena in the vocal folds. PMID:21557245

  15. Essays on probability elicitation scoring rules

    NASA Astrophysics Data System (ADS)

    Firmino, Paulo Renato A.; dos Santos Neto, Ademir B.

    2012-10-01

    In probability elicitation exercises it has been usual to considerer scoring rules (SRs) to measure the performance of experts when inferring about a given unknown, Θ, for which the true value, θ*, is (or will shortly be) known to the experimenter. Mathematically, SRs quantify the discrepancy between f(θ) (the distribution reflecting the expert's uncertainty about Θ) and d(θ), a zero-one indicator function of the observation θ*. Thus, a remarkable characteristic of SRs is to contrast expert's beliefs with the observation θ*. The present work aims at extending SRs concepts and formulas for the cases where Θ is aleatory, highlighting advantages of goodness-of-fit and entropy-like measures. Conceptually, it is argued that besides of evaluating the personal performance of the expert, SRs may also play a role when comparing the elicitation processes adopted to obtain f(θ). Mathematically, it is proposed to replace d(θ) by g(θ), the distribution that model the randomness of Θ, and do also considerer goodness-of-fit and entropylike metrics, leading to SRs that measure the adherence of f(θ) to g(θ). The implications of this alternative perspective are discussed and illustrated by means of case studies based on the simulation of controlled experiments. The usefulness of the proposed approach for evaluating the performance of experts and elicitation processes is investigated.

  16. Effect of radiation on prostaglandin production by human bowel in vitro

    SciTech Connect

    Gal, D.; Strickland, D.M.; Lifshitz, S.; Buchsbaum, H.J.; Mitchell, M.D.

    1984-05-01

    The effect of gamma irradiation on the production of prostaglandins by human colon was investigated. Squares of tissue in organ culture dishes were irradiated with 500, 1000, or 2500 rad in single applications. Tissues that were not irradiated served as controls. After treatment the tissues were superfused and prostaglandin concentrations in the effluent fluid were determined. The rates of production of prostaglandins E/sub 2/ and F/sub 2..cap alpha../ by irradiated tissues were significantly lower than those of nonirradiated tissues. Neither the release of lactate dehydrogenase nor the rate of production of 13,14-dihydro-15-keto-prostaglandin F/sub 2..cap alpha../ were increased in the irradiated samples, suggesting that neither decreased cell viability nor increased prostaglandin metabolism accounted for the decreased prostaglandin production rates. The authors conclude that irradiation of the human colon in vitro results in an acute inhibition of prostaglandin synthesis. The cytoprotective nature of prostaglandins is discussed with regard to the possible pathophysiological significance of these findings.

  17. Bacterial lipopolysaccharide induces an endocrine switch from prostaglandin F2α to prostaglandin E2 in bovine endometrium

    PubMed Central

    Herath, Shan; Lilly, Sonia T.; Fischer, Deborah P.; Williams, Erin J.; Dobson, Hilary; Bryant, Clare E.; Sheldon, I. Martin

    2009-01-01

    Escherichia coli infection of the endometrium causes uterine disease after parturition and is associated with prolonged luteal phases of the ovarian cycle in cattle. Termination of the luteal phase is initiated by prostaglandin F2α (PGF) from oxytocin-stimulated endometrial epithelial cells. Compared with normal animals, the peripheral plasma of animals with E. coli infection of the endometrium had higher concentrations of lipopolysaccharide (LPS) and prostaglandin E2 (PGE), but not PGF. Endometrial explants accumulated predominantly PGE in the culture medium in response to LPS and this effect was not reversed by oxytocin. Endometrial cells expressed the TLR4/CD14/MD-2 receptor complex necessary to detect LPS. Epithelial and stromal cells treated with LPS had higher steady-state media concentrations of PGE rather than PGF. Arachadonic acid is liberated from cell membranes by phospholipase 2 (PLA2) enzymes and converted to prostaglandins by synthase enzymes. Treatment of epithelial and stromal cells with LPS did not change the levels of PGE or PGF synthase enzymes. However, LPS stimulated increased levels of PLA2 group VI but not PLA2 group IV C immunoreactive protein in epithelial cells. Endometrial cells expressed the EP2 and EP4 receptors necessary to respond to PGE, which regulates inflammation as well as being luteotropic. In conclusion, LPS detection by endometrial cells stimulated the accumulation of PGE rather than PGF, providing a mechanism to explain prolonged luteal phases in animals with uterine disease, and this PGE may also be important for regulating inflammatory responses in the endometrium. PMID:19056817

  18. Olfactory receptor for prostaglandin F2α mediates male fish courtship behavior.

    PubMed

    Yabuki, Yoichi; Koide, Tetsuya; Miyasaka, Nobuhiko; Wakisaka, Noriko; Masuda, Miwa; Ohkura, Masamichi; Nakai, Junichi; Tsuge, Kyoshiro; Tsuchiya, Soken; Sugimoto, Yukihiko; Yoshihara, Yoshihiro

    2016-07-01

    Pheromones play vital roles for survival and reproduction in various organisms. In many fishes, prostaglandin F2α acts not only as a female reproductive hormone, facilitating ovulation and spawning, but also as a sex pheromone inducing male reproductive behaviors. Here, we unravel the molecular and neural circuit mechanisms underlying the pheromonal action of prostaglandin F2α in zebrafish. Prostaglandin F2α specifically activates two olfactory receptors with different sensitivities and expression in distinct populations of ciliated olfactory sensory neurons. Pheromone information is then transmitted to two ventromedial glomeruli in the olfactory bulb and further to four regions in higher olfactory centers. Mutant male zebrafish deficient in the high-affinity receptor exhibit loss of attractive response to prostaglandin F2α and impairment of courtship behaviors toward female fish. These findings demonstrate the functional significance and activation of selective neural circuitry for the sex pheromone prostaglandin F2α and its cognate olfactory receptor in fish reproductive behavior. PMID:27239939

  19. Prostaglandins are not involved in the differentiation or growth of cultured small intestinal cells.

    PubMed

    Stange, E F; Schneider, A; Preclik, G; Ditschuneit, H

    1986-01-01

    Prostaglandins have been reported to exert trophic effects on gastrointestinal tissues. To determine whether there is a direct interaction with enterocytes, prostaglandins PGE2, PGF2 alpha, PGA2, PGB2 and the stable PGE2 derivative suleprost as well as the prostacyclin derivative nileprost were tested in rabbit ileal mucosa under organ culture conditions. At concentrations between 10(-9) and 10(-5) M, none of the prostaglandins significantly affected biopsy DNA or protein content, or the activity of the brush border enzymes alkaline phosphatase, lactase, sucrase or maltase. The inhibition of endogenous prostaglandin synthesis with indomethacin also failed to alter these parameters. Moreover, the growth rate of a rat duodenal crypt cell line was unaffected when cultured in the presence of PGE2, PGF2 alpha or indomethacin. Thus, there was no evidence for a direct effect of exogenous or endogenous prostaglandins or their deficiency on the differentiation or growth in cultured small intestinal cells. PMID:3817331

  20. Influence of prostaglandins on contractility of the isolated human cervical muscle.

    PubMed

    Bryman, I; Sahni, S; Norström, A; Lindblom, B

    1984-03-01

    The contractile activity of smooth muscle from the pregnant and nonpregnant human cervix uteri was studied in organ bath experiments. Several patterns of spontaneous activity with varying frequency and amplitude were observed. Prostaglandin E2 inhibited muscle activity in a concentration-dependent manner, and total inhibition was achieved in pregnant tissue at extremely low concentrations. Prostaglandin F2 alpha, on the other hand, did not influence spontaneous contractions. Prostaglandin I2 and 6-keto-prostaglandin F1 alpha had an inhibitory effect but only at comparatively high concentrations. 5,8,11,14-Eicosatetraynoic acid and indomethacin abolished spontaneous contractions, indicating a regulatory influence of endogenous prostanoids on cervical contractility. The extreme sensitivity to prostaglandin E2 and enhancement of its action during early pregnancy provide evidence for a specific role of this compound in controlling cervical smooth muscle activity in the human female. PMID:6583598

  1. Intrauterine pregnancy after treatment of tubal pregnancy with local and systemic prostaglandins in a patient with a single oviduct.

    PubMed

    Hönigl, W; Lang, P F; Weiss, P A; Winter, R

    1992-04-01

    A spontaneous intrauterine pregnancy occurred after instillation of prostaglandin-F2 alpha into the solitary tube and systemic prostaglandin administration for treatment of an ectopic gestation. This is the first unequivocal proof of intact function of the affected tube after non-surgical treatment of a tubal pregnancy with prostaglandins. PMID:1325989

  2. CSF levels of prostaglandins, especially the level of prostaglandin D2, are correlated with increasing propensity towards sleep in rats.

    PubMed

    Ram, A; Pandey, H P; Matsumura, H; Kasahara-Orita, K; Nakajima, T; Takahata, R; Satoh, S; Terao, A; Hayaishi, O

    1997-03-14

    The concentration of PGD2, PGE2, and of PGF2 alpha was measured in the cerebrospinal fluid (CSF) collected from the cisterna magna of conscious rats (n = 29), which, chronically implanted with a catheter for the CSF sampling, underwent deprivation of daytime sleep. Significant elevation of the CSF level of PGD2 was observed following 2.5-h sleep deprivation (SD), and the elevation became more marked following 5- and 10-h SD, apparently reaching the maximum at 5-h SD (703 +/- 140 pg/ml (mean +/- S.E.M.) for baseline vs. 1734 +/- 363 pg/ml for SD, n = 10). The levels of PGE2, and PGF2 alpha also significantly increased following 5- and 10-h SD, but not following 2.5-h SD. It is unlikely that these changes were simply caused by some responses of the animals to stress stimuli, because stress stimuli derived from restraint of the animal at the supine position to a board for 1 h did not produce any acute responses in the CSF levels of prostaglandins (n = 13). In a different group of animals (n = 11) implanted with electrodes for recording electroencephalogram (EEG) and electromyogram (EMG) in addition to the catheter, the levels of the prostaglandins in CSF were determined for slow-wave sleep (SWS) and wakefulness in the day and for SWS and wakefulness in the night. The highest PGD2 value was obtained at daytime SWS, whereas the lowest was at night wakefulness; furthermore, a significant difference was observed between SWS and wakefulness rather than between day and night. The CSF level of PGE2 also showed a similar tendency. In an additional group of animals (n = 6), not only PGD2 but also PGE2 and PGF2 alpha significantly increased the sleeping time of the animal when applied into the subarachnoid space underlying the ventral surface area of the rostral basal forebrain, the previously defined site of action for the sleep-promoting effect of PGD2. The promotion of sleep by PGE2 applied to the subarachnoid space was an effect completely opposite to the well

  3. Prostanoid signaling: dual role for prostaglandin E2 in neurotoxicity

    PubMed Central

    Milatovic, Dejan; Montine, Thomas J.; Aschner, Michael

    2011-01-01

    The prostanoids, a naturally occurring subclass of eicosanoids, are lipid mediators generated through oxidative pathways from arachidonic acid. These cyclooxygenase metabolites, consisting of the prostaglandins (PG), prostacyclin and tromboxane, are released in response to a variety of physiological and pathological stimuli in almost all organs, including the brain. They are produced by various cell types and act upon targeted cells via specific G protein-coupled receptors. The existence of multiple receptors, cross-reactivity and coupling to different signal transduction pathways for each prostanoid, collectively establish their diverse effects. Notably, these effects can occur in functionally opposing directions within the same cell or organ. Prostaglandin E2 (PGE2) is the most versatile prostanoid because of its receptors, E Prostanoid (EP) receptor subtypes 1 through 4, its biological heterogeneity and its differential expression on neuronal and glial cells throughout the central nervous system. Since PGE2 plays an important role in processes associated with various neurological diseases, this review focuses on its dual neuroprotective and neurotoxic role in EP receptor subtype signaling pathways in different models of brain injury. PMID:21376752

  4. Prostaglandin E receptor 4 (EP4) promotes colonic tumorigenesis.

    PubMed

    Chang, Jian; Vacher, Jean; Yao, Bing; Fan, Xiaofeng; Zhang, Bixiang; Harris, Raymond C; Zhang, Ming-Zhi

    2015-10-20

    Colorectal cancer (CRC) continues to be a major cause of morbidity and mortality. Although the factors underlying CRC development and progression are multifactorial, there is an important role for tumor-host interactions, especially interactions with myeloid cells. There is also increasing evidence that cyclooxygenase-derived prostaglandins are important mediators of CRC development and growth. Although prevention trials with either nonselective NSAIDs or COX-2 selective agents have shown promise, the gastrointestinal or cardiovascular side effects of these agents have limited their implementation. The predominant prostaglandin involved in CRC pathogenesis is PGE2. Since myeloid cells express high levels of the PGE2 receptor subtype, EP4, we selectively ablated EP4 in myeloid cells and studied adenoma formation in a mouse model of intestinal adenomatous polyposis, ApcMin/+ mice. ApcMin/+mice with selective myeloid cell deletion of EP4 had marked inhibition of both adenoma number and size, with associated decreases in mTOR and ERK activation. Either genetic or pharmacologic inhibition of EP4 receptors led to an anti-tumorigenic M1 phenotype of macrophages/dendritic cells. Therefore, PGE2-mediated EP4 signaling in myeloid cells promotes tumorigenesis, suggesting EP4 as a potentially attractive target for CRC chemoprevention or treatment. PMID:26378024

  5. Prostaglandin signaling regulates ciliogenesis by modulating intraflagellar transport

    PubMed Central

    Jin, Daqing; Ni, Terri T.; Sun, Jianjian; Wan, Haiyan; Amack, Jeffrey D.; Yu, Guangju; Fleming, Jonathan; Chiang, Chin; Li, Wenyan; Papierniak, Anna; Cheepala, Satish; Conseil, Gwenaëlle; Cole, Susan P.C.; Zhou, Bin; Drummond, Iain A.; Schuetz, John D.; Malicki, Jarema; Zhong, Tao P.

    2014-01-01

    Cilia are microtubule-based organelles that mediate signal transduction in a variety of tissues. Despite their importance, the signaling cascades that regulate cilia formation remain incompletely understood. Here we report that prostaglandin signaling affects ciliogenesis by regulating anterograde intraflagellar transport (IFT). Zebrafish leakytail (lkt) mutants display ciliogenesis defects, and lkt locus encodes an ATP-binding cassette transporter (ABCC4). We show that Lkt/ABCC4 localizes to the cell membrane and exports prostaglandin E2 (PGE2), a function that is abrogated by the Lkt/ABCC4T804M mutant. PGE2 synthesis enzyme Cyclooxygenase-1 and its receptor, EP4, which localizes to the cilium and activates cAMP-mediated signaling cascade, are required for cilia formation and elongation. Importantly, PGE2 signaling increases anterograde but not retrograde velocity of IFT and promotes ciliogenesis in mammalian cells. These findings lead us to propose that Lkt/ABCC4-mediated PGE2 signaling acts through a ciliary G-protein-coupled receptor, EP4, to upregulate cAMP synthesis and increase anterograde IFT, thereby promoting ciliogenesis. PMID:25173977

  6. Prostaglandins are important in thermoregulation of a reptile (Pogona vitticeps).

    PubMed Central

    Seebacher, Frank; Franklin, Craig E

    2003-01-01

    The effectiveness of behavioural thermoregulation in reptiles is amplified by cardiovascular responses, particularly by differential rates of heart beat in response to heating and cooling (heart-rate hysteresis). Heart-rate hysteresis is ecologically important in most lineages of ectothermic reptile, and we demonstrate that heart-rate hysteresis in the lizard Pogona vitticeps is mediated by prostaglandins. In a control treatment (administration of saline), heart rates during heating were significantly faster than during cooling at any given body temperature. When cyclooxygenase 1 and 2 enzymes were inhibited, heart rates during heating were not significantly different from those during cooling. Administration of agonists showed that thromboxane B(2) did not have a significant effect on heart rate, but prostacyclin and prostaglandin F(2alpha) caused a significant increase (3.5 and 13.6 beats min(-1), respectively) in heart rate compared with control treatments. We speculate that heart-rate hysteresis evolved as a thermoregulatory mechanism that may ultimately be controlled by neurally induced stimulation of nitric oxide production, or maybe via photolytically induced production of vitamin D. PMID:12952634

  7. Canine gastric mucosal vasodilation with prostaglandins and histamine analogs

    SciTech Connect

    Gerber, J.G.; Nies, A.S.

    1982-10-01

    The effect of direct intragastric artery infusion of prostaglandins E2 and I2, arachidonic acid, dimaprit (histamine H2 agonist), and 2',2'-pyridylethylamine (histamine H1 agonist) on gastric mucosal blood flow was examined in dogs to elucidate the relationship between gastric secretory state and mucosal blood flow in dogs. These compounds were chosen because of their diverse effect on gastric acid secretion. Gastric fundus blood flow was measured both electromagnetically with a flow probe around the left gastric artery which supplies the fundus almost exclusively, and by the radioactive microsphere technique. Intraarterial infusion of all the compounds resulted in gastric mucosal vasodilation even though PGE2, PGI2, and arachidonic acid inhibit gastric acid secretion, dimaprit stimulated gastric acid secretion, and 2',2'-pyridylethylamine does not affect gastric acid secretion. There was total agreement in the blood flow measurements by the two different techniques. Our data suggest that gastric acid secretion and gastric vasodilation are independently regulated. In addition, the validity of the studies in which the aminopyrine clearance indicates that prostaglandins are mucosal vasoconstrictors needs to be questioned because of the reliance of those measurements on the secretory state of the stomach.

  8. Prostaglandin E receptor 4 (EP4) promotes colonic tumorigenesis

    PubMed Central

    Chang, Jian; Vacher, Jean; Yao, Bing; Fan, Xiaofeng; Zhang, Bixiang; Harris, Raymond C.; Zhang, Ming-Zhi

    2015-01-01

    Colorectal cancer (CRC) continues to be a major cause of morbidity and mortality. Although the factors underlying CRC development and progression are multifactorial, there is an important role for tumor-host interactions, especially interactions with myeloid cells. There is also increasing evidence that cyclooxygenase-derived prostaglandins are important mediators of CRC development and growth. Although prevention trials with either nonselective NSAIDs or COX-2 selective agents have shown promise, the gastrointestinal or cardiovascular side effects of these agents have limited their implementation. The predominant prostaglandin involved in CRC pathogenesis is PGE2. Since myeloid cells express high levels of the PGE2 receptor subtype, EP4, we selectively ablated EP4 in myeloid cells and studied adenoma formation in a mouse model of intestinal adenomatous polyposis, ApcMin/+ zmice. ApcMin/+mice with selective myeloid cell deletion of EP4 had marked inhibition of both adenoma number and size, with associated decreases in mTOR and ERK activation. Either genetic or pharmacologic inhibition of EP4 receptors led to an anti-tumorigenic M1 phenotype of macrophages/dendritic cells. Therefore, PGE2-mediated EP4 signaling in myeloid cells promotes tumorigenesis, suggesting EP4 as a potentially attractive target for CRC chemoprevention or treatment. PMID:26378024

  9. Prostaglandin E2 receptor, EP3, is induced in diabetic islets and negatively regulates glucose- and hormone-stimulated insulin secretion.

    PubMed

    Kimple, Michelle E; Keller, Mark P; Rabaglia, Mary R; Pasker, Renee L; Neuman, Joshua C; Truchan, Nathan A; Brar, Harpreet K; Attie, Alan D

    2013-06-01

    BTBR mice develop severe diabetes in response to genetically induced obesity due to a failure of the β-cells to compensate for peripheral insulin resistance. In analyzing BTBR islet gene expression patterns, we observed that Pgter3, the gene for the prostaglandin E receptor 3 (EP3), was upregulated with diabetes. The EP3 receptor is stimulated by prostaglandin E2 (PGE2) and couples to G-proteins of the Gi subfamily to decrease intracellular cAMP, blunting glucose-stimulated insulin secretion (GSIS). Also upregulated were several genes involved in the synthesis of PGE2. We hypothesized that increased signaling through EP3 might be coincident with the development of diabetes and contribute to β-cell dysfunction. We confirmed that the PGE2-to-EP3 signaling pathway was active in islets from confirmed diabetic BTBR mice and human cadaveric donors, with increased EP3 expression, PGE2 production, and function of EP3 agonists and antagonists to modulate cAMP production and GSIS. We also analyzed the impact of EP3 receptor activation on signaling through the glucagon-like peptide (GLP)-1 receptor. We demonstrated that EP3 agonists antagonize GLP-1 signaling, decreasing the maximal effect that GLP-1 can elicit on cAMP production and GSIS. Taken together, our results identify EP3 as a new therapeutic target for β-cell dysfunction in T2D. PMID:23349487

  10. Prostaglandin E2 Receptor, EP3, Is Induced in Diabetic Islets and Negatively Regulates Glucose- and Hormone-Stimulated Insulin Secretion

    PubMed Central

    Kimple, Michelle E.; Keller, Mark P.; Rabaglia, Mary R.; Pasker, Renee L.; Neuman, Joshua C.; Truchan, Nathan A.; Brar, Harpreet K.; Attie, Alan D.

    2013-01-01

    BTBR mice develop severe diabetes in response to genetically induced obesity due to a failure of the β-cells to compensate for peripheral insulin resistance. In analyzing BTBR islet gene expression patterns, we observed that Pgter3, the gene for the prostaglandin E receptor 3 (EP3), was upregulated with diabetes. The EP3 receptor is stimulated by prostaglandin E2 (PGE2) and couples to G-proteins of the Gi subfamily to decrease intracellular cAMP, blunting glucose-stimulated insulin secretion (GSIS). Also upregulated were several genes involved in the synthesis of PGE2. We hypothesized that increased signaling through EP3 might be coincident with the development of diabetes and contribute to β-cell dysfunction. We confirmed that the PGE2-to-EP3 signaling pathway was active in islets from confirmed diabetic BTBR mice and human cadaveric donors, with increased EP3 expression, PGE2 production, and function of EP3 agonists and antagonists to modulate cAMP production and GSIS. We also analyzed the impact of EP3 receptor activation on signaling through the glucagon-like peptide (GLP)-1 receptor. We demonstrated that EP3 agonists antagonize GLP-1 signaling, decreasing the maximal effect that GLP-1 can elicit on cAMP production and GSIS. Taken together, our results identify EP3 as a new therapeutic target for β-cell dysfunction in T2D. PMID:23349487

  11. Isolated sleep paralysis elicited by sleep interruption.

    PubMed

    Takeuchi, T; Miyasita, A; Sasaki, Y; Inugami, M; Fukuda, K

    1992-06-01

    We elicited isolated sleep paralysis (ISP) from normal subjects by a nocturnal sleep interruption schedule. On four experimental nights, 16 subjects had their sleep interrupted for 60 minutes by forced awakening at the time when 40 minutes of nonrapid eye movement (NREM) sleep had elapsed from the termination of rapid eye movement (REM) sleep in the first or third sleep cycle. This schedule produced a sleep onset REM period (SOREMP) after the interruption at a high rate of 71.9%. We succeeded in eliciting six episodes of ISP in the sleep interruptions performed (9.4%). All episodes of ISP except one occurred from SOREMP, indicating a close correlation between ISP and SOREMP. We recorded verbal reports about ISP experiences and recorded the polysomnogram (PSG) during ISP. All of the subjects with ISP experienced inability to move and were simultaneously aware of lying in the laboratory. All but one reported auditory/visual hallucinations and unpleasant emotions. PSG recordings during ISP were characterized by a REM/W stage dissociated state, i.e. abundant alpha electroencephalographs and persistence of muscle atonia shown by the tonic electromyogram. Judging from the PSG recordings, ISP differs from other dissociated states such as lucid dreaming, nocturnal panic attacks and REM sleep behavior disorders. We compare some of the sleep variables between ISP and non-ISP nights. We also discuss the similarities and differences between ISP and sleep paralysis in narcolepsy. PMID:1621022

  12. Eliciting nicotine craving with virtual smoking cues.

    PubMed

    Gamito, Pedro; Oliveira, Jorge; Baptista, André; Morais, Diogo; Lopes, Paulo; Rosa, Pedro; Santos, Nuno; Brito, Rodrigo

    2014-08-01

    Craving is a strong desire to consume that emerges in every case of substance addiction. Previous studies have shown that eliciting craving with an exposure cues protocol can be a useful option for the treatment of nicotine dependence. Thus, the main goal of this study was to develop a virtual platform in order to induce craving in smokers. Fifty-five undergraduate students were randomly assigned to two different virtual environments: high arousal contextual cues and low arousal contextual cues scenarios (17 smokers with low nicotine dependency were excluded). An eye-tracker system was used to evaluate attention toward these cues. Eye fixation on smoking-related cues differed between smokers and nonsmokers, indicating that smokers focused more often on smoking-related cues than nonsmokers. Self-reports of craving are in agreement with these results and suggest a significant increase in craving after exposure to smoking cues. In sum, these data support the use of virtual environments for eliciting craving. PMID:24660864

  13. Effects of methylxanthines on urinary prostaglandin E excretion in rats.

    PubMed

    Takeuchi, K; Kogo, H; Aizawa, Y

    1981-04-01

    Effect of methylxanthines (theophylline, theobromine and caffeine) on urinary prostaglandin E (PGE) excretion in male rats was studied. Oral administration of xanthines significantly increased the urinary excretion of PGE. Dose-response studies showed that the maximal excretion of urinary PGE and water was obtained by administration of theophylline (50 mg/kg), where the increase in PGE was about 20 times that of the control. The excretion of urinary sodium, potassium and chloride was also markedly increased by xanthines, particularly, theophylline. Increases in urinary PGE excretion, urine volume and electrolytes excretion were inhibited by 10 mg/kg of indomethacin administered prior to theophylline. The increase of urinary PGE excretion after theophylline administration (50 mg/kg) preceded increases in water and sodium excretion. These results suggest that renal PGE mediates, at least in part, the diuretic effect of theophylline. PMID:7311144

  14. Metabolism of prostaglandin E1 in dog kidneys

    PubMed Central

    Nakano, J.

    1970-01-01

    1. The biotransformation of prostaglandin E1 (PGE1) was studied in the isolated, perfused dog kidneys. 2. An average 43% of PGE1 was converted into the less polar metabolite I by a single passage through the kidney. As the re-circulation of the perfusate continued, PGE1 was converted not only into metabolite I but also the least polar metabolite II. The velocity of the conversion of PGE1 into metabolite I was significantly greater than that into metabolite II. Usually, six passages elapsed before maximum degradation of PGE1 occurred. 3. Further separation with silicic acid column chromatography and gas-liquid chromatography showed that metabolite II consists of two individual metabolites, metabolite IIa and metabolite IIb. 4. The present study indicates that the kidney biotransforms PGE1 rather rapidly into three metabolites which are less polar than PGE1. PMID:5492900

  15. Prostaglandin inhibitor and radiotherapy in advanced head and neck cancers

    SciTech Connect

    Pillsbury, H.C. III; Webster, W.P.; Rosenman, J.

    1986-05-01

    Radiotherapy is the usual mode of treatment for unresectable head and neck cancer. To improve cure rates, extend survival, and reduce morbidity, we use accelerated hyperfractionation radiotherapy and an adjuvant drug to inhibit prostaglandin synthesis. In this study, 19 patients received 300 rad/day of radiotherapy in two equally divided doses to a total dose averaging 6,200 rad. Either indomethacin, 25 mg, or placebo was given four times a day in a double-blind fashion during therapy. Radiation mucositis was graded as 0 to 4+; pain, nutritional status, and tumor status were monitored daily and recorded biweekly. Evaluation of the data showed delayed mucositis in the experimental group for grades 1 to 3, with a significant difference at grade 3 compared with controls. The significance of a long-term comparison of cure rates would be doubtful considering the heterogeneity of the primary sites and regional disease in this group coupled with the small size of our study.

  16. The role of nitric oxide in prostaglandin biology; update

    PubMed Central

    Kim, Sangwon F.

    2011-01-01

    The biosynthesis of nitric oxide (NO) and prostaglandin share many similarities. Two major forms of nitric oxide synthase (NOS) and cyclooxygenase (COX) have been identified: constitutive vs inducible. In general, the constitutive form functions in housekeeping and physiologic roles whereas the inducible form is up-regulated by mitogenic or inflammatory stimuli and is responsible for pathophysiological responses. The cross talk between the COX and NOS pathways was initially reported 1993 and since then, numerous studies have been undertaken to delineate the functional consequences of this interaction as well as the potential mechanism by which each pathway interacts. This review will focus in particular on recent advances in this field that extend our understanding of these two pathways under various systems. PMID:21820072

  17. Hydrogen peroxide induces spawning in mollusks, with activation of prostaglandin endoperoxide synthetase.

    PubMed

    Morse, D E; Duncan, H; Hooker, N; Morse, A

    1977-04-15

    Addition of hydrogen peroxide to seawater causes synchronous spawning in gravid male and female abalones, and certain other mollusks as well. This effect is blocked by exposure of the animals to aspirin, an inhibitor of the enzyme catalyzing oxidative synthesis of prostaglandin endoperoxide. Hydrogen peroxide activates this enzymatic reaction in cell-free extracts prepared from abalone eggs (a very rich source of the prostaglandin endoperoxide synthetase); this effect appears to reveal a fundamental property of prostaglandin endoperoxide synthesis. Applicability of these findings to both mariculture and medical purposes is suggested. PMID:403609

  18. Expression of gastric antisecretory and prostaglandin E receptor binding activity of misoprostol by misoprostol free acid.

    PubMed

    Tsai, B S; Kessler, L K; Stolzenbach, J; Schoenhard, G; Bauer, R F

    1991-05-01

    In enriched canine parietal cell preparations, misoprostol, an analog of prostaglandin E1 methyl ester, was rapidly deesterified to misoprostol free acid. Under this circumstance, misoprostol and misoprostol free acid exhibited equal antisecretory potency against histamine-stimulated acid secretion and bound equally well to prostaglandin E receptors. When the deesterification of misoprostol was inhibited by paraoxon, an esterase inhibitor, the antisecretory and receptor binding activity of misoprostol was markedly reduced, with potency much less than misoprostol free acid. These results indicate that misoprostol free acid is the active biological form of misoprostol that binds to prostaglandin E receptors and mediates the antisecretory action of misoprostol. PMID:1850690

  19. Acute Hemoperitoneum after Administration of Prostaglandin E2 for Induction of Labour

    PubMed Central

    Zhang, Zhenyu; Lou, Jiangyan

    2015-01-01

    Prostaglandin E2 is widely used in obstetrics and is thought to be relatively safe for cervical ripening and induction of labour. Here we present a case in which acute hemoperitoneum was observed after administration of prostaglandin E2 in a pregnant woman. The patient had a history of endometriosis, and a severe pelvic adhesion (ASRM stage IV) was found during her last laparoscopic surgery 3 years previously. In cases with endometriosis, use of prostaglandin E2 for induction of labour in pregnant women must be done cautiously. PMID:26495145

  20. Treatment of renal colic by prostaglandin synthetase inhibitors and avafortan (analgesic antispasmodic).

    PubMed

    el-Sherif, A E; Foda, R; Norlen, L J; Yahia, H

    1990-12-01

    In a study of the pain-relieving effect of 3 drugs commonly used to treat acute renal colic in this hospital, intravenous indomethacin and intramuscular diclofenac (prostaglandin synthetase inhibitors) were compared with intravenous Avafortan (analgesic antispasmodic). As first-line analgesics, prostaglandin synthetase inhibitors, if given intravenously, offer an effective alternative to Avafortan. Of 145 patients studied, 32 required a second injection for complete relief of pain. Administering a second dose of prostaglandin synthetase inhibitors resulted in equally significant pain relief rate even though the route was intramuscular. PMID:2265331

  1. Fetal placental prostaglandin metabolism in the peripartum cow

    SciTech Connect

    Gross, T.S.; Williams, W.F.; Lewis, G.S.

    1986-03-05

    Previous results demonstrate that fetal placental tissue synthesizes prostaglandin E (PGE) prior to parturition. When placental membranes do not separate postpartum, PGE synthesis is maintained, while prostaglandin F (PGF) synthesis predominates when the membranes separate. Concurrent with separation is a decline in fetal placental binucleate cell (BNC) numbers. These data suggest a fetal placental conversion of PGE to PGF. For this experiment, placentomes were collected at ten days prepartum (PRE, n=12) and within 1 hr postpartum. Nine of the postpartum animals had fetal membrane separation within 12 hr postpartum (S) and eight did not exhibit membrane separation (NS). For each placentome, fetal (villi) components were manually isolated and examined for the ability to interconvert /sup 3/H labeled PGE/sub 2/ and PGF/sub 2/. All villi were unable to convert PGE/sub 2/ to PGF/sub 2/ (P > .05). The PRE and NS villi were able to convert PGF/sub 2/ to PGE/sub 2/ (P < .05) while S villi could not. When the BNC decline in numbers, as in the S villi, the ability to convert PGF/sub 2/ to PGE/sub 2/ (P < .05) while S villi could not. When the BNC decline in numbers, as in the S villi, the ability to convert PGF/sub 2/ to PGE/sub 2/ also declines (P < .05). These data suggest that peripartum fetal placental tissue might synthesize PGF which is then converted to PGE. It is possible that the BNC are directly converting PGF to PGE or that they are modulating this conversion. Therefore, with a decline in BNC numbers, PGF synthesis would predominate.

  2. Antitumor immune reaction elicited by photodynamic therapy

    NASA Astrophysics Data System (ADS)

    Korbelik, Mladen

    1999-06-01

    This work examines why photodynamic therapy (PDT) is capable of eliciting a strong immune reaction against treated solid tumors. It is postulated that this phenomenon originates from the basic charter of the insult inflicted by the photodynamic treatment, which is dominated by singlet oxygen-mediated oxidative stress. The early event associated with this initial impact, which is of major relevance for the development of immune response, is the generation of photo-oxidative lesions responsible for the activation of cellular signal transduction pathways and consequent induction of stress proteins. Importantly, these lesions, as well as other types of PDT mediated oxidative injury, have a strong pro-inflammatory character. It is suggested that the antitumor immune response is primed and propagated by the PDT-induced inflammatory process. Of critical importance for the immune recognition of treated tumor is the generation of large amounts of cancer cell debris that occurs rapidly following PDT treatment.

  3. Augmenting Usability: Cultural Elicitation in HCI

    NASA Astrophysics Data System (ADS)

    Camara, Souleymane Boundaouda; Oyugi, Cecilia; Abdelnour-Nocera, José; Smith, Andy

    This paper offers context and culture elicitation in an inter-cultural and multi-disciplinary setting of ICT design. Localised usability evaluation (LUE) is augmented with a socio-technical evaluation tool (STEM) as a methodological approach to expose and address issues in a collaborative ICT design within the Village e-Science for Life (VeSeL) project in rural Kenya. The paper argues that designers need to locally identify context and culture in situ and further explicate their implications through the design process and at the global level. Stakeholders' context, culture, decisions, agendas, expectations, disciplines and requirements need to be locally identified and globally evaluated to ensure a fit for purpose solution.

  4. Eliciting consumer preferences for health plans.

    PubMed Central

    Booske, B C; Sainfort, F; Hundt, A S

    1999-01-01

    OBJECTIVE: To examine (1) what people say is important to them in choosing a health plan; (2) the effect, if any, that giving health plan information has on what people say is important to them; and (3) the effect of preference elicitation methods on what people say is important. DATA SOURCES/STUDY SETTINGS: A random sample of 201 Wisconsin state employees who participated in a health plan choice experiment during the 1995 open enrollment period. STUDY DESIGN: We designed a computer system to guide subjects through the review of information about health plan options. The system began by eliciting the stated preferences of the subjects before they viewed the information, at time 0. Subjects were given an opportunity to revise their preference structures first after viewing summary information about four health plans (time 1) and then after viewing more extensive, detailed information about the same options (time 2). At time 2, these individuals were also asked to rate the relative importance of a predefined list of health plan features presented to them. DATA COLLECTION/EXTRACTION METHODS: Data were collected on the number of attributes listed at each point in time and the importance weightings assigned to each attribute. In addition, each item on the attribute list was content analyzed. PRINCIPAL FINDINGS: The provision of information changes the preference structures of individuals. Costs (price) and coverage dominated the attributes cited both before and after looking at health plan information. When presented with information on costs, quality, and how plans work, many of these relatively well educated consumers revised their preference structures; yet coverage and costs remained the primary cited attributes. CONCLUSIONS: Although efforts to provide health plan information should continue, decisions on the information to provide and on making it available are not enough. Individuals need help in understanding, processing, and using the information to construct

  5. The release of prostaglandin E2 from the skin of the plaice, Pleuronectes platessa L.

    PubMed Central

    Anderson, A. A.; Fletcher, T. C.; Smith, G. M.

    1979-01-01

    1 A fungal extract which produces a cutaneous hypersensitivity reaction in the plaice, Pleuronectes platessa L., was incubated in vitro with the skin of this teleost fish. Samples of incubation media were assayed for smooth muscle stimulating activity. 2 Prostaglandin E2 was identified by bioassay, thin-layer chromatography, ultraviolet absorption spectroscopy and gas chromatography--mass spectrometry. Release from challenged skin was maximum after 60 min incubation. 3 Analysis of the fatty acid composition of plaice skin showed that although arachidonic acid was present (3% of total fatty acids), the precursor of prostaglandin E3, eicosapentaenoic acid contributed 9% of total. 4 Indomethacin (50 mg/kg i.p) did not inhibit the erythema induced by the fungal extract, whilst a dose of 1 mg/kg maximally inhibited prostaglandin release from skin on incubation in vitro. 5 It is concluded that prostaglandins do not have an exclusive role in the mediation of the hypersensitivity reaction. PMID:465893

  6. Management of severe preeclampsia detected in early labor by prostaglandin A1 or dihydralazine infusions.

    PubMed

    Toppozada, M K; Darwish, E; Barakat, A A

    1991-05-01

    The presence of severe pregnancy-induced hypertension at the onset of labor requires therapy with a potent hypotensive agent. Prostaglandin A1 is a powerful vasodepressor that augments renal blood flow and glomerular filtration and possesses antiplatelet aggregator and oxytocic properties. A continuous intravenous infusion of prostaglandin A1 (40 to 50 micrograms/min) or dihydralazine (35 to 50 micrograms/min) was administered to 20 women with severe preeclampsia (10 in each group). The induced hypotensive response was similar with both drugs but the maximum reduction in blood pressure was achieved sooner with dihydralazine (4 hours) compared with prostaglandin A1 (7.5 hours). The more gradual hypotensive response is probably less dangerous on placental perfusion than a sudden change. Moreover, the oxytocic property of prostaglandin A1 shortened the time to delivery, which constitutes another potential advantage. PMID:2035562

  7. Determination of prostaglandin analogs in cosmetic products by high performance liquid chromatography with tandem mass spectrometry.

    PubMed

    Wittenberg, James B; Zhou, Wanlong; Wang, Perry G; Krynitsky, Alexander J

    2014-09-12

    A method was developed and validated for the determination of 16 prostaglandin analogs in cosmetic products. The QuEChERS (Quick, Easy, Cheap, Efficient, Rugged, Safe) liquid-liquid extraction method, typically used for pesticide residue analysis, was utilized as the sample preparation technique. The prostaglandin analogs were chromatographically separated and quantified using high performance liquid chromatography with tandem mass spectrometry (HPLC-MS/MS). Thirty-one cosmetic products were surveyed, and 13 products were determined to contain a prostaglandin analog with amounts ranging from 27.4 to 297μg/g. The calculated concentrations for the cosmetic products were in a similar range when compared to the concentrations of three different prostaglandin analog-containing prescription products. PMID:25085824

  8. [Improved kidney function with intravenous prostaglandin E1 in patients with terminal heart failure].

    PubMed

    Wutte, M; Hülsmann, M; Berger, R; Rödler, S; Frey, B; Stanek, B; Pacher, R

    1998-07-31

    In end stage congestive heart failure activation of a series of compensatory mechanisms increase renal vascular resistance and impair renal function. Prostaglandin E1 is increasingly used in the treatment of severe heart failure for its vasodilating actions. In various experimental settings prostaglandin E analogues are known to improve renal function by modulating renal filtration pressure and redistribution of renal blood flow. However, prostaglandin E1 decreases systemic blood pressure and thus, also renal perfusion pressure, a fact by which renal function might be further compromized in heart failure patients. The aim of the study was to evaluate the effects of prostaglandin E1 on excretory renal function in patients with end stage heart failure and to prove the hypothesis, that the well known local actions of prostaglandins on renal microcirculation might outweigh the negative impact of an expected decrease in perfusion pressure. 25 patients with terminal congestive heart failure were investigated. 13 patients received prostaglandin E1 at a dose of 13.5 +/- 1.9 ng/kg/min in combination with constant rates of dopamine and dobutamine (group A), 12 patients received prostaglandin E1 at a dose of 10.3 +/- 1.7 ng/kg/min without catecholamines (group B). There was no significant difference in prostaglandin dosages between groups. Kidney function was assessed by measuring plasma creatinine and urea nitrogen, urinary output, creatinine clearance, osmotic and free water clearance at baseline and after 72 h of infusion therapy. Hemodynamic parameters were measured by using a balloon tipped pulmonary arterial catheter. Hemodynamic measurements during infusion showed a significant improvement in all patients. At the same time as expected mean arterial pressure decreased in both groups (p < 0.001). Nevertheless, in both groups a significant increase of creatinine clearance during infusion was observed (in group A from 45 ml/min to 78 ml/min., p < 0.05, in group B from 59

  9. Dioscorea japonica extract down-regulates prostaglandin E2 synthetic pathway and induces apoptosis in lung cancer cells

    PubMed Central

    Suzuki-Yamamoto, Toshiko; Tanaka, Sayuri; Tsukayama, Izumi; Takafuji, Miki; Hanada, Takae; Arakawa, Toshiya; Kawakami, Yuki; Kimoto, Masumi; Takahashi, Yoshitaka

    2014-01-01

    Prostaglandin E2 plays a role in an array of pathophysiological responses, including inflammation, carcinogenesis and so on. Prostaglandin E2 is synthesized from arachidonic acid by the enzymes cyclooxygenase and prostaglandin E synthase. In some pathological conditions, the isozymes cyclooxygenase-2 and microsomal prostaglandin E synthase-1 are transiently induced, leading to prostaglandin E2 overproduction. The present study showed that Dioscorea japonica extract suppresses mRNA expression of cyclooxygenase-2 and microsomal prostaglandin E synthase-1 in human non-small-cell lung carcinoma A549 cells in a dose-dependent manner. The suppressive effects of Dioscorea japonica extract on the expression of cyclooxygenase-2 and microsomal prostaglandin E synthase-1 were confirmed by Western blotting, cyclooxygenase activity and prostaglandin E2 production. Dioscorea japonica extract induced the translocation of nuclear factor-κB from the nucleus to the cytosol and inhibited the activity of the cyclooxygenase-2 promoter. Furthermore Dioscorea japonica extract suppressed the expression of the anti-apoptotic factor B-cell chronic lymphocytic leukemia/lymphoma 2 and enhanced apoptotic terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling-positive intensity in A549 cells. These results suggest that Dioscorea japonica extract suppresses the expression of cyclooxygenase-2 and microsomal prostaglandin E synthase-1, with the regulation of the transcriptional activity of cyclooxygenase-2, and induces apoptosis in cancer cells. Thus, Dioscorea japonica may contribute to the prevention of prostaglandin E2-mediated pathophysiological responses such as carcinogenesis and inflammation. PMID:25411520

  10. Web-based tool for expert elicitation of the variogram

    NASA Astrophysics Data System (ADS)

    Truong, Phuong N.; Heuvelink, Gerard B. M.; Gosling, John Paul

    2013-02-01

    The variogram is the keystone of geostatistics. Estimation of the variogram is deficient and difficult when there are no or too few observations available due to budget constraints or physical and temporal obstacles. In such cases, expert knowledge can be an important source of information. Expert knowledge can also fulfil the increasing demand for an a priori variogram in Bayesian geostatistics and spatial sampling optimization. Formal expert elicitation provides a sound scientific basis to reliably and consistently extract knowledge from experts. In this study, we aimed at applying existing statistical expert elicitation techniques to extract the variogram of a regionalized variable that is assumed to have either a multivariate normal or lognormal spatial probability distribution from expert knowledge. To achieve this, we developed an elicitation protocol and implemented it as a web-based tool to facilitate the elicitation of beliefs from multiple experts. Our protocol has two main rounds: elicitation of the marginal probability distribution and elicitation of the variogram. The web-based tool has three main components: a web interface for expert elicitation and feedback; a component for statistical computation and mathematical pooling of multiple experts' knowledge; and a database management component. Results from a test case study show that the protocol is adequate and that the online elicitation tool functions satisfactorily. The web-based tool is free to use and supports scientists to conveniently elicit the variogram of spatial random variables from experts. The source code is available from the journal FTP site under the GNU General Public License.

  11. Expert Elicitation of Population-Level Effects of Disturbance.

    PubMed

    Fleishman, Erica; Burgman, Mark; Runge, Michael C; Schick, Robert S; Kraus, Scott

    2016-01-01

    Expert elicitation is a rigorous method for synthesizing expert knowledge to inform decision making and is reliable and practical when field data are limited. We evaluated the feasibility of applying expert elicitation to estimate population-level effects of disturbance on marine mammals. Diverse experts estimated parameters related to mortality and sublethal injury of North Atlantic right whales (Eubalaena glacialis). We are now eliciting expert knowledge on the movement of right whales among geographic regions to parameterize a spatial model of health. Expert elicitation complements methods such as simulation models or extrapolations from other species, sometimes with greater accuracy and less uncertainty. PMID:26610972

  12. Prostaglandin synthesis by chicken and rat lung microsomes

    SciTech Connect

    Craig-Schmidt, M.C.; Faircloth, S.A.; Wu-Wang, C.Y.

    1986-03-01

    A comparison between chicken and rat lung was made for microsomal prostaglandin (PG) synthesis from 1-/sup 14/C-arachidonic acid. Microsomal protein (2.0 mg) from chicken or rat lung was incubated in the presence of 20 ..mu..g of 1-/sup 14/C-arachidonic acid (specific activity = 3 x 10/sup 6/ dpm/..mu..mol for chicken; 6 x 10/sup 6/ dpm/..mu..mol for rat), 0.05 M Tris-HCl buffer (pH = 8.0), 0.5 mM epinephrine, and 1 mM reduced glutathione in a total volume of 0.5 ml in a 37/sup 0/C water bath with shaking for 15 min. After acidification with 1 M HCl to pH 3, prostaglandins were extracted with ethyl acetate. The products of the reactions were separated by reversed phase chromatography, and the radioactivity of each prostanoid fraction was determined. The predominant prostanoid synthesized by chicken lung microsomes was PGE/sub 2/, followed by much lower amounts of thromboxane B/sub 2/ (TXB/sub 2/), PGF/sub 2//sub ..cap alpha../ and PGD/sub 2/. In at lung, 6-keto-PGF/sub 1//sub ..cap alpha../ was the predominant product formed, with minor amounts of 6-keto-PGE/sub 1/, TXB/sub 2/, PGF/sub 2//sub ..cap alpha../ and PGD/sub 2/. In rat lung, 6-keto-FGF/sub 1//sub ..cap alpha../ was the predominant product formed, with minor amounts of 6-keto-PGF/sub 1//sub ..cap alpha../ was the predominant product formed, with minor amounts of 6-keto-PGE/sub 1/, TXB/sub 2/, PGF/sub 2//sub ..cap alpha../, PGE/sub 2/ and PGD/sub 2/ being formed. Enzyme specific activity (pmol of PG produced per mg microsomal protein per min) was 11.9 for PGE/sub 2/ produced by chicken lung and 16. 7 for 6-keto-P/sub 1//sub ..cap alpha../ produced by rat lung. Thus, there appears to be a species variation in chicken compared to rat for the lung prostanoids which are known to cause bronchial dilation.

  13. Intraocular pressure-lowering combination therapies with prostaglandin analogues.

    PubMed

    Aptel, Florent; Chiquet, Christophe; Romanet, Jean-Paul

    2012-07-01

    Intraocular pressure (IOP) reduction is currently the only therapeutic approach demonstrated to preserve visual function in patients with glaucoma. The first line of glaucoma treatment consists of topical IOP-lowering medications, usually initiated as monotherapy. A significant proportion of patients require more than one medication to reach a target IOP at which optic nerve damage will not progress. As prostaglandin analogues (PGAs) are the most effective class for reducing IOP, one of the other commonly used classes (β-adrenoceptor antagonist [β-blocker], carbonic anhydrase inhibitor or α(2)-adrenoceptor agonist) is frequently combined with a PGA. In the last decade, the use of fixed combinations containing two medications in a single bottle has steadily increased. Fixed combinations have the potential to simplify the dosing regimen, increase patient adherence, avoid the washout effect of the second drop on the first medication instilled, decrease exposure to preservatives and, sometimes, reduce the cost of treatment. Clinical trials have evaluated PGA-based fixed combinations versus unfixed combinations (individual components administered concomitantly) or versus individual monotherapies; however, any advantage that the fixed combinations may have in terms of IOP-lowering efficacy is still debated. For these reasons, the PGA-based fixed combinations are not approved by regulatory authorities in some countries, such as the US. We review the published studies evaluating the efficacy and tolerability of the IOP-lowering unfixed and fixed combination therapies with PGAs. Regarding unfixed combinations, the review shows that α(2)-adrenergic agonists-PGA and carbonic anhydrase inhibitor-PGA combinations seem to be at least as effective at reducing IOP as the β-blocker-PGA combinations. As for the fixed combinations, the review shows that the three PGA-timolol fixed combinations are more effective than their component medications used separately as monotherapy and

  14. Acting green elicits a literal warm glow

    NASA Astrophysics Data System (ADS)

    Taufik, Danny; Bolderdijk, Jan Willem; Steg, Linda

    2015-01-01

    Environmental policies are often based on the assumption that people only act environmentally friendly if some extrinsic reward is implicated, usually money. We argue that people might also be motivated by intrinsic rewards: doing the right thing (such as acting environmentally friendly) elicits psychological rewards in the form of positive feelings, a phenomenon known as warm glow. Given the fact that people's psychological state may affect their thermal state, we expected that this warm glow could express itself quite literally: people who act environmentally friendly may perceive the temperature to be higher. In two studies, we found that people who learned they acted environmentally friendly perceived a higher temperature than people who learned they acted environmentally unfriendly. The underlying psychological mechanism pertains to the self-concept: learning you acted environmentally friendly signals to yourself that you are a good person. Together, our studies show that acting environmentally friendly can be psychologically rewarding, suggesting that appealing to intrinsic rewards can be an alternative way to encourage pro-environmental actions.

  15. Music can elicit a visual motion aftereffect.

    PubMed

    Hedger, Stephen C; Nusbaum, Howard C; Lescop, Olivier; Wallisch, Pascal; Hoeckner, Berthold

    2013-07-01

    Motion aftereffects (MAEs) are thought to result from the adaptation of both subcortical and cortical systems involved in the processing of visual motion. Recently, it has been reported that the implied motion of static images in combination with linguistic descriptions of motion is sufficient to elicit an MAE, although neither factor alone is thought to directly activate visual motion areas in the brain. Given that the monotonic change of musical pitch is widely recognized in music as a metaphor for vertical motion, we investigated whether prolonged exposure to ascending or descending musical scales can also produce a visual motion aftereffect. After listening to ascending or descending musical scales, participants made decisions about the direction of visual motion in random-dot kinematogram stimuli. Metaphoric motion in the musical stimuli did affect the visual direction judgments, in that repeated exposure to rising or falling musical scales shifted participants' sensitivity to visual motion in the opposite direction. The finding that music can induce an MAE suggests that the subjective interpretation of monotonic pitch change as motion may have a perceptual foundation. PMID:23456973

  16. Prostaglandin signaling suppresses beneficial microglial function in Alzheimer's disease models.

    PubMed

    Johansson, Jenny U; Woodling, Nathaniel S; Wang, Qian; Panchal, Maharshi; Liang, Xibin; Trueba-Saiz, Angel; Brown, Holden D; Mhatre, Siddhita D; Loui, Taylor; Andreasson, Katrin I

    2015-01-01

    Microglia, the innate immune cells of the CNS, perform critical inflammatory and noninflammatory functions that maintain normal neural function. For example, microglia clear misfolded proteins, elaborate trophic factors, and regulate and terminate toxic inflammation. In Alzheimer's disease (AD), however, beneficial microglial functions become impaired, accelerating synaptic and neuronal loss. Better understanding of the molecular mechanisms that contribute to microglial dysfunction is an important objective for identifying potential strategies to delay progression to AD. The inflammatory cyclooxygenase/prostaglandin E2 (COX/PGE2) pathway has been implicated in preclinical AD development, both in human epidemiology studies and in transgenic rodent models of AD. Here, we evaluated murine models that recapitulate microglial responses to Aβ peptides and determined that microglia-specific deletion of the gene encoding the PGE2 receptor EP2 restores microglial chemotaxis and Aβ clearance, suppresses toxic inflammation, increases cytoprotective insulin-like growth factor 1 (IGF1) signaling, and prevents synaptic injury and memory deficits. Our findings indicate that EP2 signaling suppresses beneficial microglia functions that falter during AD development and suggest that inhibition of the COX/PGE2/EP2 immune pathway has potential as a strategy to restore healthy microglial function and prevent progression to AD. PMID:25485684

  17. Prostaglandin E2 causes hypoventilation and apnea in newborn lambs.

    PubMed

    Guerra, F A; Savich, R D; Wallen, L D; Lee, C H; Clyman, R I; Mauray, F E; Kitterman, J A

    1988-05-01

    To test the hypothesis that prostaglandin (PG) E2 is a respiratory depressant in the newborn lamb, 12 chronically catheterized, unanesthetized lambs (age 2-6 days) were infused with progressively increasing doses of PGE2 (0.1, 0.5, 1.0, and 5.0 micrograms.kg-1.min-1; 30 min for each dose) into the ascending aorta. PGE2 caused significant progressive decreases in ventilation (due to decreased tidal volume and breathing rate), heart rate, blood pressure, and percent of the time spent in low-voltage electrocortical activity (LVA). PGE2 also caused respiratory acidosis, hypoxemia, and increased frequency and duration of apneic events (greater than 3 s). During the infusion there was a dose-related increase in plasma concentration of PGE2. At 30 min postinfusion, all measured variables showed recovery, although arterial pH, CO2 tension, and plasma PGE2 remained significantly different from control values, and the percent time in LVA was even higher than during control. Infusion of the vehicle alone (n = 5) caused no significant changes in any of the measured variables. The results, taken in combination with previous fetal studies, indicate that PGE2 has marked inhibitory effects on breathing movements both before and after birth. PMID:3164715

  18. Sequential induction of prostaglandin E and D synthases in inflammation

    SciTech Connect

    Schuligoi, Rufina . E-mail: rufina.schuligoi@meduni-graz.at; Grill, Magdalena; Heinemann, Akos; Peskar, Bernhard A.; Amann, Rainer

    2005-09-30

    Enhanced biosynthesis of prostaglandin (PG)D{sub 2} and subsequent formation of 15-deoxy-{delta}{sup 12,14}-PGJ{sub 2} has been suggested to contribute to resolution of inflammation. The primary aim of the present study in mouse heart was, therefore, to determine at the transcriptional level if there is sequential induction of PGE and PGD synthases (S) during inflammation. Expression of interleukin (IL)-1{beta} in heart was enhanced 4 h after systemic inflammation and declined thereafter within 3-5 days to basal levels. In contrast to cyclooxygenase-2 and membrane-bound (m)-PGES-1, which both peaked 4 h after endotoxin administration, hematopoietic (H)-PGDS expression was enhanced only 48 h after endotoxin. The expression of lipocalin-type (L)-PGDS was not significantly influenced. mRNA encoding the putative target of 15-deoxy-{delta}{sup 12,14}-PGJ{sub 2}, peroxisome proliferator-activated receptor {gamma}, was enhanced between 4 and 24 h after induction of inflammation. Treatment of mice with acetylsalicylic acid or indomethacin at doses effective to cause near-complete inhibition of PGE{sub 2} and PGD{sub 2} biosynthesis in heart ex vivo resulted in enhanced expression of IL-1{beta} 24 h after endotoxin administration. These results provide additional support for the hypothesis of a shift towards PGD{sub 2} biosynthesis during resolution of inflammation.

  19. Influence of prostaglandin E2 on parturition in cattle.

    PubMed

    Hirsbrunner, G; Zanolari, P; Althaus, H; Hüsler, J; Steiner, A

    2007-09-22

    A double-blinded, randomised, placebo-controlled field study of the influence of prostaglandin E2 (PGE2) on cattle at parturition was carried out. The extent of cervical opening and the intensity of labour were scored before administration of the compound and 10 minutes later; routine birth assistance was then continued by the veterinarian. Successful birth occurred more quickly in the cows treated with PGE2. The extent of cervical opening before the administration of the drug had a significant effect on the time to delivery, but the intensity of labour and a concomitant infusion of calcium did not have significant effects on this period. The less open the cervix before administration of the drug, the more the duration of parturition differed between the two groups, with the placebo group taking longer. A telephone follow-up inquiry found no significant differences between the cows postpartum; there were cases of mastitis and hypocalcaemia in both groups. The incidence of retained fetal membranes and the mortality of the calves were higher in the placebo group, but in neither case was the difference significant. PMID:17890770

  20. Prostaglandin E2 Prevents Disuse-Induced Cortical Bone Loss

    NASA Technical Reports Server (NTRS)

    Jee, Webster S. S.; Akamine, T.; Ke, Hua Zhu; Li, Xiao Jian; Tang, L. Y.; Zeng, Q. Q.

    1992-01-01

    The object of this study was to determine whether prostaglandin E2 (PGE2) can prevent disuse (underloaded)-induced cortical bone loss as well as add extra bone to underloaded bones. Thirteen-month-old retired female Sprague-Dawley breeders served as controls or were subjected to simultaneous right hindlimb immobilization by bandaging and daily subcutaneous doses of 0, 1, 3, or 6 mg PGE2/kg/d for two and six weeks. Histomorphometric analyses were performed on double-fluorescent labeled undecalcified tibial shaft sections (proximal to the tibiofibular junction). Disuse-induced cortical bone loss occurred by enlarging the marrow cavity and increasing intracortical porosity. PGE2 treatment of disuse shafts further increased intracortical porosity above that in disuse alone controls. This bone loss was counteracted by enhancement of periosteal and corticoendosteal bone formation. Stimulation of periosteal and corticoendosteal bone formation slightly enlarged the total tissue (cross-sectional) area and inhibited marrow cavity enlargement. These PGE2-induced activities netted the same percentage of cortical bone with a different distribution than the beginning and age related controls. These findings indicate the PGE2-induced increase in bone formation compensated for the disuse and PGE2-induced bone loss, and thus prevented immobilization induced bone loss.

  1. Anuran calling circuits: inhibition of pretrigeminal nucleus by prostaglandin.

    PubMed

    Schmidt, R S

    1993-03-01

    Neural correlates of mating calling and pulmonary respiration were recorded from isolated brain stems of male Northern leopard frogs (Rana p. pipiens) before and after exposure of the brain stems to prostaglandin F2 alpha (PG) or saline. Diffusion of PG (but not saline) from a pipette directly over the pretrigeminal nuclei abolished "calling" temporarily. Similar application of PG nearby had no effect. Exposure of only the anterior 1/2 of the brain stem, containing the pretrigeminal nuclei but not the pulmonary respiration generator, to PG (but not saline) abolished generation of slow waves by the pretrigeminal nucleus portion of the mating calling pattern generator. Exposure of only the posterior 1/2 of the brain stem, containing the pulmonary respiration generator but not the pretrigeminal nuclei, to PG had no effect on the correlates of pulmonary respiration. These results are consistent with the hypothesis that the inhibition of calling by PG is through an effect largely, perhaps exclusively, on the pretrigeminal nuclei. PMID:8440519

  2. Renal Effects of Prostaglandins and Cyclooxygenase-2 Inhibitors

    PubMed Central

    2008-01-01

    Prostaglandins (PGs) with best-defined renal functions are PGE2 and prostacyclin (PGI2). These vasodilatory PGs increase renal blood flow and glomerular filtration rate under conditions associated with decreased actual or effective circulating volume, resulting in greater tubular flow and secretion of potassium. Under conditions of decreased renal perfusion, the production of renal PGs serves as an important compensatory mechanism. PGI2 (and possibly PGE2) increases potassium secretion mainly by stimulating secretion of renin and activating the renin-angiotensin system, which leads to increased secretion of aldosterone. In addition, PGE2 is involved in the regulation of sodium and water reabsorption and acts as a counterregulatory factor under conditions of increased sodium reabsorption. PGE2 decreases sodium reabsorption at the thick ascending limb of the loop of Henle probably via inhibition of the Na+-K+-2Cl- cotransporter type 2 (NKCC2). Cyclooxygenase inhibitors may enhance urinary concentrating ability in part through effects to upregulate NKCC2 in the thick ascending limb of Henle's loop and aquaporin-2 in the collecting duct. Thus, they may be useful to treat Bartter's syndrome and nephrogenic diabetes insipidus. PMID:24459520

  3. The prostaglandin transporter (PGT) as a potential mediator of ovulation.

    PubMed

    Yerushalmi, Gil M; Markman, Svetlana; Yung, Yuval; Maman, Ettie; Aviel-Ronen, Sarit; Orvieto, Raoul; Adashi, Eli Y; Hourvitz, Ariel

    2016-05-11

    Prostaglandins (PGs) play an important role in the ovulatory process. However, the role of the PG transporter (PGT) in this context remains unknown. We report that the expression of PGT, a transmembrane PG carrier protein, is markedly up-regulated in preovulatory human granulosa cells (GCs). Treatment with human chorionic gonadotropin (hCG), an ovulatory trigger, significantly increases the expression of PGT mRNA and protein in human GCs both in vivo and in vitro. The hCG-induced increase in the expression of PGT in cultured human GCs is mediated via protein kinase A and protein kinase C by way of the extracellular signal-regulated kinase pathway. PGT in cultured human GCs mediates the uptake of PGE2, thereby regulating its extracellular concentration. In vivo treatment of mice with PGT inhibitors effectively blocks ovulation and markedly attenuates the expression of key ovulatory genes. We hypothesize that the inhibition of PGT activity in GCs increases the extracellular concentration of PGE2, the ability of which to exert its ovulatory effect is compromised by desensitization of its cognate receptors. Together, these findings support the idea that PGT is an important mediator of ovulation and that its inhibitors may be viewed as potential candidates for nonhormonal contraception. These findings may also fill the gap in the understanding of PGT signaling, enhance the understanding of ovulatory disorders, and facilitate the treatment of infertility or subfertility in women by using nonsteroidal PG-based therapeutic approaches. PMID:27169804

  4. Developmental changes of prostaglandin processing in rat small intestine

    SciTech Connect

    Koldovsky, O.; Bedrick, A.

    1986-03-01

    Cytoprotective prostaglandins are present in milk and can be absorbed intact from the gastrointestinal tract in suckling animals. To examine developmental changes in intestinal metabolism of PGF/sub 2..cap alpha../, everted sacs of small intestinal segments in suckling and weanling rats were prepared. Incubation (60 min) was performed in KRB buffer, pH 7.4 at 37/sup 0/C. Bathing mucosal fluid (MF) contained /sup 3/H-PGF/sub 2..cap alpha../. MF, intestinal wall (IW) and serosal fluid (SF) were analyzed quantitatively for total radioactivity, and qualitatively by organic solvent extraction followed by thin layer chromatography. Changes in MF radioactivity were minimal after incubation. SU had greater capacity for PGF/sub 2..cap alpha../ transfer into SF. Compared to WE, SU had greater proportion of intact, unmetabolized PGF/sub 2..cap alpha../ present in IW of all intestinal segments; i.e., in middle segment: 32.9% +/- 4.5 (mean +/- SEM) vs 17.1% +/- 2.4 (N = 6/group; p < 0.2). WE had more nonpolar PGF/sub 2..cap alpha../ degradation products present. In each age group, chromatographic patterns of IW and SF were similar for each intestinal region. Intestinal everted sacs of SU and WE transfer PGF/sub 2..cap alpha../. SU have a greater proportion and amount of unmetabolized PGF/sub 2..cap alpha../ present in IW and SF than WE. Possible functional significance to the integrity of intestinal mucosal of sucklings has to be considered.

  5. Prostaglandin-E2 Mediated Increase in Calcium and Phosphate Excretion in a Mouse Model of Distal Nephron Salt Wasting

    PubMed Central

    Soleimani, Manoocher; Barone, Sharon; Xu, Jie; Alshahrani, Saeed; Brooks, Marybeth; McCormack, Francis X.; Smith, Roger D.; Zahedi, Kamyar

    2016-01-01

    Contribution of salt wasting and volume depletion to the pathogenesis of hypercalciuria and hyperphosphaturia is poorly understood. Pendrin/NCC double KO (pendrin/NCC-dKO) mice display severe salt wasting under basal conditions and develop profound volume depletion, prerenal renal failure, and metabolic alkalosis and are growth retarded. Microscopic examination of the kidneys of pendrin/NCC-dKO mice revealed the presence of calcium phosphate deposits in the medullary collecting ducts, along with increased urinary calcium and phosphate excretion. Confirmatory studies revealed decreases in the expression levels of sodium phosphate transporter-2 isoforms a and c, increases in the expression of cytochrome p450 family 4a isotypes 12 a and b, as well as prostaglandin E synthase 1, and cyclooxygenases 1 and 2. Pendrin/NCC-dKO animals also had a significant increase in urinary prostaglandin E2 (PGE-2) and renal content of 20-hydroxyeicosatetraenoic acid (20-HETE) levels. Pendrin/NCC-dKO animals exhibit reduced expression levels of the sodium/potassium/2chloride co-transporter 2 (NKCC2) in their medullary thick ascending limb. Further assessment of the renal expression of NKCC2 isoforms by quantitative real time PCR (qRT-PCR) reveled that compared to WT mice, the expression of NKCC2 isotype F was significantly reduced in pendrin/NCC-dKO mice. Provision of a high salt diet to rectify volume depletion or inhibition of PGE-2 synthesis by indomethacin, but not inhibition of 20-HETE generation by HET0016, significantly improved hypercalciuria and salt wasting in pendrin/NCC dKO mice. Both high salt diet and indomethacin treatment also corrected the alterations in NKCC2 isotype expression in pendrin/NCC-dKO mice. We propose that severe salt wasting and volume depletion, irrespective of the primary originating nephron segment, can secondarily impair the reabsorption of salt and calcium in the thick ascending limb of Henle and/or proximal tubule, and reabsorption of sodium and

  6. Prostaglandin-E2 Mediated Increase in Calcium and Phosphate Excretion in a Mouse Model of Distal Nephron Salt Wasting.

    PubMed

    Soleimani, Manoocher; Barone, Sharon; Xu, Jie; Alshahrani, Saeed; Brooks, Marybeth; McCormack, Francis X; Smith, Roger D; Zahedi, Kamyar

    2016-01-01

    Contribution of salt wasting and volume depletion to the pathogenesis of hypercalciuria and hyperphosphaturia is poorly understood. Pendrin/NCC double KO (pendrin/NCC-dKO) mice display severe salt wasting under basal conditions and develop profound volume depletion, prerenal renal failure, and metabolic alkalosis and are growth retarded. Microscopic examination of the kidneys of pendrin/NCC-dKO mice revealed the presence of calcium phosphate deposits in the medullary collecting ducts, along with increased urinary calcium and phosphate excretion. Confirmatory studies revealed decreases in the expression levels of sodium phosphate transporter-2 isoforms a and c, increases in the expression of cytochrome p450 family 4a isotypes 12 a and b, as well as prostaglandin E synthase 1, and cyclooxygenases 1 and 2. Pendrin/NCC-dKO animals also had a significant increase in urinary prostaglandin E2 (PGE-2) and renal content of 20-hydroxyeicosatetraenoic acid (20-HETE) levels. Pendrin/NCC-dKO animals exhibit reduced expression levels of the sodium/potassium/2chloride co-transporter 2 (NKCC2) in their medullary thick ascending limb. Further assessment of the renal expression of NKCC2 isoforms by quantitative real time PCR (qRT-PCR) reveled that compared to WT mice, the expression of NKCC2 isotype F was significantly reduced in pendrin/NCC-dKO mice. Provision of a high salt diet to rectify volume depletion or inhibition of PGE-2 synthesis by indomethacin, but not inhibition of 20-HETE generation by HET0016, significantly improved hypercalciuria and salt wasting in pendrin/NCC dKO mice. Both high salt diet and indomethacin treatment also corrected the alterations in NKCC2 isotype expression in pendrin/NCC-dKO mice. We propose that severe salt wasting and volume depletion, irrespective of the primary originating nephron segment, can secondarily impair the reabsorption of salt and calcium in the thick ascending limb of Henle and/or proximal tubule, and reabsorption of sodium and

  7. Introducing Forum Theatre to Elicit and Advocate Children's Views

    ERIC Educational Resources Information Center

    Hammond, Nick

    2013-01-01

    Eliciting and advocating the voice of the child remains at the heart of international political agenda and also remains a central role for educational psychologists (EPs). Previous research indicates that EPs tend to use language-based methods for eliciting and advocating views of children. However, these approaches are often limited. Taking a…

  8. Science Teachers' Elicitation Practices: Insights for Formative Assessment

    ERIC Educational Resources Information Center

    Ateh, Comfort M.

    2015-01-01

    In evaluating teachers' instructional decisions during instruction, it is clear that the nature of their elicitation is crucial for student learning. When instructional decisions are informed by information about students' conceptual understanding, significant learning is possible. This article examined the elicitation practices of two high school…

  9. Freeze or Flee? Negative Stimuli Elicit Selective Responding

    ERIC Educational Resources Information Center

    Estes, Zachary; Verges, Michelle

    2008-01-01

    Humans preferentially attend to negative stimuli. A consequence of this automatic vigilance for negative valence is that negative words elicit slower responses than neutral or positive words on a host of cognitive tasks. Some researchers have speculated that negative stimuli elicit a general suppression of motor activity, akin to the freezing…

  10. Elicited Emotions and Cognitive Functioning in Preschool Children

    ERIC Educational Resources Information Center

    Blau, Rivka; Klein, Pnina S.

    2010-01-01

    In this study, the effects of eliciting positive and negative emotions on various cognitive functions of four- to five-year-old preschool children were examined. Emotions were elicited through presentations of "happy" and "sad" video clips, before the children performed the cognitive tasks. Behavioural (facial expressions) and physiological (heart…

  11. A facile reproducible radioimmunoassay of the mixed metabolites of prostaglandins E, suitable for measurement of relative differences of phospholipase/prostaglandin synthetase activity in vivo.

    PubMed

    Fretland, D J; Cammarata, P S

    1984-04-01

    A relatively simple, reproducible, radioimmunoassay for the mixed metabolites of prostaglandins E (U-PGE-M) in rat and human urine is described. Results of the assay of treated versus control urine extracts correlate well with differences expected from treatments known to alter in vivo phospholipase/prostaglandin synthetase activity. Cross-reactivity of heterogeneous metabolite antiserum with 5 available endogenous prostaglandins and a single metabolite was determined and showed little or no cross reaction. Sensitivity, within-assay precision, interassay reproducibility, and parallelism were also determined and found acceptable. Excretion rates of U-PGE-M by rats and humans were determined, and statistically significant differences could be shown, although absolute values were smaller than estimated absolute values obtained from mass-spectrometric measurements of single, purified metabolites. Normal human male excretion rates differed significantly from those of females. Injection of prostaglandin E1 caused a significant rise in U-PGE-M excretion in rats whereas aspirin and indomethacin caused it to fall. U-PGE-M excretion rates of spontaneous hypertensive rats were significantly less than rates of normotensive controls. Adrenalectomy resulted in excretion of significantly larger amounts of U-PGE-M than in normal or sham-operated controls. A screen of clinically active pharmacological agents and hormones gave results consistent with previously published reports. PMID:6427792

  12. Stage-dependent reduction in T colony formation in Hodgkin's disease. Coincidence with monocyte synthesis of prostaglandins.

    PubMed Central

    Bockman, R S

    1980-01-01

    Prostaglandin synthesis and T lymphocyte colony formation have been examined in previously untreated patients with Hodgkin's disease. Mononuclear cells have been isolated from peripheral blood and spleens of these patients. Significant augmentation in prostaglandin E levels were noted in the mononuclear cell cutures from Hodgkin's disease patients compared with controls (1.64 +/- 0.29 vs. 0.39 +/- 0.09 ng/10(6) cells, P < 0.005). Measured prostaglandin E levels increased with advancing stage of disease. Virtually all of the prostaglandins were synthesized by the adherent monocyte cell population. Prostaglandin E was the major product. Clonal expansion of a T lymphocyte precursor cell, which gives rise to colonies > 50 cells, was determined by a layered soft agar method. T colony formation was significantly reduced in patients with stage II, III, and IV disease. There were progressively reduced colony numbers seen with advancing stage of disease (609 +/- 209, 416 +/- 158, 207 +/- 58 compared with normals 2,274 +/- 360 colonies/10(6) cells plated; P < 0.005). The addition of inhibitors of endogenous prostaglandin synthesis resulted in significant augmentation of T colony number. However, a consistent relative decrease in T colony number was seen even when endogenous prostaglandin E synthesis was blocked. It would appear that both the prostaglandin-dependent and independent T colony precursor cells are lost with progressive stage of disease. A causative role of augmented prostaglandin synthesis in this stage-dependent reduction of T colony formation could not be established. PMID:6967491

  13. Prostaglandin F{sub 2{alpha}} regulates cytokine responses of mast cells through the receptors for prostaglandin E

    SciTech Connect

    Kaneko, Izumi; Hishinuma, Takanori; Suzuki, Kaori; Owada, Yuji; Kitanaka, Noriko; Kondo, Hisatake; Goto, Junichi; Furukawa, Hiroshi; Ono, Masao

    2008-03-14

    There is an increasing body of evidence that prostanoids modulate mast cell functions and contribute to the development of allergic inflammation. The present study aimed to identify an undetermined function of prostaglandin (PG) F{sub 2{alpha}} in mast cell activation and the signaling mechanism involved in it. Simultaneous quantification of prostanoids by liquid chromatography/tandem mass spectrometry revealed the constitutive release of PGF{sub 2{alpha}}, thromboxane B{sub 2}, and 6-keto-PGF{sub 1{alpha}} from bone marrow-derived mast cells (BMMCs). Upon activation of BMMCs by lipopolysaccharide, the cytokine production in BMMCs was enhanced when the culture was supplemented with PGF{sub 2{alpha}}. However, F prostanoid receptor-a selective receptor for PGF{sub 2{alpha}}-was not detected in BMMCs. Further investigations performed using prostanoid receptor antagonists revealed an alternative mechanism wherein the receptors for PGE species-E prostanoid receptors-mediated the PGF{sub 2{alpha}} signal in BMMCs. The present study provides an insight into a novel function of PGF{sub 2{alpha}}, i.e., an autocrine accelerator for mast cell activation.

  14. Long-term anabolic effects of prostaglandin-E2 on tibial diaphyseal bone in male rats

    NASA Technical Reports Server (NTRS)

    Jee, Webster S. S.; Ke, Hua Zhu; Li, Xiao Jian

    1991-01-01

    The effects of long-term prostaglandin E2 (PGE2) on tibial diaphyseal bone were studied in 7-month-old male Sprague-Dawley rats given daily subcutaneous injections of 0, 1, 3 and 6 mg PGE2/kg/day for 60, 120 and 180 days. The tibial shaft was measured by single photon absorptiometry and dynamic histomorphometric analyses were performed on double-fluorescent labeled undecalcified tibial diaphyseal bone samples. Exogenous PGE2 administration produced the following transient changes in a dose-response manner between zero and 60 days: (1) increased bone width and mineral density; (2) increased total tissue and total bone areas; (3) decreased marrow area; (4) increased periosteal and corticoendosteal lamellar bone formation; (5) activated corticoendosteal lamellar and woven trabecular bone formation; and (6) activated intracortical bone remodeling. A new steady-state of increased tibial diaphyseal bone mass and elevated bone activities were observed from day 60 onward. The elevated bone mass level attained after 60 days of PGE2 treatment was maintained at 120 and 180 days. These observations indicate that the powerful anabolic effects of PGE2 will increase both periosteal and corticoendosteal bone mass and sustain the transient increase in bone mass with continuous daily administration of PGE2.

  15. Inhibition of 15-hydroxy prostaglandin dehydrogenase and increase of prostaglandin E2: effect of sofalcone on rat gastric mucosa.

    PubMed

    Muramatsu, M; Tanaka, M; Murakami, S; Aihara, H

    1987-07-20

    The effect of sofalcone, an anti-ulcer agent, on gastric mucosal prostaglandin (PG) metabolism was studied. Gastric mucosal PGE2 was determined in rats in which PGE2 synthesis was inhibited by preadministration of indomethacin. Oral administration of sofalcone at doses of 200 and 400 mg/kg significantly inhibited the PG metabolizing enzyme, 15-hydroxy-PG-dehydrogenase (15-OH-PG-DH) activity and increased PGE2 contents in the rat gastric mucosa. The inhibition of 15-OH-PG-DH activity was accompanied by an increase of PGE2 contents up to 6 hours after the administration of sofalcone. These changes, however, were not observed 12 hours after its administration. Intraperitoneally administered sofalcone also inhibited 15-OH-PG-DH activity and increased PGE2 content. The inhibition of 15-OH-PG-DH activity by sofalcone was noncompetitive and uncompetitive against substrates NAD and PGE1, respectively. These results suggest that the increase of the gastric PGE2 level is mainly due to the inhibition of 15-OH-PG-DH activity, and this increase in PGE2 may be involved in the anti-ulcer effect of sofalcone. PMID:3474485

  16. Inhibition of prostaglandin synthesis after metabolism of menadione by cultured porcine endothelial cells.

    PubMed Central

    Barchowsky, A; Tabrizi, K; Kent, R S; Whorton, A R

    1989-01-01

    We have examined the effects of menadione on porcine aortic endothelial cell prostaglandin synthesis. Addition of 1-20 microM menadione caused a dose- and time-dependent inhibition of stimulated prostaglandin synthesis with an IC50 of 5 microM at 15 min. Concentrations greater than 100 microM menadione were necessary to increase 51Cr release from prelabeled cells. Recovery of enzyme inactivated by menadione required a 6-h incubation in 1% serum. In a microsomal preparation, menadione was shown to have no direct effect on conversion of arachidonic acid to prostaglandins. In intact cells menadione caused only a 40% inhibition of the conversion of PGH2 to prostacyclin. Enzymes involved in the incorporation and the release of arachidonic acid were not affected by menadione (20 microM, 15 min). Menadione undergoes oxidation/reduction reactions in intact cells leading to partial reduction of oxygen-forming, reactive oxygen species. In our cells menadione was found to increase KCN-resistant oxygen consumption. Further, an increased accumulation of H2O2 was observed with a time course consistent with menadione-induced inhibition of prostaglandin synthesis. We conclude that menadione at sublethal doses caused inhibition of prostaglandin synthesis. The mechanism involves inactivation of PGH2 synthase by a reactive species resulting from metabolism of menadione by endothelial cells. PMID:2495300

  17. The effect of cloprostenol on human luteal steroid and prostaglandin secretion in vitro.

    PubMed Central

    McDougall, A N; Walker, F M; Watson, J

    1977-01-01

    1 Human luteal tissue slices from days 18, 21 and 25 of the menstrual cycle were superfused in vitro with Medium 199 alone or containing cloprostenol (1 microgram/ml). Concentrations of progesterone, oestradiol-17beta and prostaglandins F2alpha and E2 were determined in the superfusate samples. 2 Secretion of steroids and prostaglandins was maintained at an approximately constant level throughout the experiments (21 h in one case) when the tissue was perfused with M199 alone. 3 Superfusion with cloprostenol (1 microgram/ml) resulted in an initial depression of progesterone and oestradiol-17beta but this was not maintained, levels returning to control values or showing an increase, while superfusion with cloprostenol continued. Cloprostenol is not therefore considered to be luteolytic at this dose and under these conditions for human luteal tissue in vitro. 4 Superfusion with cloprostenol (1 microgram/ml) also resulted in a large stimulation of secretion of endogenous prostaglandin F2 alpha following a short lag phase. This stimulation was possibly due to the initial depression of progesterone secretion. A short-lived stimulation of prostaglandin E2 secretion was also observed. 5 The significance of the increase in prostaglandin E2 secretion and the interrelationships between the various changes observed with cloprostenol are difficult to interpret. PMID:890210

  18. Conceptus-derived prostaglandins regulate gene expression in the endometrium prior to pregnancy recognition in ruminants

    PubMed Central

    Spencer, Thomas E.; Forde, Niamh; Dorniak, Piotr; Hansen, Thomas R.; Romero, Jared J.; Lonergan, Patrick

    2013-01-01

    In cattle, the blastocyst hatches from the zona pellucida on days 8 to 9 and then forms a conceptus that grows and elongates into an ovoid and then filamentous shape between days 9 and 16. The growing conceptus synthesizes and secretes prostaglandins and interferon tau. Our hypothesis was that the ovoid conceptus exerts a local effect on the endometrium prior to maternal recognition of pregnancy on day 16 in cattle. In Study One, synchronized cyclic heifers received nothing or 20 in vitro produced blastocysts on day 7, and uteri were collected on day 13. Interferon tau was not detected by radioimmunoassay in the uterine flush of pregnant heifers containing multiple ovoid conceptuses; however, total prostaglandin levels were higher in the uterine lumen of pregnant as compared to cyclic heifers. Microarray analysis revealed that 44 genes were increased in the endometrium of day 13 pregnant as compared to cyclic heifers, and many of those genes were classical Type I IFN-stimulated genes (ISGs). Studies Two and Three determined effects of infusing prostaglandins at the levels produced by the elongating day 14 conceptus into the uterine lumen of cyclic ewes on ISG expression in the endometrium. Results indicated that prostaglandin infusion increased the abundance of several ISGs in the endometrium. These studies support the hypothesis that the day 13 conceptus secretes prostaglandins that act locally in a paracrine manner to alter gene expression in the endometrium prior to pregnancy recognition in cattle. PMID:23966582

  19. Contractile and relaxant actions of prostaglandins on guinea-pig isolated trachea.

    PubMed Central

    Coleman, R. A.; Kennedy, I.

    1980-01-01

    1 The effects of 12 prostaglandins on guinea-pig isolated trachea have been examined in the presence of indomethacin. Two series of experiments were carried out, the first on preparations without tone ('zero tone'), and the second on preparations with tone induced with acetylcholine ('high tone'). 2 The compounds tested fell into two groups. The first, comprising prostaglandins F1 alpha, F2 alpha, F2 alpha acetal, I2 and Wy 17186, contracted both zero and high tone preparations. The second, comprising prostaglandins A1, A2, B1, B2, E1, E2 and F2 beta, contracted zero, but relaxed high tone preparations. Responses to the second group of compounds are probably the resultant of their contractile and relaxant actions. 3 The order of potency for contracting zero tone preparations was prostaglandin E (PGE) greater than F = 1 = Wy 17186 greater than B greater than A, 2-series compounds being 5 to 18 times more potent than 1-series compounds. 4 The order of potency for relaxing high tone preparations was PGE greater than F beta greater than B greater than A greater than Wy 17186 greater than F alpha = I = 0. There was little difference between the potency of 1- and 2-series compounds. 5 The possible relevance of these results to the interpretation of the effects of prostaglandins on human airways is discussed. PMID:7052343

  20. Prostaglandin E and F2 alpha receptors in human myometrium during the menstrual cycle and in pregnancy and labor

    SciTech Connect

    Giannopoulos, G.; Jackson, K.; Kredentser, J.; Tulchinsky, D.

    1985-12-15

    The binding of prostaglandins E1 and F2 alpha has been studied in the human myometrium and cervix during the menstrual cycle and in the myometrium of pregnant patients at term before and during labor. Tritium-labeled prostaglandin E1 and F2 alpha binding was saturable and reversible. Scatchard analysis of tritium-labeled prostaglandin E1 binding was linear, which suggests a single class of high-affinity binding sites with an estimated apparent equilibrium dissociation constant of 2.5 to 5.4 nmol/L and inhibitor affinities of 0.9, 273, 273, and 217 nmol/L for prostaglandins E2, A1, B1, and F2 alpha, respectively. Scatchard analysis of tritium-labeled prostaglandin F2 alpha, binding was also linear, but the affinity of these binding sites was much lower, with an average dissociation constant of 50 nmol/L and inhibitor affinities of 1.6, 2.2, and 11.2 nmol/L for prostaglandins E1, E2, and A1, respectively. In nonpregnant patients, the concentrations and affinities of tritium-labeled prostaglandin E1 binding sites were similar in the myometrium during the proliferative and secretory phases of the menstrual cycle, but the concentration of these sites was much lower in the cervix. The concentration of the tritium-labeled prostaglandin E1 binding sites was significantly lower in the myometrium of pregnant patients at term than in the myometrium of nonpregnant patients. The concentrations and affinities of tritium-labeled prostaglandin E1 binding sites were not significantly different in the upper and lower myometrium of pregnant patients at term or in the myometrium of such patients before and during labor. The concentrations of the tritium-labeled prostaglandin F2 alpha binding sites during the menstrual cycle and in pregnancy at term were similar to those of tritium-labeled prostaglandin E1 binding sites.

  1. Prostaglandin F(2alpha) receptor in the neurohypophysis of hens.

    PubMed

    Takahashi, T; Kawashima, M

    2009-08-01

    To elucidate whether the receptor for prostaglandin (PG) F(2alpha), one of PG, exists in the neurohypophysis in hens and whether the binding of receptor changes with relation to oviposition, the PGF(2alpha) binding component in the membrane fraction of the neurohypophysis of laying hens was analyzed by radioligand binding assay using [5,6,8,9,11,12,14,15(n)-(3)H]PGF(2alpha). The binding component had characteristics of a receptor such as binding specificity, high affinity, and limited capacity for PGF(2alpha). Scatchard analysis indicated that the binding site was of a single class. The binding capacity of the receptor was smaller in laying hens than in nonlaying hens, whereas the binding affinity was not significantly different between these hens. When non-laying hens received an i.m. injection of estradiol-17beta or progesterone (0.5 mg/hen), the specific binding of the PGF(2alpha) receptor in the neurohypophysis was decreased. In laying hens, the specific binding decreased and the blood arginine vasotocin (AVT) concentration increased just after oviposition but did not change during a 24-h day in nonlaying hens. An i.v. injection of PGF(2alpha) (2 microg/hen) induced oviposition and caused an increase in the blood AVT concentration with a decrease in the specific binding of PGF(2alpha) receptor. The present study suggests a possibility that PGF(2alpha) may directly cause the AVT release from the neurohypophysis at oviposition time in hens. PMID:19590087

  2. Prostaglandin E2 modulation of rheumatoid factor synthesis.

    PubMed

    Alvarellos, A; Lipsky, P E; Jasin, H E

    1988-12-01

    We examined the influence of prostaglandin E2 (PGE2) on the in vitro synthesis of rheumatoid factor (RF) by purified human B and T lymphocytes stimulated with Staphylococcus aureus Cowan 1 or pokeweed mitogen (PWM). Supernatants were assayed for total IgM and RF. PGE2 at concentrations of 10(-7) M to 10(-9) M significantly inhibited RF and IgM secretion stimulated by S aureus Cowan 1, a cross-linker of B cell surface Ig. The magnitude of inhibition of RF production was significantly greater than that of total IgM at low PGE2 concentrations (P less than 0.05). In contrast, PWM-stimulated cultures were only minimally inhibited by PGE2 at all concentrations tested. Since cross-linking of surface Ig renders B cells more susceptible to inhibition by PGE2, heat-aggregated IgG (HAIgG) was added to the PWM-stimulated cultures in an attempt to increase the sensitivity of precursors of RF-secreting cells to the inhibitory effects of PGE2. Addition of HAIgG markedly increased PGE2-mediated inhibition of RF synthesis without significantly affecting IgM production. Inhibition could not be overcome by the addition of soluble T helper cell factors, indicating that PGE2-mediated suppression was not the result of an inhibitory action of T helper cells. When lymphocytes from patients with rheumatoid arthritis were examined, HAIgG was found to be unable to induce sensitivity to PGE2-mediated inhibition of responsiveness. These results suggest that down-regulation of RF synthesis requires both cross-linking of surface Ig and the influence of PGE2. Abnormalities in this immunoregulatory mechanism may explain the ongoing production of RF in patients with rheumatoid arthritis. PMID:3264162

  3. Multifactorial regulation of prostaglandin synthesis in preovulatory goldfish ovarian follicles.

    PubMed

    Kellner, R G; Van der Kraak, G

    1992-04-01

    Goldfish preovulatory ovarian follicles (prior to germinal vesicle breakdown) were utilized for studies investigating the actions of activators of different signal transduction pathways on prostaglandin (PG) production. The protein kinase C (PKC) activators phorbol 12-myristate 13-acetate (PMA; 100-400 nM), 1-oleoyl-2-acetylglycerol (5 and 25 micrograms/ml), and 1,2-dioctanoylglycerol (10 and 50 micrograms/ml) stimulated PGE production; the inactive phorbol 4 alpha-phorbol didecanoate, which does not activate PKC, had no effect. Calcium ionophore A23187 (0.25-4.0 microM) stimulated PGE production and acted in a synergistic manner with activators of PKC. Although produced in lower amounts than PGE, PGF was stimulated by PMA and A23187. The direct activator of phospholipase A2, melittin (0.1-1.0 microM), stimulated a dose-related increase in PGE production, whereas chloroquine (100 microM), a putative inhibitor of phospholipase A2, blocked basal and PMA + A23187-stimulated PGE production. Several drugs known to elevate intracellular levels of cAMP including the phosphodiesterase inhibitor 3-isobutyl-1-methylxanthine (0.1-1.0 mM), forskolin (10 microM), and dibutyryl cAMP (dbcAMP; 5 mM) attenuate PMA + A23187-stimulated PGE production. Melittin-stimulated production of PGE was inhibited by dbcAMP, suggesting that the action of cAMP was distal to the activation of phospholipase A2. In summary, these studies demonstrate that activation of PKC and elevation of intracellular calcium levels stimulate PG production, in part, through activation of phospholipase A2. The adenylate cyclase/cAMP signalling pathway is inhibitory to PG production by goldfish ovarian follicles. PMID:1315582

  4. Conceptus-derived prostaglandins regulate endometrial function in sheep.

    PubMed

    Dorniak, Piotr; Bazer, Fuller W; Wu, Guoyao; Spencer, Thomas E

    2012-07-01

    In sheep, the trophectoderm of the elongating conceptus secretes interferon tau (IFNT) and prostaglandins (PGE2, PGF2alpha, PGI2). The PGs are derived from PG synthase 2 (PTGS2), and inhibition of PTGS2 in utero prevents conceptus elongation. IFNT increases expression of many genes in the endometrial epithelia that regulate conceptus elongation. This study tested the hypothesis that PGs secreted by the conceptus regulate endometrial functions that govern conceptus elongation. Cyclic ewes received intrauterine infusions of control vehicle or early pregnancy levels of IFNT, PGE2, PGF2alpha, or PGI2 from Days 10-14 postestrus. Expression levels of endometrial GRP, IGFBP1, and LGALS15, whose products stimulate trophectoderm cell migration and attachment, were increased by PGE2, PGI2, and IFNT. All PGs and IFNT increased expression of the HEXB protease gene, but only IFNT increased the CST6 protease inhibitor gene. Differential effects of PGs were observed for expression of the CTSL protease gene and its inhibitor, CST3. IFNT, PGF2alpha, and PGI2 increased ANGPTL3 expression, but only IFNT and PGE2 increased HIF1A expression, both of which regulate angiogenesis. For glucose transporters, IFNT and all PGs increased SLC2A1 expression, but only PGs increased SLC2A5 expression, whereas endometrial SLC2A12 and SLC5A1 expression levels were increased by IFNT, PGE2, and PGF2alpha. Infusions of all PGs and IFNT increased the amino acid transporter SLC1A5, but only IFNT increased SLC7A2 expression. In the uterine lumen, only IFNT increased glucose levels, and only PGE2 and PGF2alpha increased total amino acids. These results indicate that PGs and IFNT from the conceptus coordinately regulate endometrial functions important for growth and development of the conceptus during the peri-implantation period of pregnancy. PMID:22517622

  5. BVDV alters uterine prostaglandin production during pregnancy recognition in cows.

    PubMed

    Cheng, Zhangrui; Abudureyimu, Ayimuguli; Oguejiofor, Chike F; Ellis, Rebekah; Barry, Amy Teresa; Chen, Xing; Anstaett, Olivia L; Brownlie, Joe; Wathes, D Claire

    2016-06-01

    Embryonic mortality in cows is at least in part caused by failure of pregnancy recognition (PR). Evidence has shown that bovine viral diarrhoea virus (BVDV) infection can disrupt pregnancy. Prostaglandins (PG) play important roles in many reproductive processes, such as implantation. The aim of this study was to investigate the effect of BVDV infection on uterine PG production and PR using an in vitro PR model. Bovine uterine endometrial cells isolated from ten BVDV-free cows were cultured and treated with 0 or 100ng/mL interferon-τ (IFNT) in the absence or presence of non-cytopathic BVDV (ncpBVDV). PGF2α and PGE2 concentrations in the spent medium were measured using radioimmunoassays, and in the treated cells expression of the genes associated with PG production and signalling was quantified using qPCR. The results showed that the IFNT challenge significantly stimulated PTGS1 and PTGER3 mRNA expression and PGE2 production; however, these stimulatory effects were neutralised in the presence of ncpBVDV infection. ncpBVDV infection significantly increased PTGS1 and mPGES1 mRNA expression and decreased AKR1B1 expression, leading to increased PGE2 and decreased PGF2α concentrations and an increased PGE2:PGF2α ratio. The other tested genes, including PGR, ESR1, OXTR, PTGS2, PTGER2 and PTGFR, were not significantly altered by IFNT, ncpBVDV or their combination. Our study suggests that BVDV infection may impair PR by (1) inhibiting the effect of IFNT on uterine PG production and (2) inducing an endocrine switch of PG production from PGF2α to PGE2 to decrease uterine immunity, thereby predisposing the animals to uterine disease. PMID:26952097

  6. Reversal of Myofibroblast Differentiation by Prostaglandin E2

    PubMed Central

    Garrison, Garth; Huang, Steven K.; Okunishi, Katsuhide; Scott, Jacob P.; Kumar Penke, Loka Raghu; Scruggs, Anne M.

    2013-01-01

    Differentiation of fibroblasts into α-smooth muscle actin (SMA)–expressing myofibroblasts represents a critical step in the pathogenesis of fibrotic disorders, and is generally regarded as irreversible. Prostaglandin E2 (PGE2) has been shown to prevent multiple aspects of fibroblast activation, including the differentiation of fibroblasts to myofibroblasts. Here, we investigated its ability to reverse this differentiated phenotype. Fetal and adult lung fibroblasts were induced to differentiate into myofibroblasts by 24-hour culture with transforming growth factor (TGF)-β1 or endothelin-1. Cells were then treated without or with PGE2 for various intervals and assessed for α-SMA expression. In the absence of PGE2 treatment, α-SMA expression induced by TGF-β1 was persistent and stable for up to 8 days. By contrast, PGE2 treatment effected a dose-dependent decrease in α-SMA and collagen I expression that was observed 2 days after PGE2 addition, peaked at 3 days, and persisted through 8 days in culture. This effect was not explained by an increase in myofibroblast apoptosis, and indeed, reintroduction of TGF-β1 2 days after addition of PGE2 prompted dedifferentiated fibroblasts to re-express α-SMA, indicating redifferentiation to myofibroblasts. This effect of PGE2 was associated with inhibition of focal adhesion kinase signaling, and a focal adhesion kinase inhibitor was also capable of reversing myofibroblast phenotype. These data unambiguously demonstrate reversal of established myofibroblast differentiation. Because many patients have established or even advanced fibrosis by the time they seek medical attention, this capacity of PGE2 has the potential to be harnessed for therapy of late-stage fibrotic disorders. PMID:23470625

  7. Prostaglandin D2-loaded microspheres effectively activate macrophage effector functions.

    PubMed

    Pereira, Priscilla Aparecida Tartari; Bitencourt, Claudia da Silva; dos Santos, Daiane Fernanda; Nicolete, Roberto; Gelfuso, Guilherme Martins; Faccioli, Lúcia Helena

    2015-10-12

    Biodegradable lactic-co-glycolic acid (PLGA) microspheres (MS) improve the stability of biomolecules stability and allow enable their sustained release. Lipid mediators represent a strategy for improving host defense; however, most of these mediators, such as prostaglandin D2 (PGD2), have low water solubility and are unstable. The present study aimed to develop and characterize MS loaded with PGD2 (PGD2-MS) to obtain an innovative tool to activate macrophages. PGD2-MS were prepared using an oil-in-water emulsion solvent extraction-evaporation process, and the size, zeta potential, surface morphology and encapsulation efficiency were determined. It was also evaluated in vitro the phagocytic index, NF-κB activation, as well as nitric oxide and cytokine production by alveolar macrophages (AMs) in response to PGD2-MS. PGD2-MS were spherical with a diameter of 5.0±3.3 μm and regular surface, zeta potential of -13.4±5.6 mV, and 36% of encapsulation efficiency, with 16-26% release of entrapped PGD2 at 4 and 48 h, respectively. PGD2-MS were more efficiently internalized by AMs than unloaded-MS, and activated NF-κB more than free PGD2. Moreover, PGD2-MS stimulated the production of nitric oxide, TNF-α, IL-1β, and TGF-β, more than free PGD2, indicating that microencapsulation increased the activating effect of PGD2 on cells. In LPS-pre-treated AMs, PGD2-MS decreased the release of IL-6 but increased the production of nitric oxide and IL-1β. These results show that the morphological characteristics of PGD2-MS facilitated interaction with, and activation of phagocytic cells; moreover, PGD2-MS retained the biological activities of PGD2 to trigger effector mechanisms in AMs. It is suggested that PGD2-MS represent a strategy for therapeutic intervention in the lungs of immunocompromised subjects. PMID:26143263

  8. Opposing roles of Prostaglandin D2 receptors in ulcerative colitis

    PubMed Central

    Sturm, Eva M.; Radnai, Balazs; Jandl, Katharina; Stančić, Angela; Parzmair, Gerald P.; Högenauer, Christoph; Kump, Patrizia; Wenzl, Heimo; Petritsch, Wolfgang; Pieber, Thomas R.; Schuligoi, Rufina; Marsche, Gunther; Ferreirós, Nerea; Heinemann, Akos; Schicho, Rudolf

    2014-01-01

    Pro-resolution functions were reported for Prostaglandin D2 (PGD2) in colitis, but the role of its two receptors, DP and in particular CRTH2 are less well defined. We investigated DP and CRTH2 expression and function during human and murine ulcerative colitis (UC). Expression of receptors was measured by flow cytometry on peripheral blood leukocytes, and by immunohistochemistry and immunoblotting in colon biopsies of patients with active UC and healthy individuals. Receptor involvement in UC was evaluated in a mouse model of DSS colitis. DP and CRTH2 expression changed in leukocytes of patients with active UC in a differential manner. In UC patients, DP showed higher expression in neutrophils but lower in monocytes as compared to control subjects. In contrast, CRTH2 was decreased in eosinophils, NK and CD3+ T cells but not in monocytes and CD3+/CD4+ T cells. The decrease of CRTH2 on blood eosinophils clearly correlated with disease activity. DP correlated positively with disease activity in eosinophils but inversely in neutrophils. CRTH2 internalized upon treatment with PGD2 and 11-dehydroTXB2 in eosinophils of controls. Biopsies of UC patients revealed an increase of CRTH2-positive cells in the colonic mucosa and high CRTH2 protein content. The CRTH2 antagonist CAY10595 improved while the DP antagonist MK0524 worsened inflammation in murine colitis. DP and CRTH2 play differential roles in UC. Although expression of CRTH2 on blood leukocytes is downregulated in UC, CRTH2 is present in colon tissue where it may contribute to inflammation whereas DP likely promotes anti-inflammatory actions. PMID:24929001

  9. Ovarian cancer stem-like cells elicit the polarization of M2 macrophages.

    PubMed

    Zhang, Qing; Cai, Da-Jun; Li, Bin

    2015-06-01

    Ovarian cancer is a life‑threatening disease in females worldwide. The polarization of macrophages is crucial in oncogenesis and the development of ovarian cancer. Increasing evidence has supported the correlation between ovarian cancer stem‑like cells (OCSCs) and macrophages, however, whether OCSCs can affect the polarization of macrophages and the underlying mechanisms involved remain to be elucidated. To examine the interplay between OCSCs and macrophages, a co‑culture system was used to detect the effect of OCSCs on macrophage polarization. The expression of cluster of differentiation 206+ and the secretion of interleukin‑10 were significantly increased and the production of tumor necrosis factor‑α was suppressed, confirming macrophage polarization to M2 macrophages. Further investigation of the macrophages in a Transwell culture system with OCSCs revealed polarization to the M2 macrophages to a similar extent, indicating that the cytokines of the OCSCs, rather than direct cell‑cell contact, are important for the polarization of M2 macrophages. Furthermore, the expression levels of chemokine (C‑C motif) ligand (CCL)2, cyclooxygenase (COX)‑2 and prostaglandin E2 (PGE2) were increased in the Transwell system and the inhibition of COX‑2, but not CCL2, significantly decreased the polarization of the M2 macrophages. In addition, mechanistic analysis revealed the importance of the COX‑2/PGE2 pathway in OCSCs to activate Janus kinase (JAK) signaling in macrophages to elicit M2 polarization. These findings provided the first evidence, to the best of our knowledge, that OCSCs are capable of altering macrophages into the M2 phenotype via the overexpression of COX‑2 and the increased production of PGE2 cytokines and that the JAK signaling pathway in macrophages is important for this alteration. The present study provided evidence supporting possible molecular targets for cancer treatment. PMID:25672286

  10. Upregulation of Cyclooxygenase-2/Prostaglandin E2 (COX-2/PGE2) Pathway Member Multiple Drug Resistance-Associated Protein 4 (MRP4) and Downregulation of Prostaglandin Transporter (PGT) and 15-Prostaglandin Dehydrogenase (15-PGDH) in Triple-Negative Breast Cancer

    PubMed Central

    Kochel, Tyler J.; Goloubeva, Olga G.; Fulton, Amy M.

    2016-01-01

    Elevated levels of cyclooxygenase-2 (COX-2) and prostaglandin E2 (PGE2) are indicators of a poor prognosis in breast cancer. Using several independent publicly available breast cancer gene expression databases, we investigated other members of the PGE2 pathway. PGE2 is produced by COX-2 and actively exported by multiple drug resistance-associated protein 4 (MRP4) into the extracellular microenvironment, where PGE2 can bind four cognate EP receptors (EP1–EP4) and initiate diverse biological signaling pathways. Alternatively, PGE2 is imported via the prostaglandin transporter (PGT) and metabolized by 15-prostaglandin dehydrogenase (15-PGDH/HPGD). We made the novel observation that MRP4, PGT, and 15-PGDH are differentially expressed among distinct breast cancer molecular subtypes; this finding was confirmed in independent datasets. In triple-negative breast cancer, the observed gene expression pattern (high COX-2, high MRP4, low PGT, and low 15-PGDH) would favor high levels of tumor-promoting PGE2 in the tumor microenvironment that may contribute to the overall poor prognosis of triple-negative breast cancer. PMID:27257388

  11. The EP1 receptor for prostaglandin E2 promotes the development and progression of malignant murine skin tumors

    PubMed Central

    Surh, Inok; Rundhaug, Joyce E.; Pavone, Amy; Mikulec, Carol; Abel, Erika; Simper, Melissa; Fischer, Susan M.

    2011-01-01

    High levels of prostaglandin E2 (PGE2) synthesis resulting from the upregulation of COX-2 has been shown to be critical for the development of non-melanoma skin tumors. This effect of PGE2 is likely mediated by one or more of its 4 G-protein coupled membrane receptors, EP1–4. A previous study showed that BK5.EP1 transgenic mice produced more carcinomas than wild type (WT) mice using initiation/promotion protocols, although the tumor response was dependent on the type of tumor promoter used. In this study, a single topical application of either 7,12-dimethylbenz[a]anthracene (DMBA) or benzo[a]pyrene (B[a]P), alone, was found to elicit squamous cell carcinomas (SCC) in the BK5.EP1 transgenic mice, but not in WT mice. While the epidermis of both WT and transgenic mice was hyperplastic several days after DMBA, this effect regressed in the WT mice while proliferation continued in the transgenic mice. Several parameters associated with carcinogen initiation were measured and were found to be similar between genotypes, including CYP1B1 and aromatase expression, B[a]P adduct formation, Ras activity and keratinocyte stem cell numbers. However, EP1 transgene expression elevated COX-2 levels in the epidermis and SCC could be completely prevented in DMBA-treated BK5.EP1 mice either by feeding the selective COX-2 inhibitor celecoxib in their diet or by crossing them onto a COX-2 null background. These data suggest that the tumor promoting/progressing effects of EP1 require the PGE2 synthesized by COX-2. PMID:21739481

  12. Acute effect of prostaglandins and somatostatin on thymidine uptake of gastric mucosa cells

    SciTech Connect

    Alino, S.F.; Hilario, E. )

    1988-12-01

    This study compares the in vivo effect of exogenous administration of prostaglandin E2 (30 {mu}g/kg) and its precursor, arachidonic acid (30 {mu}g/kg), with the effect of indomethacin (5 mg/kg) on the 6-({sup 3}H)thymidine uptake of antral mucosa of mice by autoradiographical methods. Likewise, the effect of somatostatin (30 {mu}g/kg) on 6-({sup 3}H)thymidine uptake is studied. Evaluation of the number of labeled cells, in the histological sections of the gastric mucosa, showed that arachidonic acid, prostaglandin E2, and somatostatin induced an increase in the number of labeled cells (107, 44, and 45%, respectively), while indomethacin induced a decrease of 32% compared to the control group. These results suggest that prostaglandins may mediate stimulatory effects on thymidine uptake of gastric mucosa cells in the first step after drug administration.

  13. Promising alternative clinical uses of prostaglandin F2α analogs: beyond the eyelashes.

    PubMed

    Choi, Young M; Diehl, Joseph; Levins, Paul C

    2015-04-01

    Prostaglandin F2α analogs, commonly prescribed for glaucoma treatment, have been shown to induce side effects such as cutaneous hypertrichosis and hyperpigmentation. Therefore, these medications have theoretic applications in the treatment of alopecia and disorders of hypopigmentation. We reviewed the literature to find original studies assessing the use of prostaglandin F2α analogs in these settings. Studies and reports were analyzed in regards to androgenic alopecia, alopecia areata, chemotherapy-induced alopecia, vitiligo, and hypopigmented scarring. Based on the results of these studies, and consideration of pathophysiologic mechanism, the most promising applications for prostaglandin F2α analogs include androgenic alopecia, chemotherapy-induced alopecia, and alopecia areata concurrently treated with corticosteroids. PMID:25601618

  14. Adipocyte Mineralocorticoid Receptor Activation Leads to Metabolic Syndrome and Induction of Prostaglandin D2 Synthase.

    PubMed

    Urbanet, Riccardo; Nguyen Dinh Cat, Aurelie; Feraco, Alessandra; Venteclef, Nicolas; El Mogrhabi, Soumaya; Sierra-Ramos, Catalina; Alvarez de la Rosa, Diego; Adler, Gail K; Quilliot, Didier; Rossignol, Patrick; Fallo, Francesco; Touyz, Rhian M; Jaisser, Frédéric

    2015-07-01

    Metabolic syndrome is a major risk factor for the development of diabetes mellitus and cardiovascular diseases. Pharmacological antagonism of the mineralocorticoid receptor (MR), a ligand-activated transcription factor, limits metabolic syndrome in preclinical models, but mechanistic studies are lacking to delineate the role of MR activation in adipose tissue. In this study, we report that MR expression is increased in visceral adipose tissue in a preclinical mouse model of metabolic syndrome and in obese patients. In vivo conditional upregulation of MR in mouse adipocytes led to increased weight and fat mass, insulin resistance, and metabolic syndrome features without affecting blood pressure. We identified prostaglandin D2 synthase as a novel MR target gene in adipocytes and AT56, a specific inhibitor of prostaglandin D2 synthase enzymatic activity, blunted adipogenic aldosterone effects. Moreover, translational studies showed that expression of MR and prostaglandin D2 synthase is strongly correlated in adipose tissues from obese patients. PMID:25966493

  15. Stretch-induced prostaglandins and protein turnover in cultured skeletal muscle

    NASA Technical Reports Server (NTRS)

    Vandenburgh, Herman H.; Hatfaludy, Sophia; Sohar, Istvan; Shansky, Janet

    1990-01-01

    The purpose of the study is to determine whether mechanical stimulation of cultured muscle cells influences prostaglandin efflux rates and whether they are related to stretch-induced alterations in protein turnover rates. The materials and methods of the experiment, including cell cultures, mechanical stimulation, protein synthesis, and degradation assays are outlined, and emphasis is placed on the effect of short-term mechanical stimulation in basal medium prostaglandin efflux from cultured skeletal muscle and stretch-induced alterations in prostaglandins efflux in complete medium. The major finding of the study is that mechanical stimulation of tissue-cultured skeletal-muscle cells under conditions inducing skeletal-muscle hypertropy increases the efflux of PGE(2) and PGE(2-alpha) but not 6-keto-PGF(1-alpha), the prostacyclin product.

  16. Ulcerating and stenosing enteropathy treated with misoprostol: a case report with analysis of prostaglandin metabolism.

    PubMed

    Havelund, Troels; Jensen, Boye L; Vinholt, Pernille J; Engvad, Birte; Stubbe, Jane

    2012-10-01

    A case of a 40-year-old man with chronic anaemia because of nonspecific ulcerating and stenosing enteropathy is presented. The diagnosis was made on the basis of capsule endoscopy, histology of resected ileum and no use of NSAIDs. He showed a clinical response to treatment with misoprostol, and therefore, he was investigated for a possible impairment in eicosanoid biosynthesis compared with healthy controls. No deficient synthesis of prostacyclin, prostaglandin E2 and thromboxane was found on examination of metabolites in blood and urine. This suggests a normal release of arachidonic acid from phospholipids. Ex-vivo cyclooxygenase (COX) assays showed normal COX-1 and COX-2 activities. The clinical response to treatment with the prostaglandin E1 analogue misoprostol suggests a defective prostaglandin E synthesis in the intestinal mucosa. PMID:22786573

  17. Improving placental blood flow in pre-eclampsia with prostaglandin A1.

    PubMed

    Toppozada, M; Medhat, I; Sallam, H; Ismail, A A; el-Badawy, E S; Abd Rabbo, S

    1992-01-01

    Prostaglandin A1 is a potent hypotensive, peripheral vasodilator, a weak oxytocic, antiplatelet aggregator. It improves the renal hemodynamics. Its effect on placental circulation was evaluated (expressed as systolic/diastolic ratio and umbilical artery resistance index) in 20 women with severe pre-eclampsia and 10 normotensive pregnant women, by using the Doppler technique. Moreover, another 10 women with severe pre-eclampsia received dextrose 5% as a placebo for comparative purposes. Significant improvements in both parameters studied were observed in the women with severe pre-eclampsia. The beneficial changes differed significantly from the recorded values when using dextrose in pre-eclampsia or prostaglandin A1 in normotensive subjects. Such promising data add another important perspective to prostaglandin A1 in severe pre-eclampsia and may open up new avenues for its use in other situations with compromised placental flow. PMID:1315092

  18. Inhibition of the Prostaglandin Degrading Enzyme 15-PGDH Potentiates Tissue Regeneration *

    PubMed Central

    Zhang, Yongyou; Desai, Amar; Yang, Sung Yeun; Bae, Ki Beom; Antczak, Monika I.; Fink, Stephen P.; Tiwari, Shruti; Willis, Joseph E.; Williams, Noelle S.; Dawson, Dawn M.; Wald, David; Chen, Wei-Dong; Wang, Zhenghe; Kasturi, Lakshmi; Larusch, Gretchen A.; He, Lucy; Cominelli, Fabio; Di Martino, Luca; Djuric, Zora; Milne, Ginger L.; Chance, Mark; Sanabria, Juan; Dealwis, Chris; Mikkola, Debra; Naidoo, Jacinth; Wei, Shuguang; Tai, Hsin-Hsiung; Gerson, Stanton L.; Ready, Joseph M.; Posner, Bruce; Willson, James K. V.; Markowitz, Sanford D.

    2015-01-01

    Tissue regeneration is a medical challenge faced in injury from disease and during medical treatments such as bone marrow transplantation. Prostaglandin PGE2, which supports expansion of several types of tissue stem cells, is a candidate therapeutic target for promoting tissue regeneration in vivo. Here we show that inhibition of 15-hydroxyprostaglandin dehydrogenase (15-PGDH), a prostaglandin-degrading enzyme, potentiates tissue regeneration in multiple organs in mice. In a chemical screen, we identify a small-molecule inhibitor of 15-PGDH (SW033291) that increases prostaglandin PGE2 levels in bone marrow and other tissues. SW033291 accelerates hematopoietic recovery in mice receiving a bone marrow transplant. SW033291 also promotes tissue regeneration in mouse models of colon and liver injury. Tissues from 15-PGDH knockout mice demonstrate similar increased regenerative capacity. These findings raise the possibility that inhibiting 15-PGDH could be a useful therapeutic strategy in several distinct clinical settings. PMID:26068857

  19. Prostaglandin D2 modulates calcium signals induced by prostaglandin E2 in neurons of rat dorsal root ganglia.

    PubMed

    Ott, Daniela; Simm, Björn; Pollatzek, Eric; Gerstberger, Rüdiger; Rummel, Christoph; Roth, Joachim

    2015-06-15

    Fever in response to a localized subcutaneous stimulation with a low dose of lipopolysaccharide (LPS) can be attenuated by co-administration of a local anesthetic or the non-selective cyclooxygenase (COX) inhibitor diclofenac at doses, which do not exert systemic effects when injected at sites remote from the area of inflammatory stimulation. These results suggest a participation of neuronal afferent signals mediated by COX-products in the manifestation of fever under these conditions. We therefore, measured intracellular Ca(2+)-concentrations in cultured neurons from rat dorsal root ganglia (DRG) stimulated with the pyrogenic mediator prostaglandin E2 (PGE2), the anti-inflammatory and antipyretic mediator PGD2, mixtures of both PGs, and menthol using the fura-2 ratio imaging technique. Neurons could be grouped according to their size with diameters of about 15μm (small), 35μm (medium sized), or 55μm (large). 96 out of 264 neurons responded to PGE2 with pronounced Ca(2+)-signals, 53 of them being also responsive to menthol, indicative of their function as cold-sensors. 80% of these neurons belonged to the medium sized group. In a next experiment, we tested whether Ca(2+)-signals of PGE2 responsive neurons were modulated by PGD2. In 60% of all neurons investigated (n=57), the strength of the PGE2-induced Ca(2+)-signals was reduced by co-administration of PGD2. This effect was also observed in those neurons that were responsive to PGE2 and menthol (n=23; p<0.001). This observation indicates antagonistic effects of PGE2 and PGD2 on a neuronal pathway that involves cold sensors and is activated during a localized subcutaneous inflammation. This finding might provide an explanation for the reported antipyretic and anti-inflammatory capacities of PGD2. PMID:25912777

  20. A novel multifunctional metabolic pathway in a marine mollusc leads to unprecedented prostaglandin derivatives (prostaglandin 1,15-lactones).

    PubMed Central

    Di Marzo, V; Cimino, G; Crispino, A; Minardi, C; Sodano, G; Spinella, A

    1991-01-01

    The discovery of high levels of prostaglandin (PG) 1,15-lactones of both the E and F series and their co-existence with PGs has been recently described in the opisthobranch mollusc Tethys fimbria. The present study was undertaken in order to investigate the biosynthesis of these novel natural PG derivatives in vivo using radiolabelled precursors, and to gain a preliminary understanding of their biological role. PGE2 1,15-lactone was shown to be produced from both PGE2 and PGF2 alpha in the mollusc mantle and appeared to be quickly transferred to the mollusc dorsal appendices (cerata). The detachment of the latter during the typical defence behaviour of T. fimbria was accompanied by the conversion of PGE2 and PGE3 1,15-lactones back to the corresponding PGs. Both PGE2 and PGE2 1,15-lactone were also shown to be biosynthesized from arachidonic acid. Lactones of the F series were present as 11-acetyl derivatives in T. fimbria mantle and as 9- and 11-fatty acyl esters in the mollusc egg-mass and reproductive gland, and their biosynthesis from PGF2 alpha was demonstrated in all of these tissues. A multiple biological role of PG 1,15-lactones in T. fimbria defensive behaviour, smooth muscle contraction and egg production/fertilization control is hypothesized. The high amounts of PG derivatives found in T. fimbria and the biosynthetic studies described herein indicate that this marine mollusc may be a useful model for future studies on PG biosynthesis. PMID:1899996

  1. Prostaglandins of the E-series inhibit connective tissue proliferation in the liver wound of the rat.

    PubMed

    Arend, A; Aunapuu, M; Masso, R; Selstam, G

    2005-03-01

    The present study was undertaken to relate wound healing of an internal organ to prostaglandins of the E and F series. A small liver wound was induced by a galvanic cauter via the abdominal route under general anesthesia and prostaglandin E1, E2 and F2alpha were injected twice daily at a dose of 250 microg/kg. Proliferation of the connective tissue in the liver wound was estimated morphometrically 6 days after liver wound infliction. Levels of prostaglandins E2 and F2alpha were measured in the liver wound as well as in normal liver tissue from adjacent lobes using radioimmunoassay. The results show that exogenous prostaglandins of the E-series suppress connective tissue proliferation. Three minutes after the last prostaglandin E2 injection, high prostaglandin concentrations were measured both in the liver wound and in the liver tissue of the adjacent lobe. Prostaglandin F2alpha injections had no effect on wound healing. We believe that the rat thermic liver wound model can be used for different studies on wound healing mechanisms and that prostaglandins of the E-series are involved in wound healing in the specific time period studied. PMID:15835401

  2. A Heterogeneous Mixture of F-Series Prostaglandins Promotes Sperm Guidance in the Caenorhabditis elegans Reproductive Tract

    PubMed Central

    Hoang, Hieu D.; Prasain, Jeevan K.; Dorand, Dixon; Miller, Michael A.

    2013-01-01

    The mechanisms that guide motile sperm through the female reproductive tract to oocytes are not well understood. We have shown that Caenorhabditis elegans oocytes synthesize sperm guiding F-series prostaglandins from polyunsaturated fatty acid (PUFA) precursors provided in yolk lipoprotein complexes. Here we use genetics and electrospray ionization tandem mass spectrometry to partially delineate F-series prostaglandin metabolism pathways. We show that omega-6 and omega-3 PUFAs, including arachidonic and eicosapentaenoic acids, are converted into more than 10 structurally related F-series prostaglandins, which function collectively and largely redundantly to promote sperm guidance. Disruption of omega-3 PUFA synthesis triggers compensatory up-regulation of prostaglandins derived from omega-6 PUFAs. C. elegans F-series prostaglandin synthesis involves biochemical mechanisms distinct from those in mammalian cyclooxygenase-dependent pathways, yet PGF2α stereoisomers are still synthesized. A comparison of F-series prostaglandins in C. elegans and mouse tissues reveals shared features. Finally, we show that a conserved cytochrome P450 enzyme, whose human homolog is implicated in Bietti's Crystalline Dystrophy, negatively regulates prostaglandin synthesis. These results support the model that multiple cyclooxygenase-independent prostaglandins function together to promote sperm motility important for fertilization. This cyclooxygenase-independent pathway for F-series synthesis may be conserved. PMID:23382703

  3. Effects of prostaglandin E2 and vascular endothelial growth factor on sperm might lead to endometriosis-associated infertility.

    PubMed

    Lee, Te-Ching; Ho, Han-Chen

    2011-01-01

    Significantly higher levels of prostaglandin E2 and vascular endothelial growth factor were associated with the severity of endometriosis. In this study, pathologic concentrations of prostaglandin E2 and vascular endothelial growth factor found in endometriotic women significantly inhibited sperm motility, acrosome reaction, and sperm-oocyte interaction, which might result in endometriosis-associated subfertility/infertility. PMID:20864099

  4. Prostaglandins A1 and E1 influence gene expression in an established insect cell line (BCIRL-HzAM1)

    Technology Transfer Automated Retrieval System (TEKTRAN)

    In work to determine the biochemical mechanisms of prostaglandin (PG) action in insect cells, we posed the hypothesis that prostaglandins (PGs) influence gene expression. In separate experiments, we exposed the BCIRL-HzAM1 cell line (derived from pupal ovarian tissue of the cotton bollworm, Helicov...

  5. CCSI Risk Estimation: An Application of Expert Elicitation

    SciTech Connect

    Engel, David W.; Dalton, Angela C.

    2012-10-01

    The Carbon Capture Simulation Initiative (CCSI) is a multi-laboratory simulation-driven effort to develop carbon capture technologies with the goal of accelerating commercialization and adoption in the near future. One of the key CCSI technical challenges is representing and quantifying the inherent uncertainty and risks associated with developing, testing, and deploying the technology in simulated and real operational settings. To address this challenge, the CCSI Element 7 team developed a holistic risk analysis and decision-making framework. The purpose of this report is to document the CCSI Element 7 structured systematic expert elicitation to identify additional risk factors. We review the significance of and established approaches to expert elicitation, describe the CCSI risk elicitation plan and implementation strategies, and conclude by discussing the next steps and highlighting the contribution of risk elicitation toward the achievement of the overarching CCSI objectives.

  6. Melittin stimulates liver glycogenolysis and the release of prostaglandin D2 and thromboxane B2.

    PubMed Central

    García-Sáinz, J A; Hernández-Sotomayor, S M; Macías-Silva, M

    1990-01-01

    Melittin stimulates glycogenolysis and induces vasoconstriction in perfused rat liver. The effect was rapid and associated with production and release of prostaglandin D2 and thromboxane B2. Indomethacin blocked the release of these eicosanoids and the stimulation of glycogenolysis induced by melittin. Ibuprofen blocked the release of prostaglandin D2 induced by melittin and markedly attenuated that of thromboxane B2. Interestingly, the initial burst of glucose output induced by melittin was not inhibited by ibuprofen, although the duration of the glycogenolytic action of the peptide was greatly diminished. PMID:2375756

  7. Fenamates may antagonize the actions of prostaglandin endoperoxides in human myometrium.

    PubMed Central

    Sanger, G J; Bennett, A

    1979-01-01

    1 The prostaglandin endoperoxide analogue U-46619 potently contracted human isolated myometrium, suggesting that prostaglandin H2 (PGH2) may be a major stimulant of myometrial contractions. 2 Sodium mefenamate, flufenamate or meclofenamate 2 microgram/ml greatly reduced contractions of the myometrium induced by the PGH2 analogue. 3 Flufenamate, but not the other two drugs, also significantly inhibited contractions to acetylcholine. 4 Sodium meclofenamate 2 microgram/ml did not consistently antagonize contractions to PGF2alpha. 5 The relief of dysmenorrhoea by fenamates may be explained both by inhibition of PG synthesis, and by antagonism of contractions to PGH2 produced by incompletely blocked PG synthesis. PMID:508555

  8. Evaluation of WO 2012/177618 A1 and US-2014/0179750 A1: novel small molecule antagonists of prostaglandin-E2 receptor EP2.

    PubMed

    Ganesh, Thota

    2015-07-01

    Recent studies underscore that prostaglandin-E2 exerts mostly proinflammatory effects in chronic CNS and peripheral disease models, mainly through a specific prostanoid receptor EP2. However, very few highly characterized EP2 receptor antagonists have been reported until recently, when Pfizer and Emory University published two distinct classes of EP2 antagonists with good potency, selectivity and pharmacokinetics. The purpose of this article is to evaluate recently published patents WO 2012/177618 A1 and US-2014/0179750 A1 from Emory, which describe a number of cinnamic amide- and amide-derivatives as a potent antagonists of EP2 receptor, and their neuroprotective effects in in vitro and in an in vivo model. A selected compound from this patent(s) also attenuates prostate cancer cell growth and invasion in vitro, suggesting these compounds should be developed for therapeutic use. PMID:25772215

  9. Prostaglandins induce early growth response 1 transcription factor mediated microsomal prostaglandin E2 synthase up-regulation for colorectal cancer progression

    PubMed Central

    Stamatakis, Konstantinos; Jimenez-Martinez, Marta; Jimenez-Segovia, Alba; Chico-Calero, Isabel; Conde, Elisa; Galán-Martínez, Javier; Ruiz, Julia; Pascual, Alejandro; Barrocal, Beatriz; López-Pérez, Ricardo; García-Bermejo, María Laura; Fresno, Manuel

    2015-01-01

    Cyclooxygenase2 (COX2) has been associated with cell growth, invasiveness, tumor progression and metastasis of colorectal carcinomas. However, the downstream prostaglandin (PG)-PG receptor pathway involved in these effects is poorly characterized. We studied the PG-pathway in gene expression databases and we found that PTGS2 (prostaglandin G/H synthase and cyclooxygenase) and PTGES (prostaglandin E synthase) are co-expressed in human colorectal tumors. Moreover, we detected that COX2 and microsomal Prostaglandin E2 synthase 1 (mPGES1) proteins are both up-regulated in colorectal human tumor biopsies. Using colon carcinoma cell cultures we found that COX2 overexpression significantly increased mPGES1 mRNA and protein. This up-regulation was due to an increase in early growth response 1 (EGR1) levels and its transcriptional activity. EGR1 was induced by COX2-generated PGF2α. A PGF2α receptor antagonist, or EGR1 silencing, inhibited the mPGES1 induction by COX2 overexpression. Moreover, using immunodeficient mice, we also demonstrated that both COX2- and mPGES1-overexpressing carcinoma cells were more efficient forming tumors. Our results describe for the first time the molecular pathway correlating PTGS2 and PTGES in colon cancer progression. We demonstrated that in this pathway mPGES1 is induced by COX2 overexpression, via autocrine PGs release, likely PGF2α, through an EGR1-dependent mechanism. This signaling provides a molecular explanation to PTGS2 and PTGES association and contribute to colon cancer advance, pointing out novel potential therapeutic targets in this oncological context. PMID:26498686

  10. The prostaglandin E2 receptor EP4 is integral to a positive feedback loop for prostaglandin E2 production in human macrophages infected with Mycobacterium tuberculosis

    PubMed Central

    Nishimura, Tomoyasu; Zhao, Xiaomin; Gan, Huixian; Koyasu, Shigeo; Remold, Heinz G.

    2013-01-01

    Prostaglandin E2 (PGE2) is an important biological mediator involved in the defense against Mycobacterium tuberculosis (Mtb) infection. Previously, we reported that in macrophages (Mφs), infection with avirulent Mtb H37Ra resulted in inhibition of necrosis by an inhibitory effect on mitochondrial permeability transition via the PGE2 receptor EP2. However, human Mφs also express EP4, a PGE2 receptor functionally closely related to EP2 that also couples to stimulatory guanine nucleotide binding protein, but the functional differences between EP2 and EP4 in Mtb-infected Mφs have been unclear. EP4 antagonist addition to H37Ra-infected Mφs inhibited the expression of cyclooxygenase 2 (COX2) and microsomal prostaglandin E synthase-1 (mPGES-1), which are involved in PGE2 production. Moreover, H37Ra infection induced PGE2 production through the Toll-like receptor (TLR) 2/p38 mitogen-activated protein kinase (MAPK) signaling pathway. Induction of COX2 and mPGES-1 expression by TLR2 stimulation or Mtb infection was increased after additional stimulation with EP4 agonist. Hence, in Mtb-infected Mφs, PGE2 production induced by pathogen recognition receptors/p38 MAPK signaling is up-regulated by EP4-triggered signaling to maintain an effective PGE2 concentration.—Nishimura, T., Zhao, X., Gan, H., Koyasu, S., and Remold, H. G. The prostaglandin E2 receptor EP4 is integral to a positive feedback loop for prostaglandin E2 production in human macrophages infected with Mycobacterium tuberculosis. PMID:23759445

  11. Elicitation of structure-specific antibodies by epitope scaffolds

    PubMed Central

    Ofek, Gilad; Guenaga, F. Javier; Schief, William R.; Skinner, Jeff; Baker, David; Wyatt, Richard; Kwong, Peter D.

    2010-01-01

    Elicitation of antibodies against targets that are immunorecessive, cryptic, or transient in their native context has been a challenge for vaccine design. Here we demonstrate the elicitation of structure-specific antibodies against the HIV-1 gp41 epitope of the broadly neutralizing antibody 2F5. This conformationally flexible region of gp41 assumes mostly helical conformations but adopts a kinked, extended structure when bound by antibody 2F5. Computational techniques were employed to transplant the 2F5 epitope into select acceptor scaffolds. The resultant “2F5-epitope scaffolds” possessed nanomolar affinity for antibody 2F5 and a range of epitope flexibilities and antigenic specificities. Crystallographic characterization of the epitope scaffold with highest affinity and antigenic discrimination confirmed good to near perfect attainment of the target conformation for the gp41 molecular graft in free and 2F5-bound states, respectively. Animals immunized with 2F5-epitope scaffolds showed levels of graft-specific immune responses that correlated with graft flexibility (p < 0.04), while antibody responses against the graft—as dissected residue-by-residue with alanine substitutions—resembled more closely those of 2F5 than sera elicited with flexible or cyclized peptides, a resemblance heightened by heterologous prime-boost. Lastly, crystal structures of a gp41 peptide in complex with monoclonal antibodies elicited by the 2F5-epitope scaffolds revealed that the elicited antibodies induce gp41 to assume its 2F5-recognized shape. Epitope scaffolds thus provide a means to elicit antibodies that recognize a predetermined target shape and sequence, even if that shape is transient in nature, and a means by which to dissect factors influencing such elicitation. PMID:20876137

  12. Prostaglandins modify phosphorylation of specific proteins in the insect cell line BCIRL-HzAM1

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Prostaglandins (PGs) play crucial roles in vertebrate biology, particularly in immune functions. Because PGs also mediate specific cell functions in insect immunity, we are investigating how these signaling molecules affect insect cells. We reported that PGs, notably PGA1, PGA2, and PGE1, up and/or ...

  13. The Influence of Topical Prostaglandin Analogues in Inflammation After Selective Laser Trabeculoplasty Treatment

    PubMed Central

    Chen, Enping

    2012-01-01

    Abstract Purpose Reducing intraocular pressure (IOP) seems to be the only treatment that slows progression in glaucoma. The IOP can be decreased by pharmaceutical treatment, laser [selective laser trabeculoplasty (SLT)] treatment, or surgery. Prostaglandin analogues have been postulated to share action mechanisms with SLT and to possibly diminish the effects of SLT treatment. The aim of the current study was to investigate the effects of prostaglandin analogues in inflammation and IOP reduction after SLT treatment. Methods Prospective nonrandomized study. One hundred and eighteen patients were included in the study. Inclusion criteria: Glaucoma (open-angle or pseudoexfoliation glaucoma) patients who will be treated with SLT. Inflammation was measured with a laser flare meter (Kowa FM-500). Measurements were made before SLT and then 2 h, 1 week, and 1 month after SLT treatment. IOP was also checked at the same time intervals. The SLT treatment was performed over 90°. All patients were divided into two groups: those receiving prostaglandins analogues and those treated with nonprostaglandin analogues. Results Inflammation before and after SLT showed no significant difference between the groups at all the time intervals studied (t-test, before: P=0.16; 2 h: P=0.14; 1 week: P=0.12; and 1 month: P=0.36). IOP reduction showed no significant difference between the groups (t-test, P=0.31). Conclusions SLT treatment effects do not seem to be influenced by the use of prostaglandin analogues. PMID:22087857

  14. Effect of Diethylcarbamazine (DEC) on prostaglandin levels in Wuchereria bancrofti infected microfilaraemics.

    PubMed

    Sankari, T; Hoti, S L; Das, L K; Govindaraj, V; Das, P K

    2013-06-01

    Diethylcarbamazine (DEC) interferes with arachidonic acid metabolism for the clearance of microfilariae in Wuchereria bancrofti infected individuals. In this study, we have quantified the plasma concentrations of prostaglandin E2 (PGE2) and 6-keto-PGF1α, the end products of arachidonic acid metabolic pathway in microfilaraemics (DEC treated and untreated), and normal healthy individuals at pre- and 3,9,12,36, and 72 h of post-DEC treatment. We have also determined the microfilariae counts at pre and post day 2 (36 h) and day 3 (72 h) of DEC treatment by membrane filtration technique. Significant reduction in PGE2 and 6-keto-PGF1α concentrations was found at 12 h of DEC treatment. Rapid reduction in microfilarial counts was observed at 36 h of post-DEC treatment. Higher levels of prostaglandins were found at pre-treatment hours in microfilaraemics compared to normal healthy individuals (P < 0.05). Our findings indicate that DEC inhibits prostaglandins for the clearance of microfilariae, and increased levels of prostaglandins in microfilaraemics may be contributed by the parasite or host upon stimulation. PMID:23525692

  15. Prostaglandin F2α receptor (FP) signaling regulates Bmp signaling and promotes chondrocyte differentiation

    PubMed Central

    Kim, Joohwee; Shim, Minsub

    2015-01-01

    Prostaglandins are a group of lipid signaling molecules involved in various physiological processes. In addition, prostaglandins have been implicated in the development and progression of diseases including cancer, cardiovascular disease, and arthritis. Prostaglandins exert their effects through the activation of specific G protein-coupled receptors (GPCRs). In this report, we examined the role of prostaglandin F2α receptor (FP) signaling as a regulator of chondrocyte differentiation. We found that FP expression was dramatically induced during the differentiation of chondrocytes and was up-regulated in cartilages. Forced expression of FP in ATDC5 chondrogenic cell line resulted in the increased expression of differentiation-related genes and increased synthesis of the extracellular matrix (ECM) regardless of the presence of insulin. Similarly, PGF2α treatment induced the expression of chondrogenic marker genes. In contrast, knockdown of endogenous FP expression suppressed the expression of chondrocyte marker genes and ECM synthesis. Organ culture of cartilage rudiments revealed that PGF2α induces chondrocyte hypertrophy. Additionally, FP overexpression increased the levels of Bmp-6, phospho-Smad1/5, and Bmpr1a, while knockdown of FP reduced expression of those genes. These results demonstrate that up-regulation of FP expression plays an important role in chondrocyte differentiation and modulates Bmp signaling. PMID:25499765

  16. Insect anti-viral immunity: roles of prostaglandins and other eicosanoids

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Insect/microbe relationships are very complex, with an array of signaling systems acting in surveillance, detection and responses to the presence of microbes. We report that prostaglandins (PGs) are responsible for essential signaling in activating and coordinating insect innate immune reactions to ...

  17. Prostaglandin potentiates 5-HT responses in stomach and ileum innervating visceral afferent sensory neurons.

    PubMed

    Kim, Sojin; Jin, Zhenhua; Lee, Goeun; Park, Yong Seek; Park, Cheung-Seog; Jin, Young-Ho

    2015-01-01

    Gastrointestinal disorder is a common symptom induced by diverse pathophysiological conditions that include food tolerance, chemotherapy, and irradiation for therapy. Prostaglandin E2 (PGE2) level increase was often reported during gastrointestinal disorder and prostaglandin synthetase inhibitors has been used for ameliorate the symptoms. Exogenous administration of PGE2 induces gastrointestinal disorder, however, the mechanism of action is not known. Therefore, we tested PGE2 effect on visceral afferent sensory neurons of the rat. Interestingly, PGE2 itself did not evoked any response but enhanced serotonin (5-HT)-evoked currents up to 167% of the control level. The augmented 5-HT responses were completely inhibited by a 5-HT type 3 receptor antagonist, ondansetron. The PGE2-induced potentiation were blocked by a selective E-prostanoid type 4 (EP4) receptors antagonist, L-161,982, but type 1 and 2 receptor antagonist AH6809 has no effect. A membrane permeable protein kinase A (PKA) inhibitor, KT5720 also inhibited PGE2 effects. PGE2 induced 5-HT current augmentation was observed on 15% and 21% of the stomach and ileum projecting neurons, respectively. Current results suggest a synergistic signaling in visceral afferent neurons underlying gastrointestinal disorder involving PGE2 potentiation of 5-HT currents. Our findings may open a possibility for screen a new type drugs with lower side effects than currently using steroidal prostaglandin synthetase inhibitors by selectively targeting EP4 receptor/PKA pathway without interrupt prostaglandin synthesis. PMID:25446121

  18. Two-year treatment patterns and costs in glaucoma patients initiating treatment with prostaglandin analogs

    PubMed Central

    Schmier, Jordana K; Lau, Edmund C; Covert, David W

    2010-01-01

    Objective To determine treatment patterns and costs over a two-year period among new initiators of topical prostaglandin analogs in a managed care population by retrospective cohort analysis of an insurance claims database. Methods Patients who initiated therapy with a prostaglandin analog between September 2006 and March 2007 were identified. The use of monotherapy and adjunctive therapies were compared by index prostaglandin. Days to initiation of adjunctive therapy and rates of glaucoma surgical procedures were also calculated. Medical costs (antiglaucoma medications and ophthalmic visits) over the two-year period were estimated. Results The analysis identified 5018 patients with at least one prostaglandin analog prescription (bimatoprost, n = 747; latanoprost, n = 1651; benzalkonium chloride (BAK)-free travoprost, n = 203). The majority (51%–54%) had repeat prescriptions. Among those with repeat prescriptions, 52% were female (not significant) and mean age was 64 years (P < 0.01). Rates of adjunctive therapy use varied across groups (bimatoprost 51%, latanoprost 37%, and BAK- free travoprost 35%, P < 0.0001). Median and mean days to initiation of adjunctive therapy were 83 and 140 for bimatoprost, 101 and 181 for latanoprost, and 113 and 221 for BAK- free travoprost. Two-year medical costs were $3147, $2843, and $2557 for patients initiating treatment with bimatoprost, latanoprost, and BAK-free travoprost, respectively. Use of glaucoma surgical procedures across the treatment groups was similar over the two-year period. Conclusions Over a two-year period, the rate and time to initiation of adjunctive therapy use, as well as medical costs, varied between index prostaglandins. However, the rate of glaucoma surgical interventions did not vary significantly across index medications. PMID:20957061

  19. Inhibition of the Prostaglandin Transporter PGT Lowers Blood Pressure in Hypertensive Rats and Mice

    PubMed Central

    Chi, Yuling; Jasmin, Jean-Francois; Seki, Yoshinori; Lisanti, Michael P.; Charron, Maureen J.; Lefer, David J.; Schuster, Victor L.

    2015-01-01

    Inhibiting the synthesis of endogenous prostaglandins with nonsteroidal anti-inflammatory drugs exacerbates arterial hypertension. We hypothesized that the converse, i.e., raising the level of endogenous prostaglandins, might have anti-hypertensive effects. To accomplish this, we focused on inhibiting the prostaglandin transporter PGT (SLCO2A1), which is the obligatory first step in the inactivation of several common PGs. We first examined the role of PGT in controlling arterial blood pressure blood pressure using anesthetized rats. The high-affinity PGT inhibitor T26A sensitized the ability of exogenous PGE2 to lower blood pressure, confirming both inhibition of PGT by T26A and the vasodepressor action of PGE2 T26A administered alone to anesthetized rats dose-dependently lowered blood pressure, and did so to a greater degree in spontaneously hypertensive rats than in Wistar-Kyoto control rats. In mice, T26A added chronically to the drinking water increased the urinary excretion and plasma concentration of PGE2 over several days, confirming that T26A is orally active in antagonizing PGT. T26A given orally to hypertensive mice normalized blood pressure. T26A increased urinary sodium excretion in mice and, when added to the medium bathing isolated mouse aortas, T26A increased the net release of PGE2 induced by arachidonic acid, inhibited serotonin-induced vasoconstriction, and potentiated vasodilation induced by exogenous PGE2. We conclude that pharmacologically inhibiting PGT-mediated prostaglandin metabolism lowers blood pressure, probably by prostaglandin-induced natriuresis and vasodilation. PGT is a novel therapeutic target for treating hypertension. PMID:26121580

  20. The Role of Prostaglandins and COX-Enzymes in Chondrogenic Differentiation of ATDC5 Progenitor Cells

    PubMed Central

    Caron, Marjolein M. J.; Emans, Pieter J.; Sanen, Kathleen; Surtel, Don A. M.; Cremers, Andy; Ophelders, Daan; van Rhijn, Lodewijk W.; Welting, Tim J. M.

    2016-01-01

    Objectives NSAIDs are used to relieve pain and decrease inflammation by inhibition of cyclooxygenase (COX)-catalyzed prostaglandin (PG) synthesis. PGs are fatty acid mediators involved in cartilage homeostasis, however the action of their synthesizing COX-enzymes in cartilage differentiation is not well understood. In this study we hypothesized that COX-1 and COX-2 have differential roles in chondrogenic differentiation. Methods ATDC5 cells were differentiated in the presence of COX-1 (SC-560, Mofezolac) or COX-2 (NS398, Celecoxib) specific inhibitors. Specificity of the NSAIDs and inhibition of specific prostaglandin levels were determined by EIA. Prostaglandins were added during the differentiation process. Chondrogenic outcome was determined by gene- and protein expression analyses. Results Inhibition of COX-1 prevented Col2a1 and Col10a1 expression. Inhibition of COX-2 resulted in decreased Col10a1 expression, while Col2a1 remained unaffected. To explain this difference expression patterns of both COX-enzymes as well as specific prostaglandin concentrations were determined. Both COX-enzymes are upregulated during late chondrogenic differentiation, whereas only COX-2 is briefly expressed also early in differentiation. PGD2 and PGE2 followed the COX-2 expression pattern, whereas PGF2α and TXA2 levels remained low. Furthermore, COX inhibition resulted in decreased levels of all tested PGs, except for PGD2 and PGF2α in the COX-1 inhibited condition. Addition of PGE2 and PGF2α resulted in increased expression of chondrogenic markers, whereas TXA2 increased expression of hypertrophic markers. Conclusions Our findings point towards a differential role for COX-enzymes and PG-production in chondrogenic differentiation of ATDC5 cells. Ongoing research is focusing on further elucidating the functional partition of cyclooxygenases and specific prostaglandin production. PMID:27050768

  1. Prostaglandins attenuate cardiac contractile dysfunction produced by free radical generation but not by hydrogen peroxide.

    PubMed

    Zimmer, K M; Karmazyn, M

    1997-11-01

    The aim of this study was to examine and compare the potential influence of cyclooxygenase or lipoxygenase derived metabolites of arachidonic acid on myocardial injury produced either by a free radical generating system consisting of purine plus xanthine oxidase or that produced by hydrogen peroxide. A free radical generating system consisting of purine (2.3 mM) and xanthine oxidase (10 U/L) as well as hydrogen peroxide (75 microM) produced significant functional changes in the absence of either significant deficits in high energy phosphates or ultrastructural damage. Prostaglandin F2 alpha (30 nM) significantly attenuated both the negative inotropic effect of purine plus xanthine oxidase as well as the ability of the free radical generator to elevate diastolic pressure. An identical concentration of prostaglandin 12 (prostacyclin) significantly reduced diastolic pressure elevation only and had no effect on contractile depression. The salutary effects of the two PGs occurred in the absence of any inhibitory influence on superoxide anion generation produced by the purine and xanthine oxidase reaction. None of prostaglandins modulated the response to hydrogen peroxide. In addition, neither prostaglandin E2 nor leukotrienes exerted any effect on changes produced by either type of oxidative stress. A 5 fold elevation in the concentrations of free radical generators or hydrogen peroxide produced extensive injury as characterized by a virtual total loss in contractility, 400% elevation in diastolic pressure, ultrastructural damage and significant depletions in high energy phosphate content. None of these effects were modulated by eicosanoid treatment. Our results therefore demonstrate a selective ability of both prostaglandin F2 alpha and to a lesser extent prostacyclin, to attenuate dysfunction produced by purine plus xanthine oxidase but not hydrogen peroxide. It is possible that these eicosanoids may represent endogenous protective factors under conditions of enhanced

  2. Inhibition of [3H]catecholamine release and Ca2+ currents by prostaglandin E2 in rabbit carotid body chemoreceptor cells.

    PubMed Central

    Gómez-Niño, A; López-López, J R; Almaraz, L; González, C

    1994-01-01

    Basal release of [3H]catecholamine ([3H]CA) from rabbit carotid bodies (CBs), previously incubated in the presence of [3H]tyrosine, was not significantly modified by prostaglandin E2 (PGE2). On the contrary, PGE2 (3-300 nM) produced a dose-dependent inhibition of the low PO2-evoked release of [3H]CA. The inhibition was greatest (55%) at a low intensity of hypoxic stimulation (incubating solution PO2 approximately 66 mmHg) and decreased with increasing intensities of hypoxia. Chronic denervation of the CB did not modify the response to PGE2. The release of [3H]CA induced by incubating the CBs in a hypercapnic-acidic solution (PCO2 approximately 132 mmHg; pH = 6.60) and by dinitrophenol (100 microM) was not significantly modified by 300 nM PGE2. PGE2 (300 nM) inhibited the release of [3H]CA elicited by incubating the CBs in a high K+ (35 mM)-containing solution. The release response elicited by high K+ (25 mM) was strongly augmented by a dihydropyridine agonist of Ca2+ channels, Bay K 8644, at a concentration of 1 microM. The Bay K 8644 effect was partly inhibited by PGE2 (300 nM). Using whole-cell recordings in freshly dispersed or short-term cultured chemoreceptor cells from adult rabbits it was found that Ca2+ currents (ICa) were reversibly inhibited by bath application of PGE2. A good parallelism exits between the dose-response curves for PGE2 inhibition of ICa in isolated chemoreceptor cells and high extracellular [K+]- or hypoxia-evoked release of [3H]CA from the whole CB.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:7519263

  3. Inhibitors of phosphodiesterases PDE2, PDE3, and PDE4 do not increase the sinoatrial tachycardia of noradrenaline and prostaglandin PGE₁ in mice.

    PubMed

    Galindo-Tovar, Alejandro; Vargas, María Luisa; Kaumann, Alberto J

    2016-02-01

    Phosphodiesterases PDE2, PDE3, and PDE4 are expressed in murine sinoatrial cells. PDE3 and/or PDE4 reduce heart rate but apparently do not influence the tachycardia mediated through sinoatrial β1- and β2-adrenoceptors despite the high content of sinoatrial cAMP. The function of PDE2 is, however, uncertain. Prostaglandin PGE1 elicits sinoatrial tachycardia through EP receptors, but the control by phosphodiesterases is unknown. We investigated on spontaneously beating right atria of mice the effects of the PDE2 inhibitors Bay 60-7550 and EHNA on basal beating and the tachycardia produced by noradrenaline (3 nM) and PGE1 (1 μM). Bay 60-7550 (1 μM), but not EHNA (10 μM), increased basal sinoatrial beating. EHNA also failed to produce tachycardia in the presence of the adenosine deaminase inhibitor 2'-deoxycoformycin (10 μM), remaining inconclusive whether PDE2 reduces basal sinoatrial beating. Rolipram (10 μM) and cilostamide (300 nM) caused moderate tachycardia. The tachycardia evoked by Bay 60-7550 was similar in the absence and presence of rolipram. Noradrenaline elicited stable tachycardia that was not increased by Bay 60-7550. A stable tachycardia caused by PGE1 was not increased by the inhibitors of PDE2, PDE3, and PDE4. Unlike PDE3 and PDE4 which reduce murine basal sinoatrial beating, a possible effect of PDE2 needs further research. The stable tachycardia produced by noradrenaline and PGE1, together with the lack potentiation by the inhibitors of PDE2, PDE3, and PDE4, suggests that cAMP generated at the receptor compartments is hardly hydrolyzed by these phophodiesterases. Evidence from human volunteers is consistent with this proposal. PMID:26531832

  4. Expert elicitation on the uncertainties associated with chronic wasting disease.

    PubMed

    Tyshenko, Michael G; Oraby, Tamer; Darshan, Shalu; Westphal, Margit; Croteau, Maxine C; Aspinall, Willy; Elsaadany, Susie; Krewski, Daniel; Cashman, Neil

    2016-01-01

    A high degree of uncertainty exists for chronic wasting disease (CWD) transmission factors in farmed and wild cervids. Evaluating the factors is important as it helps to inform future risk management strategies. Expert opinion is often used to assist decision making in a number of health, science, and technology domains where data may be sparse or missing. Using the "Classical Model" of elicitation, a group of experts was asked to estimate the most likely values for several risk factors affecting CWD transmission. The formalized expert elicitation helped structure the issues and hence provide a rational basis for estimating some transmission risk factors for which evidence is lacking. Considered judgments regarding environmental transmission, latency of CWD transmission, management, and species barrier were provided by the experts. Uncertainties for many items were determined to be large, highlighting areas requiring more research. The elicited values may be used as surrogate values until research evidence becomes available. PMID:27556566

  5. Gender differences in preschoolers' help-eliciting communication.

    PubMed

    Thompson, R B

    1999-09-01

    Gender differences in help-eliciting communication and the relationship of such utterances with ability were explored. A sample of 71 preschoolers (38 boys, 33 girls; mean age 4 years 3 months) were videotaped as they solved a difficult puzzle. Spontaneous talk was analyzed for orientation (to whom or to what an utterance referred) and for the frequency of utterances coded as help eliciting. Significant main effects for gender were observed, with more frequent help-eliciting utterances (HEUs) made by the girls than by the boys, particularly HEUs about themselves (self-disclosing). Although the girls' HEUs were not predictive of ability on the puzzle, the boys' were. No gender differences in puzzle-solving ability were observed. Findings are discussed with regard to problem solving and social/linguistic development. PMID:10515069

  6. 15-Deoxy-{delta}{sup 12,14}-prostaglandin J{sub 2}-induced down-regulation of endothelial nitric oxide synthase in association with HSP70 induction

    SciTech Connect

    Hwang, Jinah; Lee, Hyun-Il; Chang, Young-Sun; Lee, Soo Jae; Kim, Kwang Pyo; Park, Sang Ick . E-mail: parksi@nih.go.kr

    2007-05-25

    A natural ligand of peroxisome proliferator-activated receptor {gamma} (PPAR{gamma}), 15-deoxy-{delta}{sup 12,14}-prostaglandin J{sub 2} (15d-PGJ{sub 2}), decreases endothelial nitric oxide synthase (eNOS) expression by an unknown mechanism. Here we found that 15d-PGJ{sub 2}-induced eNOS reduction is inversely associated with heat shock protein 70 (HSP70) induction in endothelial cells. Treatment of cells with 15d-PGJ{sub 2} decreased eNOS protein expression in a concentration- and time-dependent manner, but independently of PPAR{gamma} with no effect on mRNA levels. Although 15d-PGJ{sub 2} elicited endothelial apoptosis, inhibition of both pan-caspases and cathepsins failed to reverse reduction of eNOS protein. Interestingly, we observed that 15d-PGJ{sub 2} induced HSP70 in a dose-dependent manner. Immunoprecipitation and heat shock treatment demonstrated that eNOS reduction was strongly related to HSP70 induction. Cellular fractionation revealed that treatment with 15d-PGJ{sub 2} increased eNOS distribution 2.5-fold from soluble to insoluble fractions. These findings provide new insights into mechanisms whereby eNOS regulation by 15d-PGJ{sub 2} is related to HSP70 induction.

  7. Stimulation of prostaglandin E2-synthesis by noradrenaline in primary cell cultures from rabbit splenic pulpa is mediated by atypical alpha-adrenoceptors.

    PubMed

    Brückner-Schmidt, R; Jackisch, R; Hertting, G

    1981-02-01

    In primary cell cultures originating from rabbit splenic pulpa the effects of various adrenoceptor agonists on prostaglandin (PG)-synthesis were studied. The cells - microscopically identified as fibroblasts - released PGs into the medium: especially PGE2 besides small amounts of PGF2alpha and PGD2. Noradrenaline increased dose-dependently the amount of PGs released into the medium. Besides noradrenaline, only the catecholamines adrenaline and alpha-methylnoradrenaline strongly activated PG-synthesis. Other alpha-adrenoceptor agonists like the phenylethylamine and imidazoline derivatives were only weak agonists or completely ineffective. All adrenoceptor agonists without intrinsic activity in these cells antagonized the noradrenaline effect on PG-synthesis, the imidazolines being more potent antagonists than the phenylethylamines. The beta-adrenoceptor agonist isoprenaline stimulated PG-synthesis at high concentration only. The effects of both noradrenaline and isoprenaline were inhibited by low concentrations of phentolamine phenoxybenzamine, but not by propranolol. The preferential alpha2-adrenoceptor antagonists yohimbine and rauwolscine were about 50 times more potent in blocking the noradrenaline effect on PG-synthesis than the more alpha1-specific antagonist corynanthine. However, prazosin, another alpha1-adrenoceptor antagonist, was about equipotent with yohimbine. It is concluded that noradrenaline elicits PG-synthesis in rabbit splenic fibroblasts via alpha-adrenoceptor stimulation. The alpha-adrenoceptor involved has properties which are different from those reported so far for alpha1- or alpha2-adrenoceptors. PMID:6268994

  8. Biologically inspired robots elicit a robust fear response in zebrafish

    NASA Astrophysics Data System (ADS)

    Ladu, Fabrizio; Bartolini, Tiziana; Panitz, Sarah G.; Butail, Sachit; Macrı, Simone; Porfiri, Maurizio

    2015-03-01

    We investigate the behavioral response of zebrafish to three fear-evoking stimuli. In a binary choice test, zebrafish are exposed to a live allopatric predator, a biologically-inspired robot, and a computer-animated image of the live predator. A target tracking algorithm is developed to score zebrafish behavior. Unlike computer-animated images, the robotic and live predator elicit a robust avoidance response. Importantly, the robotic stimulus elicits more consistent inter-individual responses than the live predator. Results from this effort are expected to aid in hypothesis-driven studies on zebrafish fear response, by offering a valuable approach to maximize data-throughput and minimize animal subjects.

  9. 15-deoxy prostaglandin J2, the nonenzymatic metabolite of prostaglandin D2, induces apoptosis in keratinocytes of human hair follicles: a possible explanation for prostaglandin D2-mediated inhibition of hair growth.

    PubMed

    Joo, Hyun Woo; Kang, Yoo Ri; Kwack, Mi Hee; Sung, Young Kwan

    2016-07-01

    Recent studies have shown that prostaglandin D2 (PGD2) and its nonenzymatic metabolite, 15-deoxy-Δ(12,14)-prostaglandin J2 (15-dPGJ2), inhibit in vitro growth of explanted human hair follicles and inhibit hair growth in mice through the GPR44 (DP2). However, the underlying mechanism is still unclear. In this study, we first investigated the expression of DP2 in human hair follicles and in cultured follicular cells. We found that DP2 is strongly expressed in the outer root sheath (ORS) cells and weakly expressed in the dermal papilla (DP) cells. We observed slight growth stimulation when ORS and DP cells were treated with PGD2. We also observed slight growth stimulation when DP and ORS cells were treated with low concentrations (0.5 and 1 μM) of 15-dPGJ2. However, 5 μM 15-dPGJ2 inhibited the viability and caused apoptosis of both cell types. Exposure of cultured human hair follicles to 15-dPGJ2 resulted in significant apoptosis in follicular keratinocytes. Altogether, our data provide an evidence that 15-dPGJ2 promotes apoptosis in follicular keratinocytes and provide rationale for developing remedies for the prevention and treatment of hair loss based on DP2 antagonism. PMID:27185495

  10. Involvement of prostaglandin I(2) in nitric oxide-induced vasodilation of retinal arterioles in rats.

    PubMed

    Mori, Asami; Namekawa, Ryo; Hasebe, Masami; Saito, Maki; Sakamoto, Kenji; Nakahara, Tsutomu; Ishii, Kunio

    2015-10-01

    The soluble guanylyl cyclase/cGMP system plays an important role in the vasodilator response to nitric oxide (NO) in various vascular beds. However, in rat retinal arterioles, the cyclooxygenase-1/cAMP-mediated pathway contributes to the vasodilator effects of NO, although the specific prostanoid involved remains to be elucidated. In the present study, we investigated the role of prostaglandin I2 and its receptor (prostanoid IP receptor) system in NO-induced vasodilation of rat retinal arterioles in vivo. Fundus images were captured using a digital camera that was equipped with a special objective lens. Changes in diameter of retinal arterioles were assessed. The NO donor (±)-(E)-4-ethyl-2-[(E)-hydroxyimino]-5-nitro-3-hexenamide (NOR3) increased the diameter of retinal arterioles but decreased systemic blood pressure in a dose-dependent manner. Treatment of rats with indomethacin, a non-selective cyclooxygenase inhibitor, markedly attenuated the retinal vasodilator, but not depressor responses to NOR3. The prostanoid IP receptor antagonist 4,5-dihydro-N-[4-[[4-(1-methylethoxy)phenyl]methyl]phenyl]-1H-imadazol-2-amine (CAY10441), and the prostaglandin I2 synthase inhibitor 9α,11α-azoprosta-5Z,13E-dien-1-oic acid (U-51605), both showed similar preventive effects against the NOR3-induced retinal vasodilator response. Neither CAY10441 nor U-51605 showed any significant effects on the depressor response to NOR3. NOR3 enhanced the release of prostaglandin I2 from cultured human retinal microvascular endothelial cells and the NOR3-induced prostaglandin I2 release was almost completely abolished by the cyclooxygenase-1 inhibitor SC-560, but not by the cyclooxygenase-2 inhibitor NS-398. However, NOR3 did not increase the release of prostaglandin I2 from human intestinal microvascular endothelial cells. These results suggest that NO exerts its dilatory effect via cyclooxygenase-1/prostaglandin I2/prostanoid IP receptor signaling mechanisms in the retinal vasculature. PMID

  11. Release of prostaglandins from the isolated frog ventricle and associated changes in endogenous cyclic nucleotide levels.

    PubMed Central

    Flitney, F W; Singh, J

    1980-01-01

    1. A study has been made of the decline in contractility and some associated metabolic changes which occur in the isolated frog ventricle during the development of hypodynamic depression. 2. The release of two identified prostaglandins (PG), E1 and E2, together with several as yet unknown prostaglandin-related substances (PRS), accompanies the development of hypodynamic depression. There is a close correlation between the extent to which the isometric twitch is depressed and the quantity of prostaglandin released into the superfusate. 3. Fractionation of extracts of 'used' superfusates, using preparative-scale thin-layer chromatography, revealed the presence of six major components, four of which (PGE1 and PGE2 and two unidentified components) were found to be cardioactive and potentiated contraction when tested subsequently on hypodynamic preparations. 4. Two agents which influence prostaglandin biosynthesis, arachidonic acid and indomethacin, are found to affect both the rate at which the hypodynamic state develops and the extent to which the 'steady-state' twitch tension is depressed, in a dose-dependent manner. Indomethacin, a PG-synthetase inhibitor, accelerates the decay and depresses the final 'steady-state' tension attained, whereas arachidonic acid, the principal precursor for prostaglandin biosynthesis, has the converse effects. 5. Measurements of endogenous 3'5'-cyclic nucleotide levels reveal a time-dependent decrease in intracellular adenosine 3'5'-cyclic monophosphate (3'5'-cyclic AMP) and a concomitant increase in guanosine 3'5' cyclic monophosphate (3'5'-cyclic GMP). The decline in isometric twitch tension is paralleled almost exactly by an equivalent reduction in the ratio 3'5'-cyclic AMP: 3'5'-cyclic GMP. 6. Superfusion of isolated ventricles with Ringer solution containing exogenous, lipid-soluble derivatives of 3'5'-cyclic AMP and 3'5'-cyclic GMP affects both the rate of decline of the isometric twitch and the steady-state tension ultimately

  12. Importance of adipocyte cyclooxygenase-2 and prostaglandin E2-prostaglandin E receptor 3 signaling in the development of obesity-induced adipose tissue inflammation and insulin resistance.

    PubMed

    Chan, Pei-Chi; Hsiao, Fone-Ching; Chang, Hao-Ming; Wabitsch, Martin; Hsieh, Po Shiuan

    2016-06-01

    We examined the involvement of adipocyte cyclooxygenase-2 (COX-2) and prostaglandin E2 (PGE2)-prostaglandin E receptor (EP)3-mediated signaling during hypertrophy and hypoxia in the development of obesity-associated adipose tissue (AT) inflammation and insulin resistance. The experiments were conducted with high-fat diet (HFD)-induced obese rats, db/db mice, human subjects, and 3T3-L1 and the human Simpson-Golabi-Behmel syndrome (SGBS) adipocytes; the groups were treated with selective inhibitors of COX-2 [celecoxib 30 mg/kg, half maximal inhibitory concentration (IC50) ≈ 0.04 µM] and EP3 (L-798106 100 µg/kg, IC50 ≈ 0.5 µM) or a short interfering RNA. There were strong, positive correlations between adipocyte COX-2 and EP3 gene expressions and the AT TNF-α and monocyte chemotactic protein-1 contents and the homeostatic model assessment for insulin resistance in HFD-induced obese rats, as well as body mass index in human subjects. Treatment with COX-2 and EP3 inhibitors significantly reversed AT inflammatory gene and protein expressions (-50%) and impaired glucose and insulin tolerance in db/db mice. COX-2 inhibition diminished the chemotaxis of adipocytes isolated from HFD rats to macrophages and T cells. Targeting inhibition of adipocyte COX-2 and EP3 during hypertrophy and hypoxia reversed the release of the augmented proinflammatory adipokines and the diminished adiponectin and also suppressed NF-κB and hypoxia-inducible factor-1α transcription activation. These findings suggest that adipocyte COX-2 PGE2-EP3-mediated signaling is crucially involved in the development of obesity-associated AT inflammation and insulin resistance.-Chan, P.-C., Hsiao, F.-C., Chang, H.-M., Wabitsch, M., Hsieh, P. S. Importance of adipocyte cyclooxygenase-2 and prostaglandin E2-prostaglandin E receptor 3 signaling in the development of obesity-induced adipose tissue inflammation and insulin resistance. PMID:26932930

  13. Inhibition of microsomal prostaglandin E synthase-1 by aminothiazoles decreases prostaglandin E2 synthesis in vitro and ameliorates experimental periodontitis in vivo

    PubMed Central

    Kats, Anna; Båge, Tove; Georgsson, Pierre; Jönsson, Jörgen; Quezada, Hernán Concha; Gustafsson, Anders; Jansson, Leif; Lindberg, Claes; Näsström, Karin; Yucel-Lindberg, Tülay

    2013-01-01

    The potent inflammatory mediator prostaglandin E2 (PGE2) is implicated in the pathogenesis of several chronic inflammatory conditions, including periodontitis. The inducible enzyme microsomal prostaglandin E synthase-1 (mPGES-1), catalyzing the terminal step of PGE2 biosynthesis, is an attractive target for selective PGE2 inhibition. To identify mPGES-1 inhibitors, we investigated the effect of aminothiazoles on inflammation-induced PGE2 synthesis in vitro, using human gingival fibroblasts stimulated with the cytokine IL-1β and a cell-free mPGES-1 activity assay, as well as on inflammation-induced bone resorption in vivo, using ligature-induced experimental periodontitis in Sprague-Dawley rats. Aminothiazoles 4-([4-(2-naphthyl)-1,3-thiazol-2-yl]amino)phenol (TH-848) and 4-(3-fluoro-4-methoxyphenyl)-N-(4-phenoxyphenyl)-1,3-thiazol-2-amine (TH-644) reduced IL-1β-induced PGE2 production in fibroblasts (IC50 1.1 and 1.5 μM, respectively) as well as recombinant mPGES-1 activity, without affecting activity or expression of the upstream enzyme cyclooxygenase-2. In ligature-induced experimental periodontitis, alveolar bone loss, assessed by X-ray imaging, was reduced by 46% by local treatment with TH-848, compared to vehicle, without any systemic effects on PGE2, 6-keto PGF1α, LTB4 or cytokine levels. In summary, these results demonstrate that the aminothiazoles represent novel mPGES-1 inhibitors for inhibition of PGE2 production and reduction of bone resorption in experimental periodontitis, and may be used as potential anti-inflammatory drugs for treatment of chronic inflammatory diseases, including periodontitis.—Kats, A., Båge, T., Georgsson, P., Jönsson, J., Quezada, H. C., Gustafsson, A., Jansson, L., Lindberg, C., Näsström, K., Yucel-Lindberg, T. Inhibition of microsomal prostaglandin E synthase-1 by aminothiazoles decreases prostaglandin E2 synthesis in vitro and ameliorates experimental periodontitis in vivo. PMID:23447581

  14. Elicited Production of Relative Clauses in Children with Williams Syndrome

    ERIC Educational Resources Information Center

    Zukowski, Andrea

    2009-01-01

    Relative clauses have been implicated alternately as a strength and a weakness in the language of people with Williams Syndrome (WS). To clarify the facts, an elicited production test was administered to 10 people with WS (age 10-16 years), 10 typically developing children (age 4-7 years), and 12 typically developing adults. Nearly every WS…

  15. Computational Support for Early Elicitation and Classification of Tone

    ERIC Educational Resources Information Center

    Bird, Steven; Lee, Haejoong

    2014-01-01

    Investigating a tone language involves careful transcription of tone on words and phrases. This is challenging when the phonological categories--the tones or melodies--have not been identified. Effects such as coarticulation, sandhi, and phrase-level prosody appear as obstacles to early elicitation and classification of tone. This article presents…

  16. A Study of the Affective Responses Elicited by Occupational Stimuli

    ERIC Educational Resources Information Center

    Schoon, Craig G.

    1976-01-01

    The semantic differential was used to assess the properties of affect elicited by occupational stimuli. Vocationally committed men studying medicine, business, and engineering responded to a semantic differential containing occupational concepts. Results show a semantic space for all three groups composed of three orthogonal dimensions of affect…

  17. Creating a Framework: Art Therapy Elicits the Narrative

    ERIC Educational Resources Information Center

    Harber, Karen

    2011-01-01

    A case study illustrates how art therapy was used to elicit the narrative of an adolescent male student in transition from incarceration to a transfer school setting. Childhood trauma was addressed in individual sessions and within a literacy group co-led by a reading specialist. The art therapist responded to the client's needs by broadening the…

  18. Engaging Young Children in Research through Photo Elicitation

    ERIC Educational Resources Information Center

    Pyle, Angela

    2013-01-01

    Embracing the new sociology of childhood, this paper describes a participatory research method built on a belief in the competency of young children. The paper begins with a critical review of the photo elicitation literature exploring the varied levels of children's participation. Drawing on the strengths of the previous research, a…

  19. Photo-Elicitation: Reflexivity on Method, Analysis, and Graphic Portraits

    ERIC Educational Resources Information Center

    Richard, Veronica M.; Lahman, Maria K. E.

    2015-01-01

    In this methodological discussion, the authors detail and reflect on the processes of using photo-elicitation interviewing as a way to align with positive qualitative methodologies, to gain access to participant beliefs and values, and to highlight participant voices through their choices of words and visuals. A review of the literature and an…

  20. Clinicians as Communication Partners: Developing a Mediated Discourse Elicitation Protocol

    ERIC Educational Resources Information Center

    Hengst, Julie A.; Duff, Melissa C.

    2007-01-01

    This article presents the development and piloting of a mediated discourse elicitation protocol. Grounded in situated theories of communication and informed by mediated discourse analysis, this protocol selectively samples familiar discourse types in a manner designed to preserve interactional aspects of communication. Critically, the mediated…

  1. Stimulus Duration Preference at Electrode Sites Yielding Elicited Behavior

    NASA Technical Reports Server (NTRS)

    Cox, V. C.

    1970-01-01

    The latency to display eating or drinking during hypothalamic stimulation was compared with the preferred duration of the same stimulus intensity in a self-stimulation situation. All the animals preferred longer stimulus durations than those required to elicit eating or drinking

  2. Eliciting Design Patterns for E-Learning Systems

    ERIC Educational Resources Information Center

    Retalis, Symeon; Georgiakakis, Petros; Dimitriadis, Yannis

    2006-01-01

    Design pattern creation, especially in the e-learning domain, is a highly complex process that has not been sufficiently studied and formalized. In this paper, we propose a systematic pattern development cycle, whose most important aspects focus on reverse engineering of existing systems in order to elicit features that are cross-validated through…

  3. A Task that Elicits Reasoning: A Dual Analysis

    ERIC Educational Resources Information Center

    Yankelewitz, Dina; Mueller, Mary; Maher, Carolyn A.

    2010-01-01

    This paper reports on the forms of reasoning elicited as fourth grade students in a suburban district and sixth grade students in an urban district worked on similar tasks involving reasoning with the use of Cuisenaire rods. Analysis of the two data sets shows similarities in the reasoning used by both groups of students on specific tasks, and the…

  4. Elicitation Support Requirements of Multi-Expertise Teams

    ERIC Educational Resources Information Center

    Bitter-Rijpkema, Marlies; Martens, Rob; Jochems, Wim

    2005-01-01

    Tools to support knowledge elicitation are used more and more in situations where employees or students collaborate using the computer. Studies indicate that differences exist between experts and novices regarding their methods of work and reasoning. However, the commonly preferred approach tends to deal with team members as a single system with…

  5. Using Automatic Speech Recognition Technology with Elicited Oral Response Testing

    ERIC Educational Resources Information Center

    Cox, Troy L.; Davies, Randall S.

    2012-01-01

    This study examined the use of automatic speech recognition (ASR) scored elicited oral response (EOR) tests to assess the speaking ability of English language learners. It also examined the relationship between ASR-scored EOR and other language proficiency measures and the ability of the ASR to rate speakers without bias to gender or native…

  6. Eliciting Production of L2 Target Structures through Priming Activities

    ERIC Educational Resources Information Center

    McDonough, Kim; Trofimovich, Pavel; Neumann, Heike

    2015-01-01

    This study focuses on the pedagogical applications of structural priming research in an English for academic purposes (EAP) context, investigating whether priming activities are an effective tool for eliciting production of target grammatical structures. University students across four EAP classes carried out a total of 6 information-exchange…

  7. Transfer of Aversive Respondent Elicitation in Accordance with Equivalence Relations

    ERIC Educational Resources Information Center

    Valverde, Miguel Rodriguez; Luciano, Carmen; Barnes-Holmes, Dermot

    2009-01-01

    The present study investigates the transfer of aversively conditioned respondent elicitation through equivalence classes, using skin conductance as the measure of conditioning. The first experiment is an attempt to replicate Experiment 1 in Dougher, Augustson, Markham, Greenway, and Wulfert (1994), with different temporal parameters in the…

  8. Eliciting Students' Beliefs about Who Is Good at Mathematics

    ERIC Educational Resources Information Center

    Morge, Shelby P.

    2007-01-01

    This article highlights a series of activities designed to elicit students' mathematics-related beliefs, particularly those related to gender. As a result of the activities, females in upper-level classes rated themselves as having less confidence than males, and viewing a movie clip was sufficient for some students to modify their descriptions of…

  9. The Role of Elicited Verbal Imitation in Toddlers' Word Learning

    ERIC Educational Resources Information Center

    Hodges, Rosemary; Munro, Natalie; Baker, Elise; McGregor, Karla; Docking, Kimberley; Arciuli, Joanne

    2016-01-01

    This study is about the role of elicited verbal imitation in toddler word learning. Forty-eight toddlers were taught eight nonwords linked to referents. During training, they were asked to imitate the nonwords. Naming of the referents was tested at three intervals (one minute later [uncued], five minutes, and 1-7 days later [cued]) and recognition…

  10. Photo-Elicitation Method Gives Voice and Reactions of Subjects.

    ERIC Educational Resources Information Center

    Smith, C. Zoe; Woodward, Anne-Marie

    1999-01-01

    Describes a research assignment (called "photo-elicitation") in a graduate course on the role of photography in society in which students interview people similar to the subjects in the photographs to discover how the photographs affect them. Includes material from one research project interviewing three recovering drug addicts responding to Larry…

  11. Preparing Beginning Teachers to Elicit and Interpret Students' Mathematical Thinking

    ERIC Educational Resources Information Center

    Sleep, Laurie; Boerst, Timothy A.

    2012-01-01

    This study investigated how teacher education assignments can be designed to support beginning teachers in learning to do the work of teaching. We examined beginners' formative assessment practices--in particular, their eliciting and interpreting of students' mathematical thinking--in the context of an elementary mathematics methods assignment,…

  12. Lipopolysaccharide induces proinflammatory cytokines and chemokines in experimental otitis media through the prostaglandin D2 receptor (DP)-dependent pathway

    PubMed Central

    Eguchi, M; Kariya, S; Okano, M; Higaki, T; Makihara, S; Fujiwara, T; Nagata, K; Hirai, H; Narumiya, S; Nakamura, M; Nishizaki, K

    2011-01-01

    Otitis media is one of the most common and intractable ear diseases, and is the major cause of hearing loss, especially in children. Multiple factors affect the onset or development of otitis media. Prostaglandin D2 is the major prostanoid involved in infection and allergy. However, the role of prostaglandin D2 and prostaglandin D2 receptors on the pathogenesis of otitis media remains to be determined. Recent studies show that D prostanoid receptor (DP) and chemoattractant receptor-homologous molecule expressed on T helper type 2 (Th2) cells (CRTH2) are major prostaglandin D2 receptors. In this study, homozygous DP single gene-deficient (DP–/–) mice, CRTH2 single gene-deficient (CRTH2–/–) mice and DP/CRTH2 double gene-deficient (DP–/– CRTH2–/–) mice were used to investigate the role of prostaglandin D2 and its receptors in otitis media. We demonstrate that prostaglandin D2 is induced by lipopolysaccharide (LPS), a major component of Gram-negative bacteria, and that transtympanic injection of prostaglandin D2 up-regulates macrophage inflammatory protein 2 (MIP-2), interleukin (IL)-1β and IL-6 in the middle ear. We also show that middle ear inflammatory reactions, including infiltration of inflammatory cells and expression of MIP-2, IL-1β and IL-6 induced by LPS, are reduced significantly in DP–/– mice and DP–/– CRTH2–/– mice. CRTH2–/– mice display inflammatory reactions similar to wild-type mice. These findings indicate that prostaglandin D2 may play significant roles in LPS-induced experimental otitis media via DP. PMID:21166666

  13. Lipopolysaccharide induces proinflammatory cytokines and chemokines in experimental otitis media through the prostaglandin D2 receptor (DP)-dependent pathway.

    PubMed

    Eguchi, M; Kariya, S; Okano, M; Higaki, T; Makihara, S; Fujiwara, T; Nagata, K; Hirai, H; Narumiya, S; Nakamura, M; Nishizaki, K

    2011-02-01

    Otitis media is one of the most common and intractable ear diseases, and is the major cause of hearing loss, especially in children. Multiple factors affect the onset or development of otitis media. Prostaglandin D₂ is the major prostanoid involved in infection and allergy. However, the role of prostaglandin D₂ and prostaglandin D2 receptors on the pathogenesis of otitis media remains to be determined. Recent studies show that D prostanoid receptor (DP) and chemoattractant receptor-homologous molecule expressed on T helper type 2 (Th2) cells (CRTH2) are major prostaglandin D₂ receptors. In this study, homozygous DP single gene-deficient (DP⁻(/)⁻) mice, CRTH2 single gene-deficient (CRTH2⁻(/)⁻) mice and DP/CRTH2 double gene-deficient (DP⁻(/)⁻ CRTH2⁻(/)⁻) mice were used to investigate the role of prostaglandin D₂ and its receptors in otitis media. We demonstrate that prostaglandin D₂ is induced by lipopolysaccharide (LPS), a major component of Gram-negative bacteria, and that transtympanic injection of prostaglandin D₂ up-regulates macrophage inflammatory protein 2 (MIP-2), interleukin (IL)-1β and IL-6 in the middle ear. We also show that middle ear inflammatory reactions, including infiltration of inflammatory cells and expression of MIP-2, IL-1β and IL-6 induced by LPS, are reduced significantly in DP⁻(/)⁻ mice and DP⁻(/)⁻ CRTH2⁻(/)⁻ mice. CRTH2⁻(/)⁻ mice display inflammatory reactions similar to wild-type mice. These findings indicate that prostaglandin D₂ may play significant roles in LPS-induced experimental otitis media via DP. PMID:21166666

  14. Prostaglandin E specifically upregulates the expression of the mannose-receptor on mouse bone marrow-derived macrophages.

    PubMed Central

    Schreiber, S; Blum, J S; Chappel, J C; Stenson, W F; Stahl, P D; Teitelbaum, S L; Perkins, S L

    1990-01-01

    The macrophage mannose receptor (MMR) facilitates the binding and internalization of microorganisms and glycoproteins with terminal mannose residues. The receptor is progressively upregulated as bone marrow precursor cells mature into macrophages and thus may serve as a marker of differentiation. Prostaglandins of the E series (PGE) are known inhibitors of monocyte and macrophage precursor proliferation, an effect often associated with cellular maturation. MMR expression was therefore assessed after exposure of bone marrow macrophage precursor (BMMP) cells to these prostanoids. Receptor expression was determined by ligand binding and via immunoprecipitation of newly synthesized receptor molecules. PGE1 and PGE2 at 10(-9)-10(-6) M upregulated MMR surface expression and biosynthesis four- to sixfold in a dose-dependent manner. BMMPs responsive to prostaglandins were characterized by plastic adherence, F4/80 antigen expression, and nonspecific esterase activity. Prostaglandins accelerated the expression of the MMR in cells by 48-72h, with maximal levels of receptor expression being identical in control or treated cells. Thus, prostaglandins enhanced mannose receptor expression in adherent but not fully differentiated macrophage precursors. This effect is specific for PGE and is mimicked by dibutyrl cyclic AMP. These results indicate that prostaglandins accelerate MMR expression and hence the differentiation of macrophage precursor cells. Cells resident in the bone marrow secrete abundant prostaglandins, suggesting that a paracrine mechanism may exist to regulate MMR expression and function. Images PMID:1965946

  15. On the ability of prostaglandin E1, and arachidonic acid to modulate experimentally induced oedema in the rat paw.

    PubMed Central

    Lewis, A J; Nelson, D J; Sugrue, M F

    1975-01-01

    1 Prostaglandins E1 and E2 but not prostaglandin F2alpha, arachidonic acid or linolenic acid, produced slight oedema when injected into the rat hindpaw. 2 Prostaglandin E1 potentiated hindpaw oedema produced by carrageenan, kaolin, bradykinin and trypsin but not that produced by 5-hydroxytryptamine (5-HT), histamine, dextran B or compound 48/80. Carrageenan- and bradykinin-induced paw oedemas were also potentiated by prostaglandin E2. Arachidonic acid potentiated responses to carrageenan and kaolin but not responses to bradykinin, trypsin, 5-HT, histamine, dextran B or compound 48/80. Linolenic acid did not potentiate hindpaw oedema induced by carrageenan. 3 Potentiation of carrageenan-induced oedema by prostaglandin E1 was not diminished by pretreatment with indomethacin, hydrocortisone or cyproheptadine. However, arachidonic acid potentiation of carrageenan oedema was reduced by pretreatment with non-steroidal anti-inflammatory drugs but not by anti-inflammatory steroids or by paracetamol. 4 The enhancement of the response to carrageenan and kaolin by prostaglandins E1, E2 and arachidonic acid is discussed in terms of kinin mediation. PMID:1182349

  16. Abnormal Expression of Prostaglandins E2 and F2α Receptors and Transporters in Patients with Endometriosis

    PubMed Central

    Rakhila, Halima; Bourcier, Nathalie; Akoum, Ali; Pouliot, Marc

    2015-01-01

    Objective. To investigate the level of expression of prostaglandin receptivity and uptake factors in eutopic and ectopic endometrium of women with endometriosis. Design. Prospective study. Setting. Human reproduction research laboratory. Patients. Seventy-eight patients with endometriosis and thirty healthy control subjects. Intervention(s). Endometrial and endometriotic tissue samples were obtained during laparoscopic surgery. Main Outcome Measure(s). Real-time polymerase chain reaction assay of mRNA encoding prostaglandin E2 receptors (EP1, EP2, EP3, and EP4), prostaglandin F2α receptor (FP), prostaglandin transporter (PGT), and multidrug resistance-associated protein 4 (MRP4); immunohistochemical localization of expressed proteins. Results. Marked increases in receptors EP3, EP4, and FP and transporters PGT and MRP4 in ectopic endometrial tissue were noted, without noticeable change associated with disease stage. An increase in EP3 expression and decreases in FP and PGT were observed in the eutopic endometrium of endometriosis patients in conjunction with the phases of the menstrual cycle. Conclusion(s). This study is the first to demonstrate a possible relationship between endometriosis and enhanced prostaglandin activity. In view of the wide range of prostaglandin functions, increasing cell receptivity and facilitating uptake in endometrial tissue could contribute to the initial steps of overgrowth and have an important role to play in the pathogenesis and symptoms of this disease. PMID:26240828

  17. In vitro prostaglandin E2 stimulation of /sup 45/Ca mobilization from chick bone

    SciTech Connect

    Satterlee, D.G.; Amborski, G.F.; McIntyre, M.D.; Parker, M.S.; Jacobs-Perry, L.A.

    1984-04-01

    The ability of prostaglandin E2 (PGE2) to mobilize /sup 45/Ca from chick embryo long bones was assayed in an in vitro bone culture system. Concentrations of PGE2 tested ranged from 10(-9) to 10(-5) M. The PGE2 was effective in stimulating release of /sup 45/Ca from prelabelled bones at all concentrations tested except at 10(-9) M. In addition, stimulation of /sup 45/Ca release could be produced daily for 4 consecutive days of PGE2 culture-pulsing at what appeared to be the optimal PGE2 concentration, 10(-7) M. The authors conclude, as in mammals, PGE2 is a potent stimulator of calcium mobilization from avian bone. The potential involvement of prostaglandins in eggshell formation is discussed.

  18. Arachidonic acid release and prostaglandin synthesis in a macrophage-like cell line exposed to asbestos.

    PubMed

    Brown, R C; Poole, A

    1984-10-01

    A macrophage-like cell line (P388D1) has been treated with asbestos and the release of arachidonic acid and its metabolites has been studied using two methods. In the first monolayer cultures of the cells were labelled with tritiated arachidonic acid and the release of label into the medium was quantified: secondly the synthesis and release of prostaglandins E2 and F2 alpha were followed using radioimmune assay. Crocidolite asbestos caused the greatest release of tritium while the medium from chrysotile-treated cultures contained more of both prostaglandins. Both of the fibrous dusts were significantly more active in both test systems than were the two 'inert' materials--titanium dioxide and milled sample of crocidolite. It is suggested that these phenomena are due to the effect of mineral dusts on phospholipase activity and that differences in this activity are associated with differences in the pathogenicity of various mineral dusts. PMID:6098173

  19. A prospective self-controlled study of fertility after second-trimester prostaglandin-induced abortion.

    PubMed

    MacKenzie, I Z; Fry, A

    1988-05-01

    One hundred forty women whose pregnancies were terminated in the second trimester with prostaglandins because of suspected fetal disease have been prospectively followed to assess their subsequent fertility. In six instances difficulties had been experienced in conceiving the pregnancy that was terminated. Since abortion 104 women have conceived, 97% within 24 months of abortion but in five instances after some delay. Only one woman had not succeeded in conceiving a wished-for pregnancy. There were no apparent differences in abortion management between those women readily conceiving and those in whom there was some delay, although termination because of chromosomal reasons or anatomic abnormalities was less commonly followed by another pregnancy as compared with those terminated for rubella or other viral infections. Reduced fertility after a late prostaglandin-induced abortion thus appears to be very infrequent. PMID:3369497

  20. Inhibition of microsomal prostaglandin E synthase-1 as targeted therapy in cancer treatment.

    PubMed

    Larsson, Karin; Jakobsson, Per-Johan

    2015-07-01

    The bioactive lipid prostaglandin E2 (PGE2) is involved in several steps of carcinogenesis in some of the most common cancers, e.g. colon cancer, lung cancer, prostate cancer and breast cancer. Non-steroidal anti-inflammatory drugs (NSAIDs) that target cyclooxygenase (COX) activity, the first step of the PGE2 biosynthesis, has been found to reduce the incidence of colon cancer. Due to severe adverse effects on the gastrointestinal tract and the cardiovascular system, their use as chemopreventing agent has been hampered. Genetic deletion of microsomal prostaglandin E synthase-1 (mPGES-1), the enzyme responsible for the second step of the PGE2 biosynthesis, has resulted in reduced tumor progression in mouse models of colon cancer. Inhibition of mPGES-1 would potentially be beneficial to a great number of patients without the side effects associated with long-term treatment with traditional NSAIDs. PMID:26100239

  1. Preoperative cervical dilatation by vaginal pessaries containing prostaglandin E1 analogue.

    PubMed

    Chen, J K; Elder, M G

    1983-09-01

    A double-blind trial comparing use of placebo with use of a single intravaginal pessary of 1 mg 16,16-dimethyl-trans-delta 2-prostaglandin E1 methyl ester, inserted approximately three hours before first-trimester surgical abortion, was carried out. There were 54 women each in the study and control groups. A spring gauge was used to record the force required to dilate the cervix. With the use of the prostaglandin analogue, operative time, blood loss, and the need for additional mechanical dilatation of the cervix were significantly reduced compared with the control group (P less than .0001). This reduction greatly facilitates the operation and should reduce the incidence of cervical trauma. PMID:6348613

  2. Does Prostaglandin D2 hold the cure to male pattern baldness?

    PubMed Central

    Nieves, Ashley; Garza, Luis A.

    2014-01-01

    Lipids in the skin are the most diverse in the entire human body. Their bioactivity in health and disease is underexplored. Prostaglandin D2 has recently been identified as a factor which is elevated in the bald scalp of men with androgenetic alopecia and has the capacity to decrease hair lengthening. An enzyme which synthesizes it, prostaglandin D2 synthase (PTGDS or lipocalin-PGDS) is hormone responsive in multiple other organs. PGD2 has two known receptors, GPR44 and PTGDR. GPR44 was found to be necessary for the decrease in hair growth by PGD2. This creates an exciting opportunity to perhaps create novel treatments for androgenetic alopecia which inhibit the activity of PTGDS, PGD2 or GPR44. This review discusses the current knowledge surrounding PGD2 and future steps needed to translate these findings into novel therapies for patients with androgenetic alopecia. PMID:24521203

  3. Prostaglandin-Associated Periorbital Lipodystrophy in Cosmetic Eyelid Surgery: A Novel Cause of Facial Asymmetry.

    PubMed

    Eftekhari, Kian; Mifflin, Mark D; Anderson, Richard L

    2016-03-01

    A 70-year-old woman presented to our practice with profound ptosis of the left upper eyelid and notable asymmetry of the periocular area. On examination, she was noted to have significant atrophy of the periocular tissues on the left side, with lower eyelid retraction. These features were present but less severe on the right side. Upon further questioning, she stated that she had cataract surgery on the left side that was complicated by a high intraocular pressure and required subsequent secondary surgery. She had taken a prostaglandin eyedrop for many months after her cataract surgery to keep the eye pressure low. Recently, a newly recognized adverse effect of prostaglandin eyedrops has been described in the ophthalmic literature in which patients develop periorbital lipodystrophy. This case emphasizes that this may occur unilaterally in patients taking the eyedrop in only one eye, and should be recognized prior to considering functional and aesthetic surgery of the periocular area. PMID:26374814

  4. 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

  5. Prostaglandin synthesis in aorta of atherosclerosis susceptible and atherosclerosis resistant pigeons.

    PubMed

    Subbiah, M T; Schweiger, E; Deitmeyer, D; Gallon, L; Sinzinger, H

    1980-01-01

    The aortas of 9 months aged Show Racer and White Carneau pigeons were examined for their PGE2, PGF2 alpha and 6-keto-PGF1 alpha synthesis from labelled arachidonic acid by radiothinlayer chromatography. The prostacyclin formation was estimated by means of Moncada's bioassay. PGE2 and PGF 2 alpha synthesis in the aorta of pigeons is higher than in rats, whereas less 6-keto-PGF1 alpha is formed in pigeon aortas. The susceptible White Carneau pigeons synthesitize more prostaglandins than the resistant Show Racer pigeons. PGI2 and 6-keto-PGF 1 alpha-formation is extremely low in avian arota. These data are in part contradicting to our findings im mammalians (where the atherosclerosis susceptible animals generate less PGI2) and warrants sequential measurements of prostaglandin synthesis in aorta to assess its significance during various stages of atherogenesis. PMID:7425865

  6. [Current conservative treatment of renal colic: value of prostaglandin synthesis inhibitors].

    PubMed

    Zwergel, U; Felgner, J; Rombach, H; Zwergel, T

    1998-04-20

    Prostaglandin synthesis inhibitors and parasympatholytic drugs are often used as analgetics in the case of renal colic. This paper analyzes how and whether these drug effects are important for the analgetic therapy. In an animal and in a human model with acutely obstructed kidneys we found that intravenous application of Indometacine and dipyrone significantly reduces renal pelvic pressure. The parasympatholytic drug hyoscine butylbromide did not produce any change of upper urinary tract dynamics. Inhibitors of prostaglandin synthesis thus effect pressure reduction in the renal pelvis, which is necessary for analgetic therapy. In contrast, hyoscine butylbromide does not have any influence on the acute upper urinary tract obstruction; consequently its usefulness in the treatment of renal colic is rather doubtful. PMID:12799978

  7. I - Prostaglandin hyperalgesia, a cAMP/Ca2+ dependent process.

    PubMed

    Ferreira, S H; Nakamura, M

    1979-08-01

    Prostaglandins stimulate cAMP increase in several biological systems including CNS. The possible participation of a cAMP/Ca2+ related mechanism in prostaglandin induced hyperalgesia in the rat paw, as measured by a modification of the Randall-Selitto method was investigated. A serie of agents was administered in the paw in an attempt to change either Ca2+ or cyclic AMP concentration at the nociceptive terminations. PGE2, dibutyryl cyclic AMP, isoprenaline, noradrenaline, adrenaline, Ca2+ionophore (A23187), BaCl2 caused a dose dependent hyperalgesia. The hyperalgesic effect of these substances was enhanced by methyl-xanthines. Cyclic GMP as well as agents which interfere with Ca2+ influx (verapamil and lanthanum) were local analgesics in normal and hyperalgesic paws. PMID:230542

  8. Prostaglandin E2 induces vascular relaxation by E-prostanoid 4 receptor-mediated activation of endothelial nitric oxide synthase.

    PubMed

    Hristovska, Ana-Marija; Rasmussen, Lasse E; Hansen, Pernille B L; Nielsen, Susan S; Nüsing, Rolf M; Narumiya, Shuh; Vanhoutte, Paul; Skøtt, Ole; Jensen, Boye L

    2007-09-01

    The present experiments were designed to test the hypothesis that prostaglandin (PG) E(2) causes vasodilatation through activation of endothelial NO synthase (eNOS). Aortic rings from mice with targeted deletion of eNOS and E-prostanoid (EP) receptors were used for contraction studies. Blood pressure changes in response to PGE(2) were measured in conscious mice. Single doses of PGE(2) caused concentration-dependent relaxations during contractions to phenylephrine (EC(50)=5*10(-8) mol/L). Relaxation after PGE(2) was absent in rings without endothelium and in rings from eNOS(-/-) mice and was abolished by N(G)-nitro-l-arginine methyl ester and the soluble guanylate cyclase inhibitor 1H(1,2,4)-oxadiazolo-[4,3-a]quinoxalin-1-one. In PGE(2)-relaxed aortic rings, the cGMP content increased significantly. PGE(2)-induced relaxations were abolished by the EP4 receptor antagonist AE3-208 (10(-8) mol/L) and mimicked by an EP4 agonist (AE1-329, 10(-7) mol/L) in the presence of endothelium and eNOS only. Relaxations were attenuated significantly in rings from EP4(-/-) mice but normal in EP2(-/-). Inhibitors of the cAMP-protein kinase A pathway attenuated, whereas the inhibitor of protein phosphatase 1C, calyculin (10(-8) mol/L), abolished the PGE(2)-mediated relaxation. In aortic rings, PGE(2) dephosphorylated eNOS at Thr(495). Chronically catheterized eNOS(-/-) mice were hypertensive (137+/-3.6 mm Hg, n=13, versus 101+/-3.9 mm Hg, n=9) and exhibited a lower sensitivity of blood pressure reduction in response to PGE(2) compared with wild-type mice. There was no difference in the blood pressure response to nifedipine. These findings show that PGE(2) elicits EP4 receptor-mediated, endothelium-dependent stimulation of eNOS activity by dephosphorylation at Thr(495) resulting in guanylyl cyclase-dependent vasorelaxation and accumulation of cGMP in aortic rings. PMID:17635857

  9. Characterization of a thromboxane A2/prostaglandin H2 receptor in guinea pig lung membranes using a radioiodinated thromboxane mimetic

    SciTech Connect

    Saussy, D.L. Jr.; Mais, D.E.; Dube, G.P.; Magee, D.E.; Brune, K.A.; Kurtz, W.L.; Williams, C.M. )

    1991-01-01

    Thromboxane A2 (TXA2) and prostaglandin H2 (PGH2) are potent constrictors of airway smooth muscle and may mediate some of the pulmonary effects of leukotrienes. To date, the TXA2/PGH2 receptor in lung has not been well characterized. In this report, we describe the evaluation of the TXA2/PGH2 receptor in guinea pig lung membranes using the new radiolabeled TXA2 mimetic (1S(1 alpha,2 beta(5Z),3 alpha(1E,3S*),4 alpha))-7-(3-(3-hydroxy-4-(4'- iodophenoxy)-1-butenyl)-7-oxabicyclo-(2.2.1)heptan-2-yl)-5-h eptenoic acid (IBOP). IBOP elicited a dose-dependent contraction of guinea pig lung parenchymal strips (EC50 = 3.03 +/- 0.97 nM, three experiments), which was blocked by the TXA2/PGH2 antagonists SQ29548 (pKB = 7.44 +/- 0.2, three experiments), BM13505 (pKB = 6.29 +/- 0.26, three experiments), and I-PTA-OH (pKB = 5.82 +/- 0.36, three experiments). In radioligand binding studies, the binding of (125I)IBOP to guinea pig lung membranes prepared from perfused lungs was saturable, displaceable, and dependent upon protein concentration. Binding was optimal at pH 6.5 and was enhanced by the addition of mono- and divalent cations. The standard assay buffer was 25 mM 3-(N-morpholino)propanesulfonic acid, pH 6.5, 100 mM NaCl, 5 mM MgCl2. Binding was inhibited by pretreatment with dithiothreitol, N-ethylmaleimide, or beta-mercaptoethanol. Binding was unaffected by the addition of guanine nucleotide analogs at concentrations up to 300 microM. Analysis of the time course of binding of (125)IBOP at 30 degrees yielded k-1 = 0.0447 min-1, k1 = 2.49 x 10(8) M-1 min-1, and Kd = k-1/k1 = 180 pM. Computer analysis of equilibrium binding studies using nonlinear methods (LUNDON-1) revealed a single class of noninteracting binding sites with a Kd of 86.9 +/- 11.9 pM and a Bmax of 81.8 +/- 7.7 fmol/mg of protein (three experiments).

  10. Antagonism by antipyretics of the hyperthermic effect of a prostaglandin precursor, sodium arachidonate, in the cat.

    PubMed Central

    Clark, W G; Cumby, H R

    1976-01-01

    1. Injection of sodium arachidonate (100-400 mug) into lateral cerebral ventricles of unanaesthetized cats caused shivering and rapid development of dose-related hyperthermic responses. Unless arachidonate is hyperthermogenic per se, this indicates that in vivo formation of prostaglandins, or perhaps an endoperoxide intermediate, can cause hyperthermia. 2. Tolerance gradually developed when arachidonate was administered repeatedly at intervals of 1-7 days. Examination of the brains of several tolerant animals revealed in each case marked enlargement of the lateral ventricles which apparently accounted for the diminished response to arachidonate. 3. Sodium salicylate (40, 160 mg/kg, i.v.) antagonized arachidonate but only after a 3-4 hr latent period. 4. Paracetamol (10, 40 mg/kg, i.v.) reduced the hyperthermic effect of arachidonate but a dose of 40 mg/kg antagonized centrally administered bacterial endotoxin more effectively than it did arachidonate. 5. Indomethacin (40 mug/kg, i.v.) significantly reduced arachidonate-induced hyperthermia in only one of two studies. This reduction was comparable to the hypothermic effect of indomethacin in afebrile animals and was attributed to a non-specific action on thermoregulatory function rather than to inhibition of prostaglandin synthesis. Indomethacin antagonized endotoxin and leucocytic pyrogen to a greater degree than it did arachidonate. 6. Comparison of the relative effectiveness of the antipyretics in blocking hyperthermic responses to pyrogens and to sodium arachidonate indicates that, if prostaglandins do mediate pyrogen-induced fever, these antipyretics exert their primary at a step before prostaglandin synthesis. PMID:950606

  11. Requirement of cyclooxygenase-2 expression and prostaglandins for human prostate cancer cell invasion.

    PubMed

    Nithipatikom, Kasem; Isbell, Marilyn A; Lindholm, Paul F; Kajdacsy-Balla, Andre; Kaul, Sushma; Campell, William B

    2002-01-01

    The PC-3 Low Invasive cells and the PC-3 High Invasive cells were used to investigate the correlation of the COX-2 expression and its arachidonic acid metabolites, prostaglandins, with their invasiveness through Matrigel using a Boyden chamber assay. The COX-2 expression in PC-3 High Invasive cells was approximately 3-fold higher than in PC-3 Low Invasive cells while the COX-1 expression was similar in both cell sublines. When incubated with arachidonic acid, PGE2 was the major prostaglandin produced by these cells. PC-3 High Invasive cells produced PGE2 approximately 2.5-fold higher than PC-3 Low Invasive cells. PGD2 was the second most abundant prostaglandin produced by these cells. Both indomethacin (a nonspecific COX inhibitor) and NS-398 (a specific COX-2 inhibitor) inhibited the production of prostaglandins and the cell invasion. PGE2 alone did not induce the cell invasion of PC-3 Low Invasive cells. However, PGE2 reversed the inhibition of cell invasion by NS-398 and enhanced the cell invasion of the PC-3 High Invasive cells. In contrast, PGD2 slightly inhibited the cell invasion. These results suggest that in the PC-3 Low Invasive cells, COX-2-derived PGE2 may not be sufficient to induce cell invasion while in the PC-3 High Invasive cells, PGE2 may be sufficient to act as an enhancer for the cell invasion. Further, PGD2 may represent a weak inhibitor and counteracts the effect of PGE2 in the cell invasion. PMID:12498388

  12. Comparison of nociceptive behavior in prostaglandin E, F, D, prostacyclin and thromboxane receptor knockout mice.

    PubMed

    Popp, Laura; Häussler, Annett; Olliges, Anke; Nüsing, Rolf; Narumiya, Shuh; Geisslinger, Gerd; Tegeder, Irmgard

    2009-08-01

    Antagonist at specific prostaglandin receptors might provide analgesia with a more favourable toxicity profile compared with cyclooxygenase inhibitors. We analyzed nociceptive responses in prostaglandin D, E, F, prostacyclin and thromboxane receptor knockout mice and mice deficient of cyclooxygenase 1 or 2 to evaluate the contribution of individual prostaglandin receptors for heat, mechanical and formalin-evoked pain. None of the knockouts was uniformly protected from all of these pain stimuli but COX-1 and EP4 receptor knockouts presented with reduced heat pain and EP3 receptor and COX-2 knockout mice had reduced licking responses in the 2nd phase of the formalin assay. This was accompanied with reduced c-Fos immunoreactivity in the spinal cord dorsal horn in EP3 knockouts. Oppositely, heat pain sensitivity was increased in FP, EP1 and EP1+3 double mutant mice possibly due to a loss of FP or EP1 receptor mediated central control of thermal pain sensitivity. Deficiency of either EP2 or DP1 was associated with increased formalin-evoked flinching responses and c-Fos IR in dorsal horn neurons suggesting facilitated spinal cord pain reflex circuity. Thromboxane and prostacyclin receptor knockout mice showed normal pain behavior in all tests. The results suggest a differential, pain-stimulus and site-specific contribution of specific PG-receptors for the processing of the nociceptive stimuli, a differential modulation of nociceptive responses by COX-1 and COX-2 derived prostaglandins and compensatory and/or developmental adaptations in mice lacking specific PG receptors. PMID:18938093

  13. Biochemical Warfare on the Reef: The Role of Glutathione Transferases in Consumer Tolerance of Dietary Prostaglandins

    PubMed Central

    Whalen, Kristen E.; Lane, Amy L.; Kubanek, Julia; Hahn, Mark E.

    2010-01-01

    Background Despite the profound variation among marine consumers in tolerance for allelochemically-rich foods, few studies have examined the biochemical adaptations underlying diet choice. Here we examine the role of glutathione S-transferases (GSTs) in the detoxification of dietary allelochemicals in the digestive gland of the predatory gastropod Cyphoma gibbosum, a generalist consumer of gorgonian corals. Controlled laboratory feeding experiments were used to investigate the influence of gorgonian diet on Cyphoma GST activity and isoform expression. Gorgonian extracts and semi-purified fractions were also screened to identify inhibitors and possible substrates of Cyphoma GSTs. In addition, we investigated the inhibitory properties of prostaglandins (PGs) structurally similar to antipredatory PGs found in high concentrations in the Caribbean gorgonian Plexaura homomalla. Principal Findings Cyphoma GST subunit composition was invariant and activity was constitutively high regardless of gorgonian diet. Bioassay-guided fractionation of gorgonian extracts revealed that moderately hydrophobic fractions from all eight gorgonian species examined contained putative GST substrates/inhibitors. LC-MS and NMR spectral analysis of the most inhibitory fraction from P. homomalla subsequently identified prostaglandin A2 (PGA2) as the dominant component. A similar screening of commercially available prostaglandins in series A, E, and F revealed that those prostaglandins most abundant in gorgonian tissues (e.g., PGA2) were also the most potent inhibitors. In vivo estimates of PGA2 concentration in digestive gland tissues calculated from snail grazing rates revealed that Cyphoma GSTs would be saturated with respect to PGA2 and operating at or near physiological capacity. Significance The high, constitutive activity of Cyphoma GSTs is likely necessitated by the ubiquitous presence of GST substrates and/or inhibitors in this consumer's gorgonian diet. This generalist's GSTs may

  14. Intraocular pressure dynamics with prostaglandin analogs: a clinical application of the water-drinking test

    PubMed Central

    Özyol, Pelin; Özyol, Erhan; Baldemir, Ercan

    2016-01-01

    Aim To evaluate the clinical applicability of the water-drinking test in treatment-naive primary open-angle glaucoma patients. Methods Twenty newly diagnosed primary open-angle glaucoma patients and 20 healthy controls were enrolled in this prospective study. The water-drinking test was performed at baseline and 6 weeks and 3 months after prostaglandin analog treatment. Peak and fluctuation of intraocular pressure (IOP) measurements obtained with the water-drinking test during follow-up were analyzed. Analysis of variance for repeated measures and paired and unpaired t-tests were used for statistical analysis. Results The mean baseline IOP values in patients with primary open-angle glaucoma were 25.1±4.6 mmHg before prostaglandin analog treatment, 19.8±3.7 mmHg at week 6, and 17.9±2.2 mmHg at month 3 after treatment. The difference in mean baseline IOP of the water-drinking tests was statistically significant (P<0.001). At 6 weeks of prostaglandin analog treatment, two patients had high peak and fluctuation of IOP measurements despite a reduction in baseline IOP. After modifying treatment, patients had lower peak and fluctuation of IOP values at month 3 of the study. Conclusion Peak and fluctuation of IOP in response to the water-drinking test were lower with prostaglandin analogs compared with before medication. The water-drinking test can represent an additional benefit in the management of glaucoma patients, especially by detecting higher peak and fluctuation of IOP values despite a reduced mean IOP. Therefore, it could be helpful as a supplementary method in monitoring IOP in the clinical practice. PMID:27555742

  15. The effect of vitreous humour on prostaglandin production by cultured rabbit chorioretinal fibroblasts.

    PubMed

    Martin, C E; Croft, K D; van Bockxmeer, F M; Constable, I J

    1987-12-10

    Factors in vitreous humour which regulate prostaglandin production were investigated using cultured rabbit chorioretinal fibroblasts. These cells produced predominantly prostaglandin E2, 6-ketoprostaglandin F1 alpha, a compound likely to be a metabolite of prostaglandin E2 and 5-hydroxyeicosatetraenoic acid. The synthesis of 6-ketoprostaglandin F1 alpha was nearly completely inhibited by the cyclooxygenase inhibitor aspirin and partially inhibited by 10(-6) M dexamethasone (49%) and 10(-5) M forskolin (68%). Addition of 10% rabbit vitreous humour to subconfluent cells maintained in Dulbecco's modified Eagle's medium plus 1% fetal bovine serum resulted in stimulation of 6-ketoprostaglandin F1 alpha production by as much as 246% as measured by radioimmunoassay. Chorioretinal fibroblasts labelled by [3H]arachidonic acid incorporation into cellular phospholipids synthesised greater amounts of all labelled arachidonic acid metabolites in response to vitreous humour. It was concluded, therefore, that there are factors present in vitreous humour of molecular weight above 10 kDa which are capable of stimulating cellular cyclooxygenase activity. Confluent cells also responded to a factor(s) present in vitreous humour. The fraction of less than 10 kDa inhibited 6-ketoprostaglandin F1 alpha production by 50% when used at a concentration of 10%. Furthermore, 6-ketoprostaglandin F1 alpha production in confluent cells (but not subconfluent cells) was inhibited to 40% of control levels by vitamin C at a concentration of 1 mg/100 ml. The latter result points to an inhibitory role for vitamin C in vitreous humour. We conclude, therefore, that vitreous humour contains factors important for the regulation of prostaglandin metabolism in the eye. PMID:3118960

  16. Improvement in the quality of hematopoietic prostaglandin D synthase crystals in a microgravity environment.

    PubMed

    Tanaka, Hiroaki; Tsurumura, Toshiharu; Aritake, Kosuke; Furubayashi, Naoki; Takahashi, Sachiko; Yamanaka, Mari; Hirota, Erika; Sano, Satoshi; Sato, Masaru; Kobayashi, Tomoyuki; Tanaka, Tetsuo; Inaka, Koji; Urade, Yoshihiro

    2011-01-01

    Human hematopoietic prostaglandin synthase, one of the better therapeutic target enzymes for allergy and inflammation, was crystallized with 22 inhibitors and in three inhibitor-free conditions in microgravity. Most of the space-grown crystals showed better X-ray diffraction patterns than the terrestrially grown ones, indicating the advantage of a microgravity environment on protein crystallization, especially in the case of this protein. PMID:21169700

  17. Mechanical stimulation of skeletal muscle mitigates glucocorticoid induced decreases in prostaglandin synthesis

    NASA Technical Reports Server (NTRS)

    Chromiak, Joseph A.; Vandenburgh, Herman H.

    1993-01-01

    The glucocorticoid dexamethasone (Dex) induces a decline in protein synthesis and protein content of tissue cultured, avian skeletal muscle cells, and this atrophy is attenuated by repetitive mechanical stretch. Since the prostaglandin synthesis inhibitor indomethacin mitigated this stretch attenuation of muscle atrophy, the role of prostaglandins as growth modulators in these processes was examined. Dex at 10(exp -8) M reduced PGF(sub 2(alpha)) production 55 percent - 65 percent and PGE(sub 2) production 84 - 90 percent after 24 - 72 h of incubation in static cultures. Repetitive 10 percent stretch-relaxations of the non-Dex treated cultures increased PGF(sub 2(alpha)) efflux 41 percent at 24 h and 276 percent at 72 h and increased PGE(sub 2) production 51 percent at 24 h and 236 percent at 72 h. Mechanical stimulation of Dex treated cultures increased PGF(sub 2(alpha)) production 162 percent after 24 h, thus returning PGF(sub 2(alpha)) efflux to the level of non-Dex treated cultures. At 72 h, stretch increased PGF(sub 2(alpha)) efflux 65 percent in Dex treated cultures, but PGF(sub 2(alpha)) production was 45-84 percent less than non-Dex treated cultures. Mechanical stimulation of Dex treated cultures increased PGE(sub 2) production at 24 h, but not at 72 h. Dex reduced prostaglandin H synthase (PGHS) activity in the muscle cultures by 70 percent after 8 - 24 h of incubation, and mechanical stimulation increased PGHS activity of the Dex treated cultures by 98 percent. It is concluded that repetitive mechanical stimulation attenuates the catabolic effects of Dex on cultured skeletal muscle cells in part by reversing the Dex-induced declines in PGHS activity and prostaglandin production.

  18. Effects of anti-inflammatory agents and some other drugs on prostaglandin biotransport.

    PubMed

    Bito, L Z; Salvador, E V

    1976-08-01

    The inhibitory effects of drugs on prostaglandin biotransport were studied by measuring the concentrative accumulation of 3H by rabbit choroid plexuses, segments of anterior uvea and kidney cortex slices after incubation in tissue culture medium containing 3H-prostaglandin F2 alpha. After 10 minutes of incubation in the absence of an inhibitor, the choroid plexus showed a tissue/medium 3H accumulation ratio of 14 +/- 0.7; after 30 minutes of incubation, the anterior uvea and the kidney cortex slices showed accumulation ratios of 6.4 +/- 0.5 and 5.6 +/- 0.1, respectively. The I50 values for inhibition of 3H accumulation by indomethacin were 10, 8 and 12 muM for the three tissues, respectively. Some related drugs-oxyphenbutazone, D-naproxen, l-naproxen, ibuprofen, phenylbutazone and pirprofen-were also found to be effective inhibitors of 3H accumulation (I50 for anterior uvea, 6-28 muM) whereas aspirin, dexamethasone phosphate and penicillin had an inhibitory effect only at much higher concentrations (I50 0.1-2.0 mM). Papaverine, fursemide and probenecid were approximately as effective as the anti-inflammatory organic acids (I50 0.01-0.1 mM), whereas bromcresol green was at least 10-fold more effective. Diphenhydramine and the nonacidic prostaglandin synthesis inhibitors, phenelzine and paracetamol, showed little (I50 greater than 1 mM) or no inhibitory effect. The inhibition of this transport system by some drugs, most notably nonsteroidal anti-inflammatory organic acids, and consequent alterations in the distribution and disposition of prostaglandins must be taken into account in the development of new anti-inflammatory agents and in the interpretation of the mechansim of action and side effects of such drugs. PMID:948038

  19. Meclofenamate elicits a nephropreventing effect in a rat model of ischemic acute kidney injury by suppressing indoxyl sulfate production and restoring renal organic anion transporters.

    PubMed

    Saigo, Chika; Nomura, Yui; Yamamoto, Yuko; Sagata, Masataka; Matsunaga, Rika; Jono, Hirofumi; Nishi, Kazuhiko; Saito, Hideyuki

    2014-01-01

    Indoxyl sulfate (IS), a putative low-molecular weight uremic toxin, is excreted in the urine under normal kidney function, but is retained in the circulation and tissues during renal dysfunction in acute kidney injury and chronic kidney disease. IS, which is one of the most potent inducers of oxidative stress in the kidney and cardiovascular system, is enzymatically produced in the liver from indole by cytochrome P450-mediated hydroxylation to indoxyl, followed by sulfotransferase-mediated sulfate conjugation. We used rat liver S9 fraction to identify inhibitors of IS production. After testing several compounds, including phytochemical polyphenols, we identified meclofenamate as a potent inhibitor of IS production with an apparent IC50 value of 1.34 μM. Ischemia/reperfusion (I/R) of rat kidney caused a marked elevation in the serum IS concentration 48 hours after surgery. However, intravenous administration of meclofenamate (10 mg/kg) significantly suppressed this increase in the serum level of IS. Moreover, IS concentrations in both kidney and liver were dramatically elevated by renal I/R treatment, but this increase was blocked by meclofenamate. Serum creatinine and blood urea nitrogen were markedly elevated in rats after renal I/R treatment, but these increases were significantly restored by administration of meclofenamate. Renal expression of both basolateral membrane-localized organic anion transporters rOAT1 and rOAT3 was downregulated by I/R treatment. However, expression of rOAT1 and rOAT3 recovered after administration of meclofenamate, which is associated with the inhibition of I/R-evoked elevation of prostaglandin E2. Our results suggest that meclofenamate inhibits hepatic sulfotransferase-mediated production of IS, thereby suppressing serum and renal accumulation of IS. Meclofenamate also prevents the prostaglandin E2-dependent downregulation of rOAT1 and rOAT3 expression. In conclusion, meclofenamate was found to elicit a nephropreventive effect in

  20. Meclofenamate elicits a nephropreventing effect in a rat model of ischemic acute kidney injury by suppressing indoxyl sulfate production and restoring renal organic anion transporters

    PubMed Central

    Saigo, Chika; Nomura, Yui; Yamamoto, Yuko; Sagata, Masataka; Matsunaga, Rika; Jono, Hirofumi; Nishi, Kazuhiko; Saito, Hideyuki

    2014-01-01

    Indoxyl sulfate (IS), a putative low-molecular weight uremic toxin, is excreted in the urine under normal kidney function, but is retained in the circulation and tissues during renal dysfunction in acute kidney injury and chronic kidney disease. IS, which is one of the most potent inducers of oxidative stress in the kidney and cardiovascular system, is enzymatically produced in the liver from indole by cytochrome P450-mediated hydroxylation to indoxyl, followed by sulfotransferase-mediated sulfate conjugation. We used rat liver S9 fraction to identify inhibitors of IS production. After testing several compounds, including phytochemical polyphenols, we identified meclofenamate as a potent inhibitor of IS production with an apparent IC50 value of 1.34 μM. Ischemia/reperfusion (I/R) of rat kidney caused a marked elevation in the serum IS concentration 48 hours after surgery. However, intravenous administration of meclofenamate (10 mg/kg) significantly suppressed this increase in the serum level of IS. Moreover, IS concentrations in both kidney and liver were dramatically elevated by renal I/R treatment, but this increase was blocked by meclofenamate. Serum creatinine and blood urea nitrogen were markedly elevated in rats after renal I/R treatment, but these increases were significantly restored by administration of meclofenamate. Renal expression of both basolateral membrane-localized organic anion transporters rOAT1 and rOAT3 was downregulated by I/R treatment. However, expression of rOAT1 and rOAT3 recovered after administration of meclofenamate, which is associated with the inhibition of I/R-evoked elevation of prostaglandin E2. Our results suggest that meclofenamate inhibits hepatic sulfotransferase-mediated production of IS, thereby suppressing serum and renal accumulation of IS. Meclofenamate also prevents the prostaglandin E2-dependent downregulation of rOAT1 and rOAT3 expression. In conclusion, meclofenamate was found to elicit a nephropreventive effect in

  1. Prostaglandin I2 Attenuates Prostaglandin E2-Stimulated Expression of Interferon γ in a β-Amyloid Protein- and NF-κB-Dependent Mechanism

    PubMed Central

    Wang, Pu; Guan, Pei-Pei; Yu, Xin; Zhang, Li-Chao; Su, Ya-Nan; Wang, Zhan-You

    2016-01-01

    Cyclooxygenase-2 (COX-2) has been recently identified as being involved in the pathogenesis of Alzheimer’s disease (AD). However, the role of an important COX-2 metabolic product, prostaglandin (PG) I2, in AD development remains unknown. Using mouse-derived astrocytes as well as APP/PS1 transgenic mice as model systems, we firstly elucidated the mechanisms of interferon γ (IFNγ) regulation by PGE2 and PGI2. Specifically, PGE2 accumulation in astrocytes activated the ERK1/2 and NF-κB signaling pathways by phosphorylation, which resulted in IFNγ expression. In contrast, the administration of PGI2 attenuated the effects of PGE2 on stimulating the production of IFNγ via inhibiting the translocation of NF-κB from the cytosol to the nucleus. Due to these observations, we further studied these prostaglandins and found that both PGE2 and PGI2 increased Aβ1–42 levels. In detail, PGE2 induced IFNγ expression in an Aβ1–42-dependent manner, whereas PGI2-induced Aβ1–42 production did not alleviate cells from IFNγ inhibition by PGI2 treatment. More importantly, our data also revealed that not only Aβ1–42 oligomer but also fibrillar have the ability to induce the expression of IFNγ via stimulation of NF-κB nuclear translocation in astrocytes of APP/PS1 mice. The production of IFNγ finally accelerated the deposition of Aβ1–42 in β-amyloid plaques. PMID:26869183

  2. Cyclooxygenase-2 and Prostaglandin E2 Signaling through Prostaglandin Receptor EP-2 Favor the Development of Myocarditis during Acute Trypanosoma cruzi Infection

    PubMed Central

    Guerrero, Néstor A.; Camacho, Mercedes; Vila, Luis; Íñiguez, Miguel A.; Chillón-Marinas, Carlos; Cuervo, Henar; Poveda, Cristina; Fresno, Manuel; Gironès, Núria

    2015-01-01

    Inflammation plays an important role in the pathophysiology of Chagas disease, caused by Trypanosoma cruzi. Prostanoids are regulators of homeostasis and inflammation and are produced mainly by myeloid cells, being cyclooxygenases, COX-1 and COX-2, the key enzymes in their biosynthesis from arachidonic acid (AA). Here, we have investigated the expression of enzymes involved in AA metabolism during T. cruzi infection. Our results show an increase in the expression of several of these enzymes in acute T. cruzi infected heart. Interestingly, COX-2 was expressed by CD68+ myeloid heart-infiltrating cells. In addition, infiltrating myeloid CD11b+Ly6G- cells purified from infected heart tissue express COX-2 and produce prostaglandin E2 (PGE2) ex vivo. T. cruzi infections in COX-2 or PGE2-dependent prostaglandin receptor EP-2 deficient mice indicate that both, COX-2 and EP-2 signaling contribute significantly to the heart leukocyte infiltration and to the release of chemokines and inflammatory cytokines in the heart of T. cruzi infected mice. In conclusion, COX-2 plays a detrimental role in acute Chagas disease myocarditis and points to COX-2 as a potential target for immune intervention. PMID:26305786

  3. The prostaglandin E2 receptor EP4 is integral to a positive feedback loop for prostaglandin E2 production in human macrophages infected with Mycobacterium tuberculosis.

    PubMed

    Nishimura, Tomoyasu; Zhao, Xiaomin; Gan, Huixian; Koyasu, Shigeo; Remold, Heinz G

    2013-09-01

    Prostaglandin E2 (PGE2) is an important biological mediator involved in the defense against Mycobacterium tuberculosis (Mtb) infection. Previously, we reported that in macrophages (Mϕs), infection with avirulent Mtb H37Ra resulted in inhibition of necrosis by an inhibitory effect on mitochondrial permeability transition via the PGE2 receptor EP2. However, human Mϕs also express EP4, a PGE2 receptor functionally closely related to EP2 that also couples to stimulatory guanine nucleotide binding protein, but the functional differences between EP2 and EP4 in Mtb-infected Mϕs have been unclear. EP4 antagonist addition to H37Ra-infected Mϕs inhibited the expression of cyclooxygenase 2 (COX2) and microsomal prostaglandin E synthase-1 (mPGES-1), which are involved in PGE2 production. Moreover, H37Ra infection induced PGE2 production through the Toll-like receptor (TLR) 2/p38 mitogen-activated protein kinase (MAPK) signaling pathway. Induction of COX2 and mPGES-1 expression by TLR2 stimulation or Mtb infection was increased after additional stimulation with EP4 agonist. Hence, in Mtb-infected Mϕs, PGE2 production induced by pathogen recognition receptors/p38 MAPK signaling is up-regulated by EP4-triggered signaling to maintain an effective PGE2 concentration. PMID:23759445

  4. Gastroprotective Effect of Geopropolis from Melipona scutellaris Is Dependent on Production of Nitric Oxide and Prostaglandin.

    PubMed

    Ribeiro-Junior, Jerônimo Aparecido; Franchin, Marcelo; Cavallini, Miriam Elias; Denny, Carina; de Alencar, Severino Matias; Ikegaki, Masaharu; Rosalen, Pedro Luiz

    2015-01-01

    The aim of this study was to evaluate the gastroprotective activity of ethanolic extract of geopropolis (EEGP) from Melipona scutellaris and to investigate the possible mechanisms of action. The gastroprotective activity of the EEGP was evaluated using model ulcer induced by ethanol. To elucidate the possible mechanisms of action, we investigated the involvement of the nonprotein sulfhydryl (NP-SH) groups, nitric oxide and prostaglandins. In addition, the antisecretory activity of EEGP was also evaluated by pylorus ligated model. The EEGP orally administrated (300 mg/kg) reduced the ulcerative lesions induced by the ethanol (P < 0.05). Regarding the mechanism of action, the prior administration of nitric oxide and prostaglandins antagonists suppressed the activity of gastroprotective EEGP (P < 0.05). On the other hand the gastroprotective activity of EEGP was kept in the group pretreated with the antagonist of the NP-SH groups; furthermore the antisecretory activity was not significant (P > 0.05). These results support the alternative medicine use of geopropolis as gastroprotective and the activities observed show to be related to nitric oxide and prostaglandins production. PMID:25949263

  5. Gastroprotective Effect of Geopropolis from Melipona scutellaris Is Dependent on Production of Nitric Oxide and Prostaglandin

    PubMed Central

    Ribeiro-Junior, Jerônimo Aparecido; Franchin, Marcelo; Cavallini, Miriam Elias; Denny, Carina; de Alencar, Severino Matias; Ikegaki, Masaharu; Rosalen, Pedro Luiz

    2015-01-01

    The aim of this study was to evaluate the gastroprotective activity of ethanolic extract of geopropolis (EEGP) from Melipona scutellaris and to investigate the possible mechanisms of action. The gastroprotective activity of the EEGP was evaluated using model ulcer induced by ethanol. To elucidate the possible mechanisms of action, we investigated the involvement of the nonprotein sulfhydryl (NP-SH) groups, nitric oxide and prostaglandins. In addition, the antisecretory activity of EEGP was also evaluated by pylorus ligated model. The EEGP orally administrated (300 mg/kg) reduced the ulcerative lesions induced by the ethanol (P < 0.05). Regarding the mechanism of action, the prior administration of nitric oxide and prostaglandins antagonists suppressed the activity of gastroprotective EEGP (P < 0.05). On the other hand the gastroprotective activity of EEGP was kept in the group pretreated with the antagonist of the NP-SH groups; furthermore the antisecretory activity was not significant (P > 0.05). These results support the alternative medicine use of geopropolis as gastroprotective and the activities observed show to be related to nitric oxide and prostaglandins production. PMID:25949263

  6. Effect of radioprotectant WR 2721 on cyclic nucleotides, prostaglandins, and lysosomes

    SciTech Connect

    Trocha, P.J.; Catravas, G.N.

    1983-05-01

    Within 1 hr after ip injection of the radioprotectant WR 2721 into rats, splenic cGMP levels dropped and remained suppressed for 6 hr before returning to normal. However, if rats were exposed to ionizing radiation 30-40 min after WR 2721 treatment, they had higher cGMP levels at 3 hr postirradiation than the nonirradiUted, drug-treated controls, but the cGMP content was still found to be lower than that of the irradiated nondrug-treated controls. Radiation exposure of animals pretreated with WR 2721 also resulted in higher liver and spleen levels of cAMP and additional elevations in spleen prostaglandin content, compared with irradiated controls at 3-6 hr after radiation treatment. The secondary fluctuations of lysosomal enzyme activities, prostaglandin content, and cyclic nucleotide levels were also altered in irradiated rats pretreated with WR 2721 when compared with irradiated controls. Liver and spleen lysosomal ..beta..-glucuronidase activities, spleen cAMP and cGMP levels, and spleen prostaglandin concentrations were closer to physiological levels at 3 days postirradiation in rats given WR 2721 before the radiation treatment.

  7. [Inhibition of prostaglandins synthesis in the inflamed site results in opioid-mediated hypoalgesia in rats].

    PubMed

    Huang, Jian; Wu, Jian; Yang, Huai-Zu; Hong, Yanguo

    2016-06-25

    This study was designed to investigate the contribution of prostaglandins to the maintenance of inflammatory pain. Inflammation was induced by intraplantar (i.pl.) injection of carrageenan in right hindpaw in rats. Indomethacin (non-selective COX inhibitor) was administered i.pl. 1 h after the carrageenan injection, and paw withdrawal latency (PWL) responding to noxious heat was measured. β-endorphin (β-END) and μ-opioid receptor (MOR) expressed in the inflamed site were examined by using immunocytochemistry, ELISA and RT-PCR techniques. The results showed that indomethacin dose-dependently increased PWL to the levels that were above the baseline on the day 2 and 3, referred to as hypoalgesia. The hypoalgesia was abolished by a local injection of the non-selective opioid receptor inhibitor naloxone methiodide. The number of β-END-positive cells, the content of β-END and the expression of MOR mRNA in the inflammatory site of inflammation model rats were all significantly increased by indomethacin. These results reveal a novel mechanism of prostaglandins for the inhibition of inflammation-induced endogenous opioid activity. This study provides further evidence that inhibition of prostaglandins in inflamed site could be a promising therapy for inflammatory pain. PMID:27350196

  8. Inhibition of prostaglandin E2 receptor EP3 mitigates thrombin-induced brain injury.

    PubMed

    Han, Xiaoning; Lan, Xi; Li, Qiang; Gao, Yufeng; Zhu, Wei; Cheng, Tian; Maruyama, Takayuki; Wang, Jian

    2016-06-01

    Prostaglandin E2 EP3 receptor is the only prostaglandin E2 receptor that couples to multiple G-proteins, but its role in thrombin-induced brain injury is unclear. In the present study, we exposed mouse hippocampal slice cultures to thrombin in vitro and injected mice with intrastriatal thrombin in vivo to investigate the role of EP3 receptor in thrombin-induced brain injury and explore its underlying cellular and molecular mechanisms. In vitro, EP3 receptor inhibition reduced thrombin-induced hippocampal CA1 cell death. In vivo, EP3 receptor was expressed in astrocytes and microglia in the perilesional region. EP3 receptor inhibition reduced lesion volume, neurologic deficit, cell death, matrix metalloproteinase-9 activity, neutrophil infiltration, and the number of CD68(+) microglia, but increased the number of Ym-1(+) M2 microglia. RhoA-Rho kinase levels were increased after thrombin injection and were decreased by EP3 receptor inhibition. In mice that received an intrastriatal injection of autologous arterial blood, inhibition of thrombin activity with hirudin decreased RhoA expression compared with that in vehicle-treated mice. However, EP3 receptor activation reversed this effect of hirudin. These findings show that prostaglandin E2 EP3 receptor contributes to thrombin-induced brain damage via Rho-Rho kinase-mediated cytotoxicity and proinflammatory responses. PMID:26661165

  9. Antifibrotic Effects of Noscapine through Activation of Prostaglandin E2 Receptors and Protein Kinase A*

    PubMed Central

    Kach, Jacob; Sandbo, Nathan; La, Jennifer; Denner, Darcy; Reed, Eleanor B.; Akimova, Olga; Koltsova, Svetlana; Orlov, Sergei N.; Dulin, Nickolai O.

    2014-01-01

    Myofibroblast differentiation is a key process in the pathogenesis of fibrotic disease. We have shown previously that differentiation of myofibroblasts is regulated by microtubule polymerization state. In this work, we examined the potential antifibrotic effects of the antitussive drug, noscapine, recently found to bind microtubules and affect microtubule dynamics. Noscapine inhibited TGF-β-induced differentiation of cultured human lung fibroblasts (HLFs). Therapeutic noscapine treatment resulted in a significant attenuation of pulmonary fibrosis in the bleomycin model of the disease. Noscapine did not affect gross microtubule content in HLFs, but inhibited TGF-β-induced stress fiber formation and activation of serum response factor without affecting Smad signaling. Furthermore, noscapine stimulated a rapid and profound activation of protein kinase A (PKA), which mediated the antifibrotic effect of noscapine in HLFs, as assessed with the PKA inhibitor, PKI. In contrast, noscapine did not activate PKA in human bronchial or alveolar epithelial cells. Finally, activation of PKA and the antifibrotic effect of noscapine in HLFs were blocked by the EP2 prostaglandin E2 receptor antagonist, PF-04418948, but not by the antagonists of EP4, prostaglandin D2, or prostacyclin receptors. Together, we demonstrate for the first time the antifibrotic effect of noscapine in vitro and in vivo, and we describe a novel mechanism of noscapine action through EP2 prostaglandin E2 receptor-mediated activation of PKA in pulmonary fibroblasts. PMID:24492608

  10. Low-dose prostaglandin E2 analogue for cervical dilatation prior to pregnancy termination.

    PubMed

    Borten, M; DiLeo, L A; Friedman, E A

    1984-11-01

    The trauma of mechanical cervical dilatation preceding abortion is directly related to the degree of cervical resistance. Prostaglandins may reduce cervical rigidity but are accompanied by undesirable side effects. Our aims were to ascertain if a low-dose (10 mg) analogue (9-deoxo-16, 16 dimethyl-9-methylene PGE2) is effective and well tolerated and, if so, to try to determine the possible mechanism by which it works. To this end, we studied 39 women with gestational ages ranging from 7 to 19 weeks who were given a single vaginal suppository 1 to 4 hours before suction curettage. In addition to demographic data on age, gravidity, parity, and previous abortions, we determined progesterone, human chorionic gonadotropin and prostaglandin plasma levels. This low-dose prostaglandin E2 analogue was found to be effective in achieving cervical dilatation and softening with minimal side effects (mild nausea in one patient only). Mean cervical dilatation achieved was 7.8 +/- 2.3 mm. Softening was apparent and facilitated additional instrumental dilatation when required. No correlation was found between drug effectiveness and gravidity, gestational age, or duration of action. There was no detectable trend with regard to baseline progesterone or human chorionic gonadotropin levels. This suggested a specific sensitivity to the local effect by the drug, apparently unrelated to dosage. PMID:6496588

  11. Muscle sympathetic nerve responses to physiological changes in prostaglandin production in humans

    NASA Technical Reports Server (NTRS)

    Doerzbacher, K. J.; Ray, C. A.

    2001-01-01

    Previous studies suggest that prostaglandins may contribute to exercise-induced increases in muscle sympathetic nerve activity (MSNA). To test this hypothesis, MSNA was measured at rest and during exercise before and after oral administration of ketoprofen, a cyclooxygenase inhibitor, or placebo. Twenty-one subjects completed two bouts of graded dynamic and isometric handgrip to fatigue. Each exercise bout was followed by 2 min of postexercise muscle ischemia. The second exercise bouts were performed after 60 min of rest in which 11 subjects were given ketoprofen (300 mg) and 10 subjects received a placebo. Ketoprofen significantly lowered plasma thromboxane B(2) in the drug group (from 36 +/- 6 to 22 +/- 3 pg/ml, P < 0.04), whereas thromboxane B(2) in the placebo group increased from 40 +/- 5 to 61 +/- 9 pg/ml from trial 1 to trial 2 (P < 0.008). Ketoprofen and placebo did not change sympathetic and cardiovascular responses to dynamic handgrip, isometric handgrip, and postexercise muscle ischemia. There was no relationship between thromboxane B(2) concentrations and MSNA or arterial pressure responses during both exercise modes. The data indicate that physiological increases or decreases in prostaglandins do not alter exercise-induced increases in MSNA and arterial pressure in humans. These findings suggest that contraction-induced metabolites other than prostaglandins mediate MSNA responses to exercise in humans.

  12. Role of prostaglandins in the pathogenesis of X-linked hypophosphatemia.

    PubMed

    Baum, Michel; Syal, Ashu; Quigley, Raymond; Seikaly, Mouin

    2006-08-01

    X-linked hypophosphatemia is an X-linked dominant disorder resulting from a mutation in the PHEX gene. PHEX stands for phosphate-regulating gene with endopeptidase activity, which is located on the X chromosome. Patients with X-linked hypophosphatemia have hypophosphatemia due to renal phosphate wasting and low or inappropriately normal levels of 1,25-dihydroxyvitamin D. The renal phosphate wasting is not intrinsic to the kidney but likely due to an increase in serum levels of fibroblast growth factor-23 (FGF-23), and perhaps other phosphate-wasting peptides previously known as phosphatonins. Patients with X-linked hypophosphatemia have short stature, rickets, bone pain and dental abscesses. Current therapy is oral phosphate and vitamin D which effectively treats the rickets and bone pain but does not adequately improve short stature. In this review, we describe recent observations using Hyp mice; mice with the same mutation as patients with X-linked hypophosphatemia. We have recently found that Hyp mice have abnormal renal prostaglandin production, which may be an important factor in the pathogenesis of this disorder. Administration of FGF-23 in vivo results in phosphaturia and an increase in prostaglandin excretion, and FGF-23 increases proximal tubule prostaglandin production in vitro. In Hyp mice, indomethacin improves the phosphate transport defect in vitro and in vivo. Whether indomethacin has the same effect in patients with X-linked hypophosphatemia is unknown. PMID:16721588

  13. Role of prostaglandin D2/CRTH2 pathway on asthma exacerbation induced by Aspergillus fumigatus

    PubMed Central

    Liu, Haixia; Zheng, Mingrui; Qiao, Jianou; Dang, Yajie; Zhang, Pengyu; Jin, Xianqiao

    2014-01-01

    Aspergillus fumigatus is often associated in asthmatic patients with the exacerbation of asthma symptoms. The pathomechanism of this phenomenon has not been fully understood. Here, we evaluated the immunological mechanisms and the role of the prostaglandin D2/ Chemoattractant Receptor-Homologous Molecule Expressed on Th2 Cells (CRTH2) pathway in the development of Aspergillus-associated asthma exacerbation. We studied the effects of A. fumigatus on airway inflammation and bronchial hyper-responsiveness in a rat model of chronic asthma. Inhalation delivery of A. fumigatus conidia increased the airway eosinophilia and bronchial hyper-responsiveness in ovalbumin-sensitized, challenged rats. These changes were associated with prostaglandin D2 synthesis and CRTH2 expression in the lungs. Direct inflammation occurred in ovalbumin-sensitized, challenged animals, whereas pre-treatment with an antagonist against CRTH2 nearly completely eliminated the A. fumigatus-induced worsening of airway eosinophilia and bronchial hyper-responsiveness. Our data demonstrate that production of prostaglandin D2 followed by eosinophil recruitment into the airways via a CRTH2 receptor are the major pathogenic factors responsible for the A. fumigatus-induced enhancement of airway inflammation and responsiveness. PMID:24329550

  14. Antifibrotic effects of noscapine through activation of prostaglandin E2 receptors and protein kinase A.

    PubMed

    Kach, Jacob; Sandbo, Nathan; La, Jennifer; Denner, Darcy; Reed, Eleanor B; Akimova, Olga; Koltsova, Svetlana; Orlov, Sergei N; Dulin, Nickolai O

    2014-03-14

    Myofibroblast differentiation is a key process in the pathogenesis of fibrotic disease. We have shown previously that differentiation of myofibroblasts is regulated by microtubule polymerization state. In this work, we examined the potential antifibrotic effects of the antitussive drug, noscapine, recently found to bind microtubules and affect microtubule dynamics. Noscapine inhibited TGF-β-induced differentiation of cultured human lung fibroblasts (HLFs). Therapeutic noscapine treatment resulted in a significant attenuation of pulmonary fibrosis in the bleomycin model of the disease. Noscapine did not affect gross microtubule content in HLFs, but inhibited TGF-β-induced stress fiber formation and activation of serum response factor without affecting Smad signaling. Furthermore, noscapine stimulated a rapid and profound activation of protein kinase A (PKA), which mediated the antifibrotic effect of noscapine in HLFs, as assessed with the PKA inhibitor, PKI. In contrast, noscapine did not activate PKA in human bronchial or alveolar epithelial cells. Finally, activation of PKA and the antifibrotic effect of noscapine in HLFs were blocked by the EP2 prostaglandin E2 receptor antagonist, PF-04418948, but not by the antagonists of EP4, prostaglandin D2, or prostacyclin receptors. Together, we demonstrate for the first time the antifibrotic effect of noscapine in vitro and in vivo, and we describe a novel mechanism of noscapine action through EP2 prostaglandin E2 receptor-mediated activation of PKA in pulmonary fibroblasts. PMID:24492608

  15. Interactions between ADH and prostaglandins in isolated erythrocyte-perfused rat kidney

    SciTech Connect

    Lieberthal, W.; Vasilevsky, M.L.; Valeri, C.R.; Levinsky, N.G.

    1987-02-01

    Interactions between antidiuretic hormone (ADH) and renal prostaglandins in the regulation of sodium reabsorption and urinary concentrating ability were studied in isolated erythrocyte-perfused rat kidneys (IEPK). In this model, hemodynamic characteristics are comparable to those found in vivo, and tubular morphology is preserved throughout the period of perfusion. (Deamino)-D-arginine vasopressin (dDAVP) markedly reduced fractional sodium excretion (FE/sub Na/) in the IEPK. After indomethacin, FE/sub Na/ fell still further. In the absence of dDAVP indomethacin had no effect on sodium excretion. dDAVP increased urine osmolality in the IEPK. When prostaglandin synthesis was blocked with indomethacin, urinary osmolality increased further. In isolated kidneys perfused without erythrocytes (IPK), dDAVP decreased FE/sub Na/ from 14.5 +/- 1.8% to 9.6 +/- 1.2%. dDAVP increased urine osmolality only modestly in the IPK and indomethacin did not increase concentrating ability further. Thus the IEPK (unlike the IPK) can excrete markedly hypertonic urine in response to ADH. ADH also enhances tubular reabsorption of sodium in the IEPK. Prostaglandins inhibit both these actions of ADH but do not directly affect sodium excretion in the absence of the hormone. Prostaglandius were measured by radioimmunoassay.

  16. Role of prostaglandin D2 /CRTH2 pathway on asthma exacerbation induced by Aspergillus fumigatus.

    PubMed

    Liu, Haixia; Zheng, Mingrui; Qiao, Jianou; Dang, Yajie; Zhang, Pengyu; Jin, Xianqiao

    2014-05-01

    Aspergillus fumigatus is often associated in asthmatic patients with the exacerbation of asthma symptoms. The pathomechanism of this phenomenon has not been fully understood. Here, we evaluated the immunological mechanisms and the role of the prostaglandin D2 / Chemoattractant Receptor-Homologous Molecule Expressed on Th2 Cells (CRTH2) pathway in the development of Aspergillus-associated asthma exacerbation. We studied the effects of A. fumigatus on airway inflammation and bronchial hyper-responsiveness in a rat model of chronic asthma. Inhalation delivery of A. fumigatus conidia increased the airway eosinophilia and bronchial hyper-responsiveness in ovalbumin-sensitized, challenged rats. These changes were associated with prostaglandin D2 synthesis and CRTH2 expression in the lungs. Direct inflammation occurred in ovalbumin-sensitized, challenged animals, whereas pre-treatment with an antagonist against CRTH2 nearly completely eliminated the A. fumigatus-induced worsening of airway eosinophilia and bronchial hyper-responsiveness. Our data demonstrate that production of prostaglandin D2 followed by eosinophil recruitment into the airways via a CRTH2 receptor are the major pathogenic factors responsible for the A. fumigatus-induced enhancement of airway inflammation and responsiveness. PMID:24329550

  17. Blockade of prostaglandin production increases cachectin synthesis and prevents depression of macrophage functions after hemorrhagic shock.

    PubMed Central

    Ertel, W; Morrison, M H; Ayala, A; Perrin, M M; Chaudry, I H

    1991-01-01

    Although hemorrhage severely depresses macrophage functions, it is not known whether the increased TNF-alpha or PGE2 production is responsible for it. To study this C3H/HeN mice were bled to mean blood pressure of 35 mmHg for 60 minutes, resuscitated, and treated with either ibuprofen (1.0 mg/kg body weight) or vehicle (saline). Hemorrhage increased plasma prostaglandin E2 (PGE2) levels by 151.7% +/- 40.0% (p less than 0.05) and significantly decreased peritoneal macrophage (pM phi) antigen presentation (AP) by 60.5% +/- 7.3%, Ia expression by 52.3% +/- 7.6%, and interleukin-1 (IL-1) synthesis by 60.5% +/- 12.3% compared to shams. However ibuprofen treatment reduced PGE2 plasma levels by 61.3% +/- 12.1% and significantly increased AP (+237.0% +/- 95.3%), Ia expression (+72.8% +/- 27.5%), IL-1 synthesis (+235.7% +/- 134.7%), and cachectin synthesis (+485.8% +/- 209.0%) compared to vehicle-treated animals. These results indicate that prostaglandins but not cachectin are involved in the suppression of pM phi functions following hemorrhage because blockade of prostaglandin synthesis improved depressed macrophage functions despite enhanced cachectin synthesis. PMID:1998408

  18. [Intra-arterial administration of prostaglandin E1 in occlusive arterial diseases].

    PubMed

    Davidović, L; Vranes, M; Cernak, I; Kostić, D; Lovrić, A; Sagić, D; Lotina, S

    1992-01-01

    The authors present their result of a two-year follow-up of 106 patients to whom an intra-arterial perfusion of prostaglandin E1 was administered, as limb salvage procedure. The patients were in the IIIrd and IVth stage of occlusive diseases by Fountain, and surgical reconstructions were not possible. All patients were divided into five groups: A--diabetic angiopathy (5), B--distal form of atherosclerosis (40), C--diabetic angiopathy and atherosclerosis (45), D--Burger disease (10) and E--adjuvant therapy in reconstruction with poor run-off (6). The Doppler sonographic and angiographic measurements were performed. After transcutaneous (16 cases), or intraoperative (90 cases) introduction of the catheter into superficial of profunda femoral artery, a continuous intraarterial administration of prostaglandin E1 was carried out in a dose of 10 nanograms/kg body weight/minute (total dosage 3000 nanograms). The patients were controlled immediately after the treatment, as well as 1, 3, 6, 12, 24 and 36 months after the treatment. In efficiency of the treatment was estimated on the following basis: elimination of rest pain, healing of trophic ulceration and demarcation of gangrenous processes. Our late results of intra-arterial administration of prostaglandin E1 proved to be a very successful limb salvage procedure. The treatment was more successful in a connections between the upper knee arterial net and pedal arterial arches were preserved. PMID:1641706

  19. Major role of adipocyte prostaglandin E2 in lipolysis-induced macrophage recruitment.

    PubMed

    Hu, Xiaoqian; Cifarelli, Vincenza; Sun, Shishuo; Kuda, Ondrej; Abumrad, Nada A; Su, Xiong

    2016-04-01

    Obesity induces accumulation of adipose tissue macrophages (ATMs), which contribute to both local and systemic inflammation and modulate insulin sensitivity. Adipocyte lipolysis during fasting and weight loss also leads to ATM accumulation, but without proinflammatory activation suggesting distinct mechanisms of ATM recruitment. We examined the possibility that specific lipid mediators with anti-inflammatory properties are released from adipocytes undergoing lipolysis to induce macrophage migration. In the present study, we showed that conditioned medium (CM) from adipocytes treated with forskolin to stimulate lipolysis can induce migration of RAW 264.7 macrophages. In addition to FFAs, lipolytic stimulation increased release of prostaglandin E2(PGE2) and prostaglandin D2(PGD2), reflecting cytosolic phospholipase A2α activation and enhanced cyclooxygenase (COX) 2 expression. Reconstituted medium with the anti-inflammatory PGE2potently induced macrophage migration while different FFAs and PGD2had modest effects. The ability of CM to induce macrophage migration was abolished by treating adipocytes with the COX2 inhibitor sc236 or by treating macrophages with the prostaglandin E receptor 4 antagonist AH23848. In fasted mice, macrophage accumulation in adipose tissue coincided with increases of PGE2levels and COX1 expression. Collectively, our data show that adipocyte-originated PGE2with inflammation suppressive properties plays a significant role in mediating ATM accumulation during lipolysis. PMID:26912395

  20. Nonlinear Analyses of Elicited Modal, Raised, and Pressed Rabbit Phonation

    PubMed Central

    Awan, Shaheen N.; Novaleski, Carolyn K.; Rousseau, Bernard

    2014-01-01

    Objectives/Hypothesis The purpose of this study was to use nonlinear dynamic analysis methods such as phase space portraits and correlation dimension (D2) as well as descriptive spectrographic analyses to characterize acoustic signals produced during evoked rabbit phonation. Methods Seventeen New Zealand white breeder rabbits were used to perform the study. A Grass S-88 stimulator (SA Instrumentation, Encinitas, CA) and constant current isolation unit (Grass Telefactor, model PSIU6; West Warwick, RI) were used to provide electrical stimulation to laryngeal musculature, and transglottal airflow rate and stimulation current (mA) were manipulated to elicit modal, raised intensity, and pressed phonations. Central 1 second portions of the most stable portion of the acoustic waveform for modal, raised intensity, and pressed phonations were edited, and then analyzed via phase space portraits, Poincaré sections, and the estimation of the correlation dimension (D2). In an attempt to limit the effects of the highly variable and nonstationary characteristics of some of the signals being analyzed, D2 analysis was also performed on the most stable central 200 ms portion of the acoustic waveform. Descriptive analysis of each phonation was also conducted using sound spectrograms. Results Results showed that the complexity of phonation and the subsequent acoustic waveform is increased as transglottal airflow rate and degree of glottal adduction is manipulated in the evoked rabbit phonation model. In particular, phonatory complexity, as quantified via correlation dimension analyses and demonstrated via spectrographic characteristics, increases from “modal” (i.e., phonation elicited at just above the phonation threshold pressure) to raised intensity (phonation elicited by increasing transglottal airflow rate) to pressed (phonation elicited by increasing the stimulation current delivered to the larynx). Variations in a single dynamic dimension (airflow rate or adductory force

  1. Stimulus specificity of prostaglandin inhibition of rabbit polymorphonuclear leukocyte lysosomal enzyme release and superoxide anion production.

    PubMed Central

    Fantone, J. C.; Marasco, W. A.; Elgas, L. J.; Ward, P. A.

    1984-01-01

    Prostaglandins (PGs) of the E series and PGI2 have been shown to inhibit acute inflammatory reactions in vivo and polymorphonuclear leukocyte (PMN), chemotaxis, lysosomal enzyme release, and superoxide anion (O-2) production in vitro. This inhibition of neutrophil stimulation by PGEs and PGI2 has been correlated with their ability to increase intracellular cyclic adenosine monophosphate (cAMP) levels. However, the mechanism(s) by which PGEs and PGI2 alter the complex biochemical and biophysical events associated with stimulus-response coupling in the neutrophil are not clear. It is reported here that both PGEs and PGI2 in micromolar concentrations inhibit formyl-methionyl-leucyl-phenylalanine (FMLP)- and zymosan-induced lysosomal enzyme secretion and superoxide anion production in a dose-dependent manner. No preincubation time of PMNs with the prostaglandins is required for inhibition. Addition of PGEs 10 seconds or later after FMLP stimulation does not alter the biologic response of the neutrophils to the stimulus, suggesting that the prostaglandin inhibition effects early events associated with stimulus-response coupling in the neutrophil. Prostaglandin inhibition of lysosomal enzyme release by the calcium ionophore A23187 was overcome by increasing the extracellular ionophore and/or calcium concentration, suggesting that PGs may modulate intracellular free calcium levels in a manner similar to that observed with platelets. Inhibition of phorbol myristate acetate (PMA)-induced neutrophil lysosomal enzyme secretion by PGEs and PGI2 was overcome by increasing concentrations of PMA. However, neither PGEs nor PGI2 altered O-2 production by PMA-treated neutrophils. These data indicate a dissociation between PMA-stimulated O-2 production and lysosomal enzyme release. These findings are consistent with the hypothesis that inhibition of neutrophil stimulation by PGEs and PGI2 is a result of increased intracellular cyclic AMP levels and modulation of calcium

  2. Prostaglandin potentiates 5-HT responses in stomach and ileum innervating visceral afferent sensory neurons

    SciTech Connect

    Kim, Sojin; Jin, Zhenhua; Lee, Goeun; Park, Yong Seek; Park, Cheung-Seog; Jin, Young-Ho

    2015-01-02

    Highlights: • Prostaglandin E2 (PGE{sub 2}) effect was tested on visceral afferent neurons. • PGE{sub 2} did not evoke response but potentiated serotonin (5-HT) currents up to 167%. • PGE{sub 2}-induced potentiation was blocked by E-prostanoid type 4 receptors antagonist. • PGE{sub 2} effect on 5-HT response was also blocked by protein kinase A inhibitor KT5720. • Thus, PGE{sub 2} modulate visceral afferent neurons via synergistic signaling with 5-HT. - Abstract: Gastrointestinal disorder is a common symptom induced by diverse pathophysiological conditions that include food tolerance, chemotherapy, and irradiation for therapy. Prostaglandin E{sub 2} (PGE{sub 2}) level increase was often reported during gastrointestinal disorder and prostaglandin synthetase inhibitors has been used for ameliorate the symptoms. Exogenous administration of PGE{sub 2} induces gastrointestinal disorder, however, the mechanism of action is not known. Therefore, we tested PGE{sub 2} effect on visceral afferent sensory neurons of the rat. Interestingly, PGE{sub 2} itself did not evoked any response but enhanced serotonin (5-HT)-evoked currents up to 167% of the control level. The augmented 5-HT responses were completely inhibited by a 5-HT type 3 receptor antagonist, ondansetron. The PGE{sub 2}-induced potentiation were blocked by a selective E-prostanoid type4 (EP{sub 4}) receptors antagonist, L-161,982, but type1 and 2 receptor antagonist AH6809 has no effect. A membrane permeable protein kinase A (PKA) inhibitor, KT5720 also inhibited PGE{sub 2} effects. PGE{sub 2} induced 5-HT current augmentation was observed on 15% and 21% of the stomach and ileum projecting neurons, respectively. Current results suggest a synergistic signaling in visceral afferent neurons underlying gastrointestinal disorder involving PGE{sub 2} potentiation of 5-HT currents. Our findings may open a possibility for screen a new type drugs with lower side effects than currently using steroidal prostaglandin

  3. Elicitation of Diacetylenic Compounds in Suspension Cultured Cells of Eggplant

    PubMed Central

    Imoto, Setsuko; Ohta, Yoshimoto

    1988-01-01

    Induction of stress metabolites in the suspension cultured cells of eggplant (Solanum melongena L.) was examined. When autoclaved RNase A or nigeran, both of which are nonspecific phytoalexin elicitors in bean cells, were added to the cell culture of eggplant, greatly enhanced levels of three compounds were observed. One of them was cis-pentadeca-6-ene-1,3-diyne-5,15-diol, a novel diacetylenic compound. This compound has considerable fungitoxic activity. Also identified was falcarindiol, another fungitoxic diacetylenic compound previously reported as one of the phytoalexins in infected tomato fruits and leaves. Elicited compounds preferentially accumulated in the culture medium rather than in the cells and decreased to original levels during prolonged culturing. The elicitation of these compounds was closely correlated with cellular damage in terms of the decrease of growth rate and was inhibited by 10 micromolar cycloheximide. PMID:16665862

  4. Voltage transients elicited by sudden step-up of auxin

    NASA Technical Reports Server (NTRS)

    Pickard, B. G.

    1984-01-01

    It is hypothesized (i) that the molecular mechanism for the reception of friction and flexure and the mechanism by which auxin enhances ethylene production have in common a release of free calcium into the cytosol, (ii) that elevated cytosolic calcium initiates vesicle exocytosis, and (iii) that the vesicles release a factor or set of factors which depolarizes the plasmalemma and promotes ethylene synthesis. One consequence of such exocytosis should be small, extracellularly observable voltage transients. Transients, ranging in size up to 600 microvolts and possessing risetimes (10-90%) of approximately 200 ms, are known to be elicited in etiolated stems of Pisum sativum L. by friction and are here shown to be elicited by sudden increase of auxin concentration and also by a Ca2+ ionophore.

  5. Expert elicitation for a national-level volcano hazard model

    NASA Astrophysics Data System (ADS)

    Bebbington, Mark; Stirling, Mark; Cronin, Shane; Wang, Ting; Jolly, Gill

    2016-04-01

    The quantification of volcanic hazard at national level is a vital pre-requisite to placing volcanic risk on a platform that permits meaningful comparison with other hazards such as earthquakes. New Zealand has up to a dozen dangerous volcanoes, with the usual mixed degrees of knowledge concerning their temporal and spatial eruptive history. Information on the 'size' of the eruptions, be it in terms of VEI, volume or duration, is sketchy at best. These limitations and the need for a uniform approach lend themselves to a subjective hazard analysis via expert elicitation. Approximately 20 New Zealand volcanologists provided estimates for the size of the next eruption from each volcano and, conditional on this, its location, timing and duration. Opinions were likewise elicited from a control group of statisticians, seismologists and (geo)chemists, all of whom had at least heard the term 'volcano'. The opinions were combined via the Cooke classical method. We will report on the preliminary results from the exercise.

  6. Simplified Expert Elicitation Procedure for Risk Assessment of Operating Events

    SciTech Connect

    Ronald L. Boring; David Gertman; Jeffrey Joe; Julie Marble; William Galyean; Larry Blackwood; Harold Blackman

    2005-06-01

    This report describes a simplified, tractable, and usable procedure within the US Nuclear Regulator Commission (NRC) for seeking expert opinion and judgment. The NRC has increased efforts to document the reliability and risk of nuclear power plants (NPPs) through Probabilistic Risk Assessment (PRA) and Human Reliability Analysis (HRA) models. The Significance Determination Process (SDP) and Accident Sequence Precursor (ASP) programs at the NRC utilize expert judgment on the probability of failure, human error, and the operability of equipment in cases where otherwise insufficient operational data exist to make meaningful estimates. In the past, the SDP and ASP programs informally sought the opinion of experts inside and outside the NRC. This document represents a formal, documented procedure to take the place of informal expert elicitation. The procedures outlined in this report follow existing formal expert elicitation methodologies, but are streamlined as appropriate to the degree of accuracy required and the schedule for producing SDP and ASP analyses.

  7. Arousal recognition system based on heartbeat dynamics during auditory elicitation.

    PubMed

    Nardelli, Mimma; Valenza, Gaetano; Greco, Alberto; Lanata, Antonio; Scilingo, Enzo Pasquale

    2015-08-01

    This study reports on the recognition of different arousal levels, elicited by affective sounds, performed using estimates of autonomic nervous system dynamics. Specifically, as a part of the circumplex model of affect, arousal levels were recognized by properly combining information gathered from standard and nonlinear analysis of heartbeat dynamics, which was derived from the electrocardiogram (ECG). Affective sounds were gathered from the International Affective Digitized Sound System and grouped into four different levels of arousal. A group of 27 healthy volunteers underwent such elicitation while ECG signals were continuously recorded. Results showed that a quadratic discriminant classifier, as applied implementing a leave-one-subject-out procedure, achieved a recognition accuracy of 84.26%. Moreover, this study confirms the crucial role of heartbeat nonlinear dynamics for emotion recognition, hereby estimated through lagged Poincare plots. PMID:26737686

  8. Elicitation of specific syntactic structures in primary progressive aphasia

    PubMed Central

    DeLeon, Jessica; Gesierich, Benno; Besbris, Max; Ogar, Jennifer; Henry, Maya L.; Miller, Bruce L.; Gorno-Tempini, Maria Luisa; Wilson, Stephen M.

    2012-01-01

    Many patients with primary progressive aphasia (PPA) are impaired in syntactic production. Because most previous studies of expressive syntax in PPA have relied on quantitative analysis of connected speech samples, which is a relatively unconstrained task, it is not well understood which specific syntactic structures are most challenging for these patients. We used an elicited syntactic production task to identify which syntactic structures pose difficulties for 31 patients with three variants of PPA: non-fluent/agrammatic, semantic and logopenic. Neurodegenerative and healthy age-matched participants were included as controls. As expected, non-fluent/agrammatic patients made the most syntactic errors. The structures that resulted in the most errors were constructions involving third person singular present agreement, and constructions involving embedded clauses. Deficits on this elicited production task were associated with atrophy of the left posterior inferior frontal gyrus. PMID:23046707

  9. Chromate sensitization and elicitation from cement with iron sulfate.

    PubMed

    Bruze, M; Gruvberger, B; Hradil, E

    1990-01-01

    For some years, iron sulfate has been added to cement manufactured in the Scandinavian countries to prevent sensitization to and elicitation from chromate in cement. Allergic contact dermatitis from chromate is reported here in 3 workers with hand dermatitis and exposure to cement containing iron sulfate. Although iron sulfate had been added to the cement, high chromate concentrations were found in many samples of cement to which these workers were exposed. PMID:1969204

  10. A Step-Wise Approach to Elicit Triangular Distributions

    NASA Technical Reports Server (NTRS)

    Greenberg, Marc W.

    2013-01-01

    Adapt/combine known methods to demonstrate an expert judgment elicitation process that: 1.Models expert's inputs as a triangular distribution, 2.Incorporates techniques to account for expert bias and 3.Is structured in a way to help justify expert's inputs. This paper will show one way of "extracting" expert opinion for estimating purposes. Nevertheless, as with most subjective methods, there are many ways to do this.

  11. Elicitation of macrophages from the peritoneal cavity of channel catfish

    USGS Publications Warehouse

    Jenkins, J.A.; Klesius, P.H.

    1998-01-01

    Four chemicals were evaluated for elicitation of macrophages in peritoneal cavities of 250-300g healthy channel catfish Ictalurus punctatus. Cellular exudates were collected at 3, 5, 7, 10, 14, and 20 d following intraperitoneal injections with squalene, Freund's incomplete adjuvant (FIA), goat serum, thioglycollate, or as a control, phosphate-buffered saline. Injection with either squalene or FIA induced significantly greater (P ??? 0.0001) macrophage recruitment than the other chemicals. The effectiveness of squalene and FIA was compared further by macrophage collection daily for 7 d. Squalene and FIA elicited similarly high macrophage responses (P ??? 0.0450), the highest being 3.43 x 106 macrophages/mL (SE, 2.4 x l06) at 99% purity at day 2 and 2.1 X 106 macrophages/mL (SE, 0.7 x 106) at day 14 at 80% purity, respectively. In both experiments, the time after injection was not statistically significant, nor was there an interaction between time and chemicals. The occurrence of cells other than macrophages decreased with time to yield macrophage recoveries of 47-99% for squalene and 30-80% for FIA. Two subsets of macrophages were observed by means of flow cytometry. As demonstrated by chemiluminescence, the squalene-elicited cells produced high-energy oxygen compounds important to the phagocytic process.

  12. Eliciting and analyzing expert judgment: A practical guide

    SciTech Connect

    Meyer, M.A.; Booker, J.M. )

    1990-01-01

    In this book we describe how to elicit and analyze expert judgment. Expert judgment is defined here to include both the experts' answers to technical questions and their mental processes in reaching an answer. It refers specifically to data that are obtained in a deliberate, structured manner that makes use of the body of research on human cognition and communication. Our aim is to provide a guide for lay persons in expert judgment. These persons may be from physical and engineering sciences, mathematics and statistics, business, or the military. We provide background on the uses of expert judgment and on the processes by which humans solve problems, including those that lead to bias. Detailed guidance is offered on how to elicit expert judgment ranging from selecting the questions to be posed of the experts to selecting and motivating the experts to setting up for and conducting the elicitation. Analysis procedures are introduced and guidance is given on how to understand the data base structure, detect bias and correlation, form models, and aggregate the expert judgments.

  13. Reduced respiratory neural activity elicits phrenic motor facilitation.

    PubMed

    Mahamed, Safraaz; Strey, Kristi A; Mitchell, Gordon S; Baker-Herman, Tracy L

    2011-03-15

    We hypothesized that reduced respiratory neural activity elicits compensatory mechanisms of plasticity that enhance respiratory motor output. In urethane-anesthetized and ventilated rats, we reversibly reduced respiratory neural activity for 25-30 min using: hypocapnia (end tidal CO(2)=30 mmHg), isoflurane (~1%) or high frequency ventilation (HFV; ~100 breaths/min). In all cases, increased phrenic burst amplitude was observed following restoration of respiratory neural activity (hypocapnia: 92±22%; isoflurane: 65±22%; HFV: 54±13% baseline), which was significantly greater than time controls receiving the same surgery, but no interruptions in respiratory neural activity (3±5% baseline, p<0.05). Hypocapnia also elicited transient increases in respiratory burst frequency (9±2 versus 1±1bursts/min, p<0.05). Our results suggest that reduced respiratory neural activity elicits a unique form of plasticity in respiratory motor control which we refer to as inactivity-induced phrenic motor facilitation (iPMF). iPMF may prevent catastrophic decreases in respiratory motor output during ventilatory control disorders associated with abnormal respiratory activity. PMID:21167322

  14. Reduced respiratory neural activity elicits phrenic motor facilitation

    PubMed Central

    Mahamed, Safraaz; Strey, Kristi A.; Mitchell, Gordon S.; Baker-Herman, Tracy L.

    2011-01-01

    We hypothesized that reduced respiratory neural activity elicits compensatory mechanisms of plasticity that enhance respiratory motor output. In urethane-anesthetized and ventilated rats, we reversibly reduced respiratory neural activity for 25–30 min using: hypocapnia (end tidal CO2 = 30 mmHg), isoflurane (~ 1%) or high frequency ventilation (HFV; ~100 breaths/min). In all cases, increased phrenic burst amplitude was observed following restoration of respiratory neural activity (hypocapnia: 92 ± 22%; isoflurane: 65 ± 22%; HFV: 54 ± 13% baseline), which was significantly greater than time controls receiving the same surgery, but no interruptions in respiratory neural activity (3 ± 5% baseline, p<0.05). Hypocapnia also elicited transient increases in respiratory burst frequency (9 ± 2 versus 1 ± 1 bursts/min, p<0.05). Our results suggest that reduced respiratory neural activity elicits a unique form of plasticity in respiratory motor control which we refer to as inactivity-induced phrenic motor facilitation (iPMF). iPMF may prevent catastrophic decreases in respiratory motor output during ventilatory control disorders associated with abnormal respiratory activity. PMID:21167322

  15. Role of local neurons in cerebrocortical vasodilation elicited from cerebellum

    SciTech Connect

    Iadecola, C.; Arneric, S.P.; Baker, H.D.; Tucker, L.W.; Reis, D.J.

    1987-06-01

    The vasodilation elicited in cerebral cortex by stimulation of the cerebellar fastigial nucleus (FN) is mediated by input pathways coming from the basal forebrain. The authors studied whether these pathways mediate the cortical vasodilation via a direct action on local blood vessels or via interposed local neurons. Neurons were destroyed in the primary sensory cortex by local microinjection of the excitotoxin ibotenic acid (IBO). Five days later rats were anesthetized, paralyzed, and ventilated. Arterial pressure and blood gases were controlled, and FN was stimulated electrically. Local cerebral blood flow (LCBF) was measured using the (/sup 14/C)iodoantipyrine technique with autoradiography. Five days after IBO, neurons were destroyed in a restricted cortical area, and afferent fibers and terminals were preserved. The selectivity of the neuronal loss was established by histological and biochemical criteria and by transport of horseradish, peroxidase from or into the lesion. Within the lesion, resting LCBF was unaffected, but the increase in LCBF evoked from the FN was abolished. In contrast the vasodilation elicited by hypercapnia was preserved. In the rest of the brain the vasodilation elicited from FN was largely unaffected. The authors conclude that the vasodilation evoked from FN in cerebral cortex depends on the integrity of a restricted population of local neurons that interact with the local microvasculature.

  16. Intrathecal orphenadrine elicits spinal block in the rat.

    PubMed

    Chen, Yu-Wen; Tzeng, Jann-Inn; Chen, Yu-Chung; Hung, Ching-Hsia; Wang, Jhi-Joung

    2014-11-01

    The purpose of this study was to estimate the local anesthetic effect of orphenadrine, an anti-muscarinic agent, in spinal anesthesia and its comparison with the local anesthetic lidocaine. After the rat was injected intrathecally, the spinal block of orphenadrine and lidocaine was constructed in a dosage-dependent fashion. The potency and duration of spinal anesthesia with orphenadrine were compared with that of lidocaine. Our data demonstrated that orphenadrine and lidocaine elicited dose-dependent spinal blockades on the motor function, sensory, and proprioception. On the 50% effective dose (ED50) basis, the ranks of potency in motor function, nociception, and proprioception were orphenadrine>lidocaine (P<0.01). At equipotent doses (ED25, ED50, ED75), the block duration elicited by orphenadrine was greater than that elicited by lidocaine (P<0.01). Orphenadrine, but not lidocaine, exhibited longer duration of nociceptive/sensory blockade than that of motor blockade at equipotent doses. Ineffective-dose orphenadrine as adjuvant did not enhance spinal anesthesia with lidocaine. The preclinical data revealed that orphenadrine with a more sensory-selective action over motor block exhibited more potent and longer spinal anesthesia when compared to lidocaine. PMID:25205132

  17. Elicited versus emitted behavior: Time to abandon the distinction.

    PubMed

    Domjan, Michael

    2016-03-01

    The concept of emitted behavior was formulated as a part of the original argument for the validity of a new kind of learning called operant conditioning. The rationale for operant conditioning contrasted it with Pavlovian or classical conditioning, which was (and remains) fundamentally based on responses to conditioned and unconditioned stimuli. Classical conditioned responses were said to be elicited. In contrast, operant behavior was viewed as emitted and controlled primarily by response consequences rather than antecedents. I argue that the distinction between emitted and elicited behavior is no longer warranted for three major reasons. First, the distinction was based on a view of Pavlovian conditioning that is no longer viable. Second, the distinction is incompatible with both empirical data and contemporary conceptualizations of operant behavior. Third, the only way to overcome these problems is to define emitted and elicited in terms of the type of conditioning (operant and classical) that produces these behaviors, but that approach makes the definitions circular and does not avoid implications of the terms that are misleading and counterproductive in light of contemporary research and thinking. PMID:26872681

  18. Physiological responses induced by emotion-eliciting films.

    PubMed

    Fernández, Cristina; Pascual, Juan C; Soler, Joaquim; Elices, Matilde; Portella, Maria J; Fernández-Abascal, Enrique

    2012-06-01

    Emotion-eliciting films are commonly used to evoke subjective emotional responses in experimental settings. The main aim of the present study was to investigate whether a set of film clips with discrete emotions were capable to elicit measurable objective physiological responses. The convergence between subjective and objective measures was evaluated. Finally, the effect of gender on emotional responses was investigated. A sample of 123 subjects participated in the study. Individuals were asked to view a set of emotional film clips capable to induce seven emotions: anger, fear, sadness, disgust, amusement, tenderness and neutral state. Skin conductance level (SCL), heart rate (HR) and subjective emotional responses were measured for each film clip. In comparison with neutral films, SCL was significantly increased after viewing fear films, and HR was also significantly incremented for anger and fear films. Physiological variations were associated with arousal measures indicating a convergence between subjective and objective reactions. Women appeared to display significantly greater SCL and HR responses for films inducing sadness. The findings suggest that physiological activation would be more easily induced by emotion-eliciting films that tap into emotions with higher subjective arousal such as anger and fear. PMID:22311202

  19. The future costs of nuclear power using multiple expert elicitations: effects of RD&D and elicitation design

    NASA Astrophysics Data System (ADS)

    Díaz Anadón, Laura; Nemet, Gregory; Verdolini, Elena

    2013-09-01

    Characterization of the anticipated performance of energy technologies to inform policy decisions increasingly relies on expert elicitation. Knowledge about how elicitation design factors impact the probabilistic estimates emerging from these studies is, however, scarce. We focus on nuclear power, a large-scale low-carbon power option, for which future cost estimates are important for the design of energy policies and climate change mitigation efforts. We use data from three elicitations in the USA and in Europe and assess the role of government research, development, and demonstration (RD&D) investments on expected nuclear costs in 2030. We show that controlling for expert, technology, and design characteristics increases experts’ implied public RD&D elasticity of expected costs by 25%. Public sector and industry experts’ cost expectations are 14% and 32% higher, respectively than academics. US experts are more optimistic than their EU counterparts, with median expected costs 22% lower. On average, a doubling of public RD&D is expected to result in an 8% cost reduction, but the uncertainty is large. The difference between the 90th and 10th percentile estimates is on average 58% of the experts’ median estimates. Public RD&D investments do not affect uncertainty ranges, but US experts are less confident about costs than Europeans.

  20. Seminal plasma induces prostaglandin-endoperoxide synthase (PTGS) 2 expression in immortalized human vaginal cells: involvement of semen prostaglandin E2 in PTGS2 upregulation.

    PubMed

    Joseph, Theresa; Zalenskaya, Irina A; Sawyer, Lyn C; Chandra, Neelima; Doncel, Gustavo F

    2013-01-01

    Inflammation of the cervicovaginal mucosa is considered a risk factor for HIV infection in heterosexual transmission. In this context, seminal plasma (SP) may play an important role that is not limited to being the main carrier for the virions. It is known that SP induces an inflammatory reaction in the cervix called postcoital leukocytic reaction, which has been associated with promotion of fertility. The mechanisms by which SP triggers this reaction, however, have not been clearly established. Previously we reported the expression of prostaglandin-endoperoxide synthase 2 (PTGS2), also known as cyclooxygenase 2 (COX-2), in human vaginal cells in response to toll-like receptor (TLR) ligands and other proinflammatory stimuli. In this study, we demonstrate that SP induces transcriptional and translational increase of COX-2 expression in human vaginal cells and cervicovaginal tissue explants. Furthermore, SP potentiates vaginal PTGS2 expression induced by other proinflammatory stimulants, such as TLR ligands and a vaginal mucosal irritant (nonoxynol-9) in a synergistic manner. SP-induced PTGS2 expression is mediated by intracellular signaling pathways involving MAPKs and NF-κB. Using fractionation and functional analysis, seminal prostaglandin (PG)-E(2) was identified as a one of the major factors in PTGS2 induction. Given the critical role of this PG-producing enzyme in mucosal inflammatory processes, the finding that SP induces and potentiates the expression of PTGS2 in cervicovaginal cells and tissues has mechanistic implications for the role of SP in fertility-associated mucosal leukocytic reaction and its potential HIV infection-enhancing effect. PMID:23153564

  1. Prostaglandin-E1 has a protective effect on renal ischemia/reperfusion-induced oxidative stress and inflammation mediated gastric damage in rats.

    PubMed

    Gezginci-Oktayoglu, Selda; Orhan, Nurcan; Bolkent, Sehnaz

    2016-07-01

    Gastrointestinal complications are frequent in renal transplant recipients. In this regard, renal ischemia/reperfusion injury (IRI)-induced gastric damage seems to be important and there is no data available on the mechanism of this pathology. Because of its anti-inflammatory and anti-oxidant properties, it can be suggested that prostaglandin-E1 (PGE1) protects cells from renal IRI-induced gastric damage. The aim of this study was to investigate the molecular mechanisms of gastric damage induced by renal IRI and the effect of PGE1 on these mechanisms. We set an experiment with four different animal groups: physiological saline-injected and sham-operated rats, PGE1 (20μg/kg)-administered and sham operated rats, renal IRI subjected rats, and PGE1-administered and renal IRI subjected rats. The protective effect of PGE1 on renal IRI-induced gastric damage was determined based on reduced histological damage and lactate dehydrogenase activity. Moreover, we demonstrated that PGE1 shows its protective effect through reducing the production of reactive oxygen species and malondialdehyde levels. During histological examination, we observed the presence of common mononuclear cell infiltration. Therefore, pro-inflammatory cytokines tumor necrosis factor-α and interleukin-1β levels were measured and it has been shown that PGE1 suppressed both cytokines. Furthermore, it was found that PGE1 reduced the number of NF-κB(+) and caspase-3(+) inflammatory cells, and also NF-κB DNA-binding activity, while increasing proliferating cell nuclear antigen(+) epithelial cells in the stomach tissue of rats subjected to renal IR. Our data showed that PGE1 has a protective effect on renal IRI-induced oxidative stress and inflammation mediated gastric damage in rats. PMID:27135545

  2. Il-1β and prostaglandin E2 attenuate the hypercapnic as well as the hypoxic respiratory response via prostaglandin E receptor type 3 in neonatal mice.

    PubMed

    Siljehav, Veronica; Shvarev, Yuri; Herlenius, Eric

    2014-11-01

    Prostaglandin E2 (PGE2) serves as a critical mediator of hypoxia, infection, and apnea in term and preterm babies. We hypothesized that the prostaglandin E receptor type 3 (EP3R) is the receptor responsible for PGE2-induced apneas. Plethysmographic recordings revealed that IL-1β (ip) attenuated the hypercapnic response in C57BL/6J wild-type (WT) but not in neonatal (P9) EP3R(-/-) mice (P < 0.05). The hypercapnic responses in brain stem spinal cord en bloc preparations also differed depending on EP3R expression whereby the response was attenuated in EP3R(-/-) preparations (P < 0.05). After severe hypoxic exposure in vivo, IL-1β prolonged time to autoresuscitation in WT but not in EP3R(-/-) mice. Moreover, during severe hypoxic stress EP3R(-/-) mice had an increased gasping duration (P < 0.01) as well as number of gasps (P < 0.01), irrespective of intraperitoneal treatment, compared with WT mice. Furthermore, EP3R(-/-) mice exhibited longer hyperpneic breathing efforts when exposed to severe hypoxia (P < 0.01). This was then followed by a longer period of secondary apnea before autoresuscitation occurred in EP3R(-/-) mice (P < 0.05). In vitro, EP3R(-/-) brain stem spinal cord preparations had a prolonged respiratory burst activity during severe hypoxia accompanied by a prolonged neuronal arrest during recovery in oxygenated medium (P < 0.05). In conclusion, PGE2 exerts its effects on respiration via EP3R activation that attenuates the respiratory response to hypercapnia as well as severe hypoxia. Modulation of the EP3R may serve as a potential therapeutic target for treatment of inflammatory and hypoxic-induced detrimental apneas and respiratory disorders in neonates. PMID:25213632

  3. Evaluation of pro-inflammatory markers plasma C-reactive protein and urinary prostaglandin-E2 metabolite in colorectal adenoma risk.

    PubMed

    Davenport, James R; Cai, Qiuyin; Ness, Reid M; Milne, Ginger; Zhao, Zhiguo; Smalley, Walter E; Zheng, Wei; Shrubsole, Martha J

    2016-08-01

    C-reactive protein (CRP) is a pro-inflammatory protein with potential as a biomarker in predicting colon cancer risk. However, little is known regarding its association with risk of colorectal adenomas, particularly by subtypes. We conducted a colonoscopy-based matched case-control study to assess whether elevated plasma CRP levels may be associated with colorectal adenoma risk and further whether this association may be modified by urinary prostaglandin E2 metabolite (PGE-M), a biomarker of systemic prostaglandin E2 production. Included in the study were 226 cases with a single small tubular adenoma, 198 cases with multiple small tubular adenomas, 283 cases with at least one advanced adenoma, and 395 polyp-free controls. No apparent association between CRP level and risk of single small tubular adenomas was found (ptrend  = 0.59). A dose-response relationship with CRP level was observed for risk of either multiple small tubular adenomas (OR = 2.01, 95%CI = 1.10-3.68 for the highest versus lowest tertile comparison; ptrend   = 0.03) or advanced adenomas (OR = 1.81, 95%CI = 1.10-2.96 for the highest versus lowest tertile comparison; ptrend  = 0.02). In a joint analysis of CRP level and PGE-M, risk of multiple or advanced adenoma was greatest among those with highest levels of both CRP and PGE-M in comparison to those with low CRP and low PGE-M (OR = 3.72, 95%CI = 1.49-9.72). Our results suggest that elevated CRP, particularly in the context of concurrent elevated PGE-M, may be a biomarker of multiple or advanced adenoma risk in a screening age population. © 2015 Wiley Periodicals, Inc. PMID:26333108

  4. Stimulation of prostaglandin E/sub 2/ production by phorbol esters and epidermal growth factor in porcine thyroid cells

    SciTech Connect

    Kasai, K.; Hiraiwa, M.; Emoto, T.; Akimoto, K.; Takaoka, T.; Shimoda, S.I.

    1987-07-13

    Effects of phorbol esters and epidermal growth factor (EGF) on prostaglandin E/sub 2/ production by cultured porcine thyroid cells were examined. Both phorbol 12-myristate 13-acetate (PMA) and EGF stimulated prostaglandin E/sub 2/ production by the cells in dose related fashion. PMA stimulated prostaglandin E/sub 2/ production over fifty-fold with the dose of 10/sup -7/ M compared with control. EGF (10/sup -7/ M) also stimulated it about ten-fold. The ED/sub 50/ values of PMA and EGF were respectively around 1 x 10/sup -9/ M and 5 x 10/sup -10/ M. Thyroid stimulating hormone (TSH), however, did not stimulate prostaglandin E/sub 2/ production from 1 to 24-h incubation. The release of radioactivity from (/sup 3/H)-arachidonic acid prelabeled cells was also stimulated by PMA and EGF, but not by TSH. These results indicate that both PMA and EGF are potent stimulators of prostaglandin E/sub 2/ production, associated with the activity to stimulate arachidonic acid release in porcine thyroid cells. 36 references, 2 figures, 1 table.

  5. Blockade of prostaglandin E1 hyperthermia by sodium salicylate given into the ventral septal area of the rat brain.

    PubMed Central

    Alexander, S J; Cooper, K E; Veale, W L

    1987-01-01

    1. Sodium salicylate (30.0 micrograms microliter-1) or artificial cerebrospinal fluid (ACSF) was infused bilaterally into the ventral septal area (v.s.a.) of the unrestrained rat for 1 h before and 1 h after the injection of prostaglandin E1 at a concentration of 20.0 ng microliter-1 into a lateral cerebral ventricle. 2. During control (ACSF) infusions, 200.0 ng of prostaglandin E1 evoked a hyperthermic response (0.95 +/- 0.16 degrees C). During sodium salicylate infusions, the prostaglandin E1-evoked hyperthermia was significantly reduced (P less than 0.025) to 0.31 +/- 0.16 degrees C. 3. The fever index (degrees C h for 1.0 h) during the infusion of sodium salicylate was reduced 66% below that of control infusions (P less than 0.01). 4. These data indicate that sodium salicylate infused in the v.s.a. of rats can antagonize a prostaglandin E-evoked hyperthermia. This suggests that there may be an additional mechanism of action for sodium salicylate antipyresis other than inhibition of prostaglandin E synthesis. PMID:3656145

  6. Sample Size for Measuring Grammaticality in Preschool Children from Picture-Elicited Language Samples

    ERIC Educational Resources Information Center

    Eisenberg, Sarita L.; Guo, Ling-Yu

    2015-01-01

    Purpose: The purpose of this study was to investigate whether a shorter language sample elicited with fewer pictures (i.e., 7) would yield a percent grammatical utterances (PGU) score similar to that computed from a longer language sample elicited with 15 pictures for 3-year-old children. Method: Language samples were elicited by asking forty…

  7. Research Dilemmas Associated with Photo Elicitation in Comparative Early Childhood Education Research

    ERIC Educational Resources Information Center

    Birkeland, Asta

    2013-01-01

    Photo elicitation has become an important method to produce data in qualitative research. There is quite an extensive literature indicating the benefits of photo elicitation in order to facilitate collaboration in meaning making between researcher and the interviewee. This article addresses dilemmas associated with using photo elicitation in a…

  8. Undergraduate Students' Use of Information Elicited During E-Mail "Tutorials."

    ERIC Educational Resources Information Center

    Trushell, John; Reymond, Christine; Burrell, Clare

    1998-01-01

    Considers questions posed by students during e-mail tutorials to elicit information from guest lecturers and the use of that information by students in their essays. Findings indicate: tutees tend to pose questions to elicit information or clarification rather than to elicit opinions of the guest lecturer; and two-thirds of tutees' essays cited…

  9. Developing Socio-Cultural Scaffolding Model to Elicit Learners's Speech Production

    ERIC Educational Resources Information Center

    Englishtina, Inti

    2015-01-01

    This study is concerned with developing scaffolding model to elicit bilingual kindergarten children's English speech production. It is aimed at describing what the teachers need in eliciting their students' speech production; how a scaffolding model should be developed to elicit the children's speech production; and how effective is the…

  10. Importance of endogenous prostaglandins for the toxicity of cyclosporin A to rat endocrine and exocrine pancreas?

    PubMed Central

    Rünzi, M; Peskar, B M; von Schönfeld, J; Müller, M K

    1992-01-01

    Previous work has shown that cyclosporin A is toxic to the endocrine and exocrine pancreas. The aim of this study was to examine whether endogenous eicosanoids play a role in controlling cyclosporin A induced toxicity. Rats were treated for eight days with indomethacin (2 mg/kg, twice daily) in addition to cyclosporin A (5 or 10 mg/kg daily). Effects of drug treatments on exocrine (as assessed by amylase and protein secretion into the pancreatic juice) and endocrine (as assessed by the glucose dependent insulin release) pancreatic functions, and pancreatic formation of prostaglandins and thromboxane were evaluated. Treatment with cyclosporin A in the doses used did not inhibit eicosanoid formation by the pancreatic tissue ex vivo. Indomethacin caused significant inhibition of pancreatic formation of prostaglandin E2, 6k prostaglandin F1 alpha and thromboxane B2. Combined treatment with indomethacin and cyclosporin A (5 or 10 mg/kg) augmented cyclosporin A induced pancreatic toxicity with further impairment of insulin release, amylase secretion, and pancreatic juice protein content, but did not result in more pronounced inhibition of pancreatic eicosanoid formation. The increased toxicity of the combined treatment was, however, associated with raised cyclosporin A whole blood concentrations. The data suggest that the potentiation of pancreatic toxicity of cyclosporin A observed during coadministration of indomethacin is not the result of suppression of endogenous pancreatic eicosanoid biosynthesis, but more likely results from altered cyclosporin A pharmacokinetic which may be caused by an interference of indomethacin with the hepatic cytochrome P-450 dependent monooxygenase involved in cyclosporin A metabolism. The possibility that coadministration of non-steroidal antiinflammatory drugs aggravates toxic effects in cyclosporin A treated patients should be considered. PMID:1280611

  11. Effects of Prostaglandin Cyclic Endoperoxides on the Lung Circulation of Unanesthetized Sheep

    PubMed Central

    Bowers, Ronald E.; Ellis, Earl F.; Brigham, Kenneth L.; Oates, John A.

    1979-01-01

    Although prostaglandins E2 and F2α have been suggested as mediators of the pulmonary hypertension seen after endotoxin infusion or during alveolar hypoxia, their precursors, the endoperoxides (prostaglandins G2 and H2) are much more potent vasoconstrictors in vitro. In this study we compared the effects of prostaglandin (PG)H2, a stable 9-methylene ether analogue of PGH2 (PGH2-A), PGE2, and PGF2α on pulmonary hemodynamics in awake sheep. The animals were prepared to allow for measurement of (a) lung lymph flow; (b) plasma and lymph protein concentration; (c) systemic and pulmonary vascular pressures; and (d) cardiac output. We also determined the effect of prolonged PGH2-A infusions on lung fluid balance and vascular permeability by indicator dilution methods, and by assessing the response of lung lymph. Both PGH2 and PGH2-A caused a dose-related increase in pulmonary artery pressure: 0.25 μg/kg × min tripled pulmonary vascular resistance without substantially affecting systemic pressures. Both were 100 times more potent than PGE2 or PGF2α in this preparation. PGH2-A, as our analysis of lung lymph and indicator dilution measurements show, does not increase the permeability of exchanging vessels in the lung to fluid and protein. It does, however, augment lung fluid transport by increasing hydrostatic pressure in the pulmonary circulation. We conclude: (a) that PGH2 is likely to be an important mediator of pulmonary vasoconstriction; (b) its effects are probably not a result of its metabolites PGE2 or PGF2α. PMID:762242

  12. Nitric oxide synthase stimulates prostaglandin synthesis and barrier function in C. parvum-infected porcine ileum.

    PubMed

    Gookin, Jody L; Duckett, Laurel L; Armstrong, Martha U; Stauffer, Stephen H; Finnegan, Colleen P; Murtaugh, Michael P; Argenzio, Robert A

    2004-09-01

    Cell culture models implicate increased nitric oxide (NO) synthesis as a cause of mucosal hyperpermeability in intestinal epithelial infection. NO may also mediate a multitude of subepithelial events, including activation of cyclooxygenases. We examined whether NO promotes barrier function via prostaglandin synthesis using Cryptosporidium parvum-infected ileal epithelium in residence with an intact submucosa. Expression of NO synthase (NOS) isoforms was examined by real-time RT-PCR of ileal mucosa from control and C. parvum-infected piglets. The isoforms mediating and mechanism of NO action on barrier function were assessed by measuring transepithelial resistance (TER) and eicosanoid synthesis by ileal mucosa mounted in Ussing chambers in the presence of selective and nonselective NOS inhibitors and after rescue with exogenous prostaglandins. C. parvum infection results in induction of mucosal inducible NOS (iNOS), increased synthesis of NO and PGE2, and increased mucosal permeability. Nonselective inhibition of NOS (NG-nitro-L-arginine methyl ester) inhibited prostaglandin synthesis, resulting in further increases in paracellular permeability. Baseline permeability was restored in the absence of NO by exogenous PGE2. Selective inhibition of iNOS [L-N6-(1-iminoethyl)-L-lysine] accounted for approximately 50% of NOS-dependent PGE2 synthesis and TER. Using an entire intestinal mucosa, we have demonstrated for the first time that NO serves as a proximal mediator of PGE2 synthesis and barrier function in C. parvum infection. Expression of iNOS by infected mucosa was without detriment to overall barrier function and may serve to promote clearance of infected enterocytes. PMID:15155179

  13. The cyclopentenone prostaglandin 15d-PGJ2 inhibits the NLRP1 and NLRP3 inflammasomes

    PubMed Central

    Maier, Nolan K.; Leppla, Stephen H.; Moayeri, Mahtab

    2015-01-01

    Inflammasomes are cytosolic protein complexes that respond to diverse danger signals by activating caspase-1. The sensor components of the inflammasome, often proteins of the nucleotide-binding oligomerization domain-like receptor (NLR) family, detect stress, danger stimuli, and pathogen-associated molecular patterns. We report that the eicosanoid 15-deoxy-Δ12,14-prostaglandin J2 (15d-PGJ2) and related cyclopentenone prostaglandins inhibit caspase-1 activation by the NLRP1 and NLRP3 inflammasomes. This inhibition was independent of 15d-PGJ2’s well characterized role as a peroxisome proliferator receptor-γ agonist, its activation of NRF2, or its anti-inflammatory function as an inhibitor of NF-κB. Instead, 15d-PGJ2 prevents the autoproteolytic activation of caspase-1 and the maturation of IL-1β through induction of a cellular state inhibitory to caspase-1 proteolytic function. The eicosanoid does not directly modify or inactivate the caspase-1 enzyme. Rather, inhibition is dependent on de novo protein synthesis. In a mouse peritonitis model of gout, using monosodium urate crystals to activate NLRP3,15d-PGJ2 caused a significant inhibition of cell recruitment and associated IL-1β release. Furthermore, in a murine anthrax infection model, 15d-PGJ2 reversed anthrax lethal toxin-mediated NLRP1-dependent resistance. The findings reported in this work suggest a novel mechanism for the anti-inflammatory properties of the cyclopentenone prostaglandins through inhibition of caspase-1 and the inflammasome. PMID:25681332

  14. Anti-inflammatory role of microsomal prostaglandin E synthase-1 in a model of neuroinflammation.

    PubMed

    Brenneis, Christian; Coste, Ovidiu; Altenrath, Kai; Angioni, Carlo; Schmidt, Helmut; Schuh, Claus-Dieter; Zhang, Dong Dong; Henke, Marina; Weigert, Andreas; Brüne, Bernhard; Rubin, Barry; Nusing, Rolf; Scholich, Klaus; Geisslinger, Gerd

    2011-01-21

    A major immunological response during neuroinflammation is the activation of microglia, which subsequently release proinflammatory mediators such as prostaglandin E(2) (PGE(2)). Besides its proinflammatory properties, cyclooxygenase-2 (COX-2)-derived PGE(2) has been shown to exhibit anti-inflammatory effects on innate immune responses. Here, we investigated the role of microsomal PGE(2) synthase-1 (mPGES-1), which is functionally coupled to COX-2, in immune responses using a model of lipopolysaccharide (LPS)-induced spinal neuroinflammation. Interestingly, we found that activation of E-prostanoid (EP)2 and EP4 receptors, but not EP1, EP3, PGI(2) receptor (IP), thromboxane A(2) receptor (TP), PGD(2) receptor (DP), and PGF(2) receptor (FP), efficiently blocked LPS-induced tumor necrosis factor α (TNFα) synthesis and COX-2 and mPGES-1 induction as well as prostaglandin synthesis in spinal cultures. In vivo, spinal EP2 receptors were up-regulated in microglia in response to intrathecally injected LPS. Accordingly, LPS priming reduced spinal synthesis of TNFα, interleukin 1β (IL-1β), and prostaglandins in response to a second intrathecal LPS injection. Importantly, this reduction was only seen in wild-type but not in mPGES-1-deficient mice. Furthermore, intrathecal application of EP2 and EP4 agonists as well as genetic deletion of EP2 significantly reduced spinal TNFα and IL-1β synthesis in mPGES-1 knock-out mice after LPS priming. These data suggest that initial inflammation prepares the spinal cord for a negative feedback regulation by mPGES-1-derived PGE(2) followed by EP2 activation, which limits the synthesis of inflammatory mediators during chronic inflammation. Thus, our data suggest a role of mPGES-1-derived PGE(2) in resolution of neuroinflammation. PMID:21075851

  15. Molecular characterization and knock-down of salmon louse (Lepeophtheirus salmonis) prostaglandin E synthase.

    PubMed

    Eichner, Christiane; Øvergård, Aina-Cathrine; Nilsen, Frank; Dalvin, Sussie

    2015-12-01

    The salmon louse (Lepeophtheirus salmonis) is a major parasite of salmonid fish in the marine environment. The interaction between the parasite and the host upon infection is not completely understood. However, it is clear that the parasite influences the host and its immune system. Prostaglandins produced by parasites such as flatworms, roundworms and ticks are documented or assumed to play a role in immunomodulation of the host. In the salmon louse, the effect of prostaglandins on the host is assumed, but remains to be documented. In this study, a salmon louse prostaglandin E2 synthase (LsPGES2) is characterized. Ontogenetic analysis showed that LsPGES2 is relatively stable expressed during development. The highest level of expression was seen in the free living stages, although elevated levels of LsPGES2 were also found in adult females. In copepodids, LsPGES2 is found around muscle cells, while it is observed in the reproductive organs of adult female lice. LsPGES2 expression was knocked-down by RNA interference in nauplii, but emerging copepodids did not display any changes in morphology nor ability to infect and develop to adult stages on fish. Additional knock-down of LsPGES2 in adult female lice did not produce any characteristic changes in phenotype nor reproductive output. It is concluded that under these experimental conditions, knock-down of LsPGES2 did not affect any essential functions of the salmon louse, neither in the free-living nor the parasitic stages. PMID:26348267

  16. Prostaglandin transporter in the rat brain: its localization and induction by lipopolysaccharide

    PubMed Central

    Hosotani, Rika; Inoue, Wataru; Takemiya, Takako; Yamagata, Kanato; Kobayashi, Shigeo; Matsumura, Kiyoshi

    2015-01-01

    Prostaglandin E2 (PGE2) is produced in the brain during infectious/inflammatory diseases, and it mediates acute-phase responses including fever. In the recovery phase of such diseases, PGE2 disappears from the brain through yet unidentified mechanisms. Rat prostaglandin transporter (PGT), which facilitates transmembrane transport of PGE2, might be involved in the clearance of PGE2 from the brain. Here, we examined the cellular localization of PGT mRNA and its protein in the brains of untreated rats and those injected intraperitoneally with a pyrogen lipopolysaccharide (LPS) or saline. PGT mRNA was weakly expressed in the arachnoid membrane of untreated rats and saline-injected ones, but was induced in blood vessels of the subarachnoidal space and choroid plexus and in arachnoid membrane at 5 h and 12 h after LPS injection. In the same type of cells, PGT-like immunoreactivity was found in the cytosol and cell membrane even under nonstimulated conditions, and its level was also elevated after LPS injection. PGT-positive cells in blood vessels were identified as endothelial cells. In most cases, PGT was not colocalized with cyclooxygenase-2, a marker of prostaglandin-producing cells. The PGE2 level in the cerebrospinal fluid reached its peak at 3 h after LPS, and then dropped over 50% by 5 h, which time point coincides with the maximum PGT mRNA expression and enhanced level of PGT protein. These results suggest that PGT is involved in the clearance of PGE2 from the brain during the recovery phase of LPS-induced acute-phase responses. PMID:27227056

  17. Electron microscopic aspects of the effects of certain prostaglandin analogs on mouse testes.

    PubMed

    Sava, Anca; Motoc, Andrei Gheorghe Marius; Stan, Cristinel Ionel

    2015-01-01

    Prostaglandins were highlighted in the seminal plasma and then in the rest of the male and female genital tract. Prostaglandin analogs, firstly used in obstetrics and gynecology, are now widespread in both sexes, especially in the treatment of gastric and duodenal ulcers, glaucoma, etc. Therefore, we tried to highlight the effects of repeated administration of Cloprostenol and CIPG isopropyl ester (both prostaglandin F2α analogs) for the male gonad. In our experiment, we used Cloprostenol and CIPG isopropyl ester. We used three groups of white, male mice, aged 50-80 days, kept in standard laboratory conditions, which received the same feed. Each group included 12 mice. The first batch was the control group and received no substance at all. The second batch received 25 μg/kg of Cloprostenol dose per body per day, intraperitoneal administration (a single dose per day) on a daily basis for a four weeks period of time. The third batch received a 25 μg/kg CIPG isopropyl ester dose per body/day intraperitoneal administration (a single dose per day) on a daily basis for a four weeks period of time. After 7, 14 and 28 days of treatment, we sacrificed four animals in each of the batches by cutting their carotid arteries. The prostanoid analogs we used, Cloprostenol and CIPG isopropyl ester, have similar actions on male gonad in mice. These analogs induced significant changes in the evolution of the spermatogenesis and spermiogenesis. In relation to the treatment duration there were cellular changes suggesting apoptosis in different stages. With regard to spermiogenesis, the ultrastructural aspects indicate a decrease of the sperm structuring processes, especially in the acrosomal apparatus and chromatin. PMID:26429171

  18. Production of prostaglandins in placentae and corpus luteum in pregnant hinds of red deer (Cervus elaphus).

    PubMed

    Korzekwa, A J; Szczepańska, A; Bogdaszewski, M; Nadolski, P; Malż, P; Giżejewski, Z

    2016-03-01

    Prostaglandins (PGs) are synthesized from arachidonic acid by prostaglandin synthase 2 (PTGS2) and specific terminal PG synthases such as PGES and PGFS. The role of PGs in the reproductive processes of domestic ruminants is well recognized, whereas in cervidae, it is almost unknown, although it is noteworthy because some species of this family are valued in meat production and trophies. The aim of this study was to determine an effective marker of pregnancy and investigate the production and secretion of PGs in placenta and CL tissue in pregnancy. In the preliminary experiment, the levels of progesterone and 17-β estradiol (RIA; N = 14 divided into seven pregnant and seven nonpregnant hinds) were measured in the peripheral blood. In the main experiment, a comparison of messenger RNA (real-time polymerase chain reaction) and protein expression (Western blotting) of PTGS2, PGES, and PGFS, the level of prostaglandin E2 (PGE2) and PGF2α in the placentae and CL in pregnant hinds (aged 3-4 years, ca. 100 days of pregnancy, N = 6). In pregnant hinds, the level of progesterone in the blood was higher than that in nonpregnant hinds (P < 0.05), whereas the level of E2 was similar in all animals (P > 0.05). The highest messenger RNA expression of PTGS2, PGES, and PGFS was observed in the placentae than in the CL (P < 0.05). The protein expression of PTGS2 and PGES was elevated in the placentae compared with the CL (P < 0.05). The PGE2 output was the highest in cotyledonary tissue (P < 0.05). Pregnancy development in hinds around 100 days is regulated by arachidonic acid metabolites, especially PGE2 produced by the placentae, which production increases in pregnancy. Further studies are required to unravel the mechanisms involved in the regulation of PG and biosynthetic enzymes in uteroplacental and ovarian tissues during pregnancy in red deer females. PMID:26553568

  19. Prostaglandin E2-induced colonic secretion in patients with and without colorectal neoplasia

    PubMed Central

    2010-01-01

    Background The pathogenesis for colorectal cancer remains unresolved. A growing body of evidence suggests a direct correlation between cyclooxygenase enzyme expression, prostaglandin E2 metabolism and neoplastic development. Thus further understanding of the regulation of epithelial functions by prostaglandin E2 is needed. We hypothesized that patients with colonic neoplasia have altered colonic epithelial ion transport and express functionally different prostanoid receptor levels in this respect. Methods Patients referred for colonoscopy were included and grouped into patients with and without colorectal neoplasia. Patients without endoscopic findings of neoplasia served as controls. Biopsy specimens were obtained from normally appearing mucosa in the sigmoid part of colon. Biopsies were mounted in miniaturized modified Ussing air-suction chambers. Indomethacin (10 μM), various stimulators and inhibitors of prostanoid receptors and ion transport were subsequently added to the chamber solutions. Electrogenic ion transport parameters (short circuit current and slope conductance) were recorded. Tissue pathology and tissue damage before and after experiments was assessed by histology. Results Baseline short circuit current and slope conductance did not differ between the two groups. Patients with neoplasia were significantly more sensitive to indomethacin with a decrease in short circuit current of 15.1 ± 2.6 μA·cm-2 compared to controls, who showed a decrease of 10.5 ± 2.1 μA·cm-2 (p = 0.027). Stimulation or inhibition with theophylline, ouabain, bumetanide, forskolin or the EP receptor agonists prostaglandin E2, butaprost, sulprostone and prostaglandin E1 (OH) did not differ significantly between the two groups. Histology was with normal findings in both groups. Conclusions Epithelial electrogenic transport is more sensitive to indomethacin in normal colonic mucosa from patients with previous or present colorectal neoplasia compared to colonic mucosa from

  20. Pharmacotherapy of intraocular pressure - part II. Carbonic anhydrase inhibitors, prostaglandin analogues and prostamides.

    PubMed

    Costagliola, Ciro; dell'Omo, Roberto; Romano, Mario R; Rinaldi, Michele; Zeppa, Lucia; Parmeggiani, Francesco

    2009-12-01

    The second part of this two part review (please see Expert Opinion on Pharmacotherapy 10(16)) reports the characteristics of other antiglaucoma medications: systemic (acetazomide) and topical (dorzolamide and brinzolamide) carbonic anhydrase inhibitors, which suppress aqueous humour formation; and prostaglandin analogues (latanoprost and travoprost) and prostamides (bimatoprost), which raise aqueous humour outflow. The pharmacologic properties of each compound and its efficacy in the medical treatment of glaucoma, mainly the primary open-angle form, are discussed briefly, focusing on the clinical evidence supporting their use. PMID:19929706

  1. Isoprostane 8-epi-prostaglandin F2 alpha is a potent contractor of human peripheral lymphatics.

    PubMed

    Sinzinger, H; Oguogho, A; Kaliman, J

    1997-09-01

    Isoprostanes are products of free radical-catalyzed peroxidation and 8-epi-prostaglandin (PG) F2 alpha is the most important vasomodulator of this group of compounds. In human lower leg lymphatics isolated from 5 different patients without a smoking history or hyperlipidemia, 8-epi-PGF2 alpha stimulated in vitro contraction more strongly than the thromboxane receptor agonist U46619. Other isoprostanes (8-epi-PGE1, 8-epi-PGE2) had only limited lymphatic contractile potency. These data suggest a potentially relevant role for epi-8-PGF2 alpha in facilitating lymph transport especially in conditions of inflammation. PMID:9313207

  2. Audio-vocal responses elicited in adult cochlear implant users

    PubMed Central

    Loucks, Torrey M.; Suneel, Deepa; Aronoff, Justin M.

    2015-01-01

    Auditory deprivation experienced prior to receiving a cochlear implant could compromise neural connections that allow for modulation of vocalization using auditory feedback. In this report, pitch-shift stimuli were presented to adult cochlear implant users to test whether compensatory motor changes in vocal F0 could be elicited. In five of six participants, rapid adjustments in vocal F0 were detected following the stimuli, which resemble the cortically mediated pitch-shift responses observed in typical hearing individuals. These findings suggest that cochlear implants can convey vocal F0 shifts to the auditory pathway that might benefit audio-vocal monitoring. PMID:26520350

  3. Unattractive infant faces elicit negative affect from adults

    PubMed Central

    Schein, Stevie S.; Langlois, Judith H.

    2015-01-01

    We examined the relationship between infant attractiveness and adult affect by investigating whether differing levels of infant facial attractiveness elicit facial muscle movement correlated with positive and negative affect from adults (N = 87) using electromyography. Unattractive infant faces evoked significantly more corrugator supercilii and levator labii superioris movement (physiological correlates of negative affect) than attractive infant faces. These results suggest that unattractive infants may be at risk for negative affective responses from adults, though the relationship between those responses and caregiving behavior remains elusive. PMID:25658199

  4. Beyond reminiscence: using generic video to elicit conversational language.

    PubMed

    Davis, Boyd H; Shenk, Dena

    2015-02-01

    Videos and multimedia are increasingly used to stimulate reminiscence in dementia care. However, they are also valuable in eliciting a wide range of language patterns that are not necessarily keyed to reminiscence about self. Low-technology, home-made generic and personalized videos were tested with 2 samples of persons with dementia, to increase engagement and support the retention of identity. Participants showed a slight, though not significant, preference for looking first at personalized videos and produced a wider range of conversational language topics and phrasal patterns in response to the generic videos. PMID:24851873

  5. Simplifying Probability Elicitation and Uncertainty Modeling in Bayesian Networks

    SciTech Connect

    Paulson, Patrick R; Carroll, Thomas E; Sivaraman, Chitra; Neorr, Peter A; Unwin, Stephen D; Hossain, Shamina S

    2011-04-16

    In this paper we contribute two methods that simplify the demands of knowledge elicitation for particular types of Bayesian networks. The first method simplify the task of providing probabilities when the states that a random variable takes can be described by a new, fully ordered state set in which a state implies all the preceding states. The second method leverages Dempster-Shafer theory of evidence to provide a way for the expert to express the degree of ignorance that they feel about the estimates being provided.

  6. Albumin-Binding and Tumor Vasculature Determine the Antitumor Effect of 15-Deoxy-Δ12,14-Prostaglandin-J2 in vivo1

    PubMed Central

    Prakash, Jai; Bansal, Ruchi; Post, Eduard; de Jager-Krikken, Alie; Lub-de Hooge, Marjolijn N; Poelstra, Klaas

    2009-01-01

    15-Deoxy-Δ12,14-prostaglandin-J2 (15d-PGJ2), a peroxisome proliferator-activated receptor γ (PPARγ) agonist, induces cell death in tumor cells in vitro; however, no study showed its in vivo effect on tumors. Here, we report that 15d-PGJ2 shows antitumor effects in vivo in mice. However, its effects correlate with tumor uptake of albumin, to which it reversibly binds. 15d-PGJ2 induces cell death in B16F10 melanoma and C26 colon carcinoma cells in vitro. These effects were not elicited through PPARγ-dependent pathways because an irreversible PPARγ antagonist GW9662 did not inhibit these effects. Caspase- and nuclear factor κB- (NF-κB) dependent pathways were found to be involved as determined with caspase-3/7 fluorescent assay and NF-κB containing plasmid transfection assay, respectively. Noticeably, 15d-PGJ2 had significantly stronger effects in C26 cells compared with B16 cells in all assays. However, in vivo, there was no effect on C26 tumors, yet it significantly inhibited the B16 tumor growth in mice by 75%. We found that 15d-PGJ2 rapidly bound to albumin and in vivo albumin greatly distributed to B16 tumors compared with C26 tumors, shown with γ-camera imaging and immunohistochemical staining. Albumin accumulation can be attributed to the large blood vessel diameter in B16 tumors and an enhanced permeability and retention effect. These findings suggest that 15d-PGJ2 can be an effective therapeutic agent for cancer, although its effects seem to be limited to the tumors allowing albumin penetration. PMID:20019843

  7. Transcription of Liver X Receptor Is Down-Regulated by 15-Deoxy-Δ12,14-Prostaglandin J2 through Oxidative Stress in Human Neutrophils

    PubMed Central

    Alba, Gonzalo; Reyes, María Edith; Santa-María, Consuelo; Ramírez, Remedios; Geniz, Isabel; Jiménez, Juan; Martín-Nieto, José; Pintado, Elízabeth; Sobrino, Francisco

    2012-01-01

    Liver X receptors (LXRs) are ligand-activated transcription factors of the nuclear receptor superfamily. They play important roles in controlling cholesterol homeostasis and as regulators of inflammatory gene expression and innate immunity, by blunting the induction of classical pro-inflammatory genes. However, opposite data have also been reported on the consequences of LXR activation by oxysterols, resulting in the specific production of potent pro-inflammatory cytokines and reactive oxygen species (ROS). The effect of the inflammatory state on the expression of LXRs has not been studied in human cells, and constitutes the main aim of the present work. Our data show that when human neutrophils are triggered with synthetic ligands, the synthesis of LXRα mRNA became activated together with transcription of the LXR target genes ABCA1, ABCG1 and SREBP1c. An inflammatory mediator, 15-deoxy-Δ12,14-prostaglandin J2 (15dPGJ2), hindered T0901317-promoted induction of LXRα mRNA expression together with transcription of its target genes in both neutrophils and human macrophages. This down-regulatory effect was dependent on the release of reactive oxygen species elicited by 15dPGJ2, since it was enhanced by pro-oxidant treatment and reversed by antioxidants, and was also mediated by ERK1/2 activation. Present data also support that the 15dPGJ2-induced serine phosphorylation of the LXRα molecule is mediated by ERK1/2. These results allow to postulate that down-regulation of LXR cellular levels by pro-inflammatory stimuli might be involved in the development of different vascular diseases, such as atherosclerosis. PMID:23115616

  8. Coronary flow regulation in patients with ischemic heart disease: release of purines and prostacyclin and the effect of inhibitors of prostaglandin formation.

    PubMed

    Edlund, A; Berglund, B; van Dorne, D; Kaijser, L; Nowak, J; Patrono, C; Sollevi, A; Wennmalm, A

    1985-06-01

    The present investigation was undertaken to study cardiac release of adenosine and prostacyclin (prostaglandin [PG] I2) in patients with ischemic heart disease (IHD), and to assess coronary vascular resistance before and after inhibition of synthesis in such patients. In 48 patients with IHD, arterial and coronary sinus blood samples were taken at rest, during atrial pacing to angina, and after pacing. Levels of purines were determined by high-performance liquid chromatography and the PGI2 metabolite 6-keto-PGF1 alpha was measured with radioimmunoassay. Coronary sinus blood flow was determined with retrograde continuous thermodilution before and after oral administration of indomethacin, aspirin, naproxen, or ibuprofen. Atrial pacing induced myocardial ischemia, as evidenced by typical chest pain and arrested lactate extraction. Adenosine was extracted at rest, but during ischemia there was a significant release of its metabolite hypoxanthine, indicating increased myocardial breakdown of high-energy adenine nucleotides. Arterial and coronary sinus concentrations of 6-keto-PGF1 alpha were low and no significant differences between them were found. After administration of the PG-synthesis inhibitor indomethacin, coronary vascular resistance was elevated, as was the cardiac oxygen extraction. The three other PG-synthesis inhibitors (aspirin, naproxen, and ibuprofen) did not, however, induce any change in coronary vascular resistance or in the cardiac extraction of oxygen. On the basis of these data we suggest that in patients with IHD cardiac ischemia results in increased myocardial production and release of purines, cardiac ischemia does not elicit any detectable increase in coronary production of prostacyclin, and the increased coronary resistance induced by indomethacin does not reflect the involvement of locally formed PG in the maintenance of coronary flow, but is rather a direct effect of the drug. PMID:3888437

  9. Effects of yohimbine, rauwolscine and corynanthine on contractions and calcium fluxes induced by depolarization and prostaglandin F2 alpha in rat aorta.

    PubMed Central

    Godfraind, T.; Miller, R. C.; Socrates Lima, J.

    1983-01-01

    The effects of the selective alpha 2-adrenoceptor antagonists yohimbine and its stereo-isomer rauwolscine and the selective alpha 1-adrenoceptor antagonist corynanthine (a third yohimbine stereoisomer) on contractions induced in rat aorta by depolarization and prostaglandin F2 alpha (PGF2 alpha) have been compared. In calcium-free solution, depolarization with 100 mM K+ failed to produce a contraction of rat aorta but PGF2 alpha (3 microM) stimulated a contraction equal to about 23% of maximal elicited in normal physiological solution. Yohimbine had no significant effect on depolarization-induced contractions except at concentrations greater than 30 microM. Rauwolscine and corynanthine (1 to 100 microM) depressed depolarization-induced contractions in a concentration-dependent manner, but the characteristics of inhibition were not identical. Contractions induced by PGF2 alpha (3 microM) were depressed in a concentration-dependent manner by rauwolscine (3 to 100 microM) but were unaffected by yohimbine or corynanthine. Depolarization-stimulated 45Ca influx was depressed by rauwolscine and corynanthine to about the same extent as were the contractions; while rauwolscine (100 microM) completely inhibited PGF2 alpha-stimulated 45Ca influx, it also depressed part of the PGF2 alpha-stimulated contraction dependent on intracellular calcium. Rauwolscine (100 microM) partly inhibited PGF2 alpha-stimulated release of 45Ca from aortic smooth muscle in calcium-free solution. It is concluded that the yohimbine structure possesses a calcium entry blocking action as well as a depressant action on contractions not dependent on calcium entry. The predominant effect depends on the structural configuration and the nature of the stimulating agent. PMID:6580937

  10. Impaired E Prostanoid2 Expression and Resistance to Prostaglandin E2 in Nasal Polyp Fibroblasts from Subjects with Aspirin-Exacerbated Respiratory Disease.

    PubMed

    Cahill, Katherine N; Raby, Benjamin A; Zhou, Xiaobo; Guo, Feng; Thibault, Derek; Baccarelli, Andreas; Byun, Hyang-Min; Bhattacharyya, Neil; Steinke, John W; Boyce, Joshua A; Laidlaw, Tanya M

    2016-01-01

    Recurrent, rapidly growing nasal polyps are hallmarks of aspirin-exacerbated respiratory disease (AERD), although the mechanisms of polyp growth have not been identified. Fibroblasts are intimately involved in tissue remodeling, and the growth of fibroblasts is suppressed by prostaglandin E2 (PGE2), which elicits antiproliferative effects mediated through the E prostanoid (EP)2 receptor. We now report that cultured fibroblasts from the nasal polyps of subjects with AERD resist this antiproliferative effect. Fibroblasts from polyps of subjects with AERD resisted the antiproliferative actions of PGE2 and a selective EP2 agonist (P < 0.0001 at 1 μM) compared with nasal fibroblasts from aspirin-tolerant control subjects undergoing polypectomy or from healthy control subjects undergoing concha bullosa resections. Cell surface expression of the EP2 receptor protein was lower in fibroblasts from subjects with AERD than in fibroblasts from healthy control subjects and aspirin-tolerant subjects (P < 0.01 for both). Treatment of the fibroblasts with trichostatin A, a histone deacetylase inhibitor, significantly increased EP2 receptor mRNA in fibroblasts from AERD and aspirin-tolerant subjects but had no effect on cyclooxygenase-2, EP4, and microsomal PGE synthase 1 (mPGES-1) mRNA levels. Histone acetylation (H3K27ac) at the EP2 promoter correlated strongly with baseline EP2 mRNA (r = 0.80; P < 0.01). These studies suggest that the EP2 promotor is under epigenetic control, and one explanation for PGE2 resistance in AERD is an epigenetically mediated reduction of EP2 receptor expression, which could contribute to the refractory nasal polyposis typically observed in this syndrome. PMID:26051534

  11. Bromoenol Lactone, an Inhibitor of Calcium-Independent Phospholipase A2, Suppresses Carrageenan-Induced Prostaglandin Production and Hyperalgesia in Rat Hind Paw

    PubMed Central

    Tsuchida, Keiichiro; Ibuki, Takae; Matsumura, Kiyoshi

    2015-01-01

    Prostaglandin (PG) E2 and PGI2 are essential to hyperalgesia in inflammatory tissues. These prostaglandins are produced from arachidonic acid, which is cleaved from membrane phospholipids by the action of phospholipase A2 (PLA2). Which isozyme of PLA2 is responsible for the cleavage of arachidonic acid and the production of prostaglandins essential to inflammation-induced hyperalgesia is not clear. In this study, we examined the effects of two PLA2 isozyme-specific inhibitors on carrageenan-induced production of PGE2 and PGI2 in rat hind paw and behavioral nociceptive response to radiant heat. Local administration of bromoenol lactone (BEL), an inhibitor of calcium-independent PLA2 (iPLA2), significantly reduced carrageenan-induced elevation of prostaglandins in the inflamed foot pad 3 h after injection. It also ameliorated the hyperalgesic response between 1 h and 3 h after carrageenan injection. On the other hand, AACOCF3, an inhibitor of cytosolic PLA2, suppressed neither prostaglandin production nor the hyperalgesic response. BEL did not suppress the mRNA levels of iPLA2β, iPLA2γ, cyclooxygenase-2, microsomal prostaglandin E synthase, prostaglandin I synthase, or proinflammatory cytokines in the inflamed foot pad, indicating that BEL did not suppress inflammation itself. These results suggest that iPLA2 is involved in the production of prostaglandins and hyperalgesia at the inflammatory loci. PMID:26063975

  12. Peripheral prostaglandin E2 prolongs the sensitization of nociceptive dorsal root ganglion neurons possibly by facilitating the synthesis and anterograde axonal trafficking of EP4 receptors.

    PubMed

    St-Jacques, Bruno; Ma, Weiya

    2014-11-01

    Prostaglandin E2 (PGE2), a well-known pain mediator enriched in inflamed tissues, plays a pivotal role in the genesis of chronic pain conditions such as inflammatory and neuropathic pain. PGE2-prolonged sensitization of nociceptive dorsal root ganglion (DRG) neurons (nociceptors) may contribute to the transition from acute to chronic pain. However, the underlying cellular mechanisms are poorly understood. In this study, we tested the hypothesis that facilitating synthesis and anterograde axonal trafficking of EP receptors contribute to PGE2-prolonged nociceptor sensitization. Intraplantar (i.pl.) injection of a stabilized PGE2 analog, 16,16 dimethyl PGE2 (dmPGE2), in a dose- and time-dependent manner, not only elicited primary tactile allodynia which lasted for 1d, but also prolonged tactile allodynia evoked by a subsequent i.pl. injection of dmPGE2 from 1d to 4d. Moreover, the duration of tactile allodynia was progressively prolonged following multiple sequential i.pl. injections of dmPGE2. Co-injection of the selective EP1 or EP4 receptor antagonist, the inhibitors of cAMP, PKA, PKC, PKCε or PLC as well as an interleukin-6 (IL-6) neutralizing antiserum differentially blocked primary tactile allodynia elicited by the 1st dmPGE2 and the prolonged tactile allodynia evoked by the 2nd dmPGE2, suggesting the involvement of these signaling events in dmPGE2-induced nociceptor activation and sensitization. Co-injection of a selective COX2 inhibitor or two EP4 antagonists prevented or shortened inflammagen-prolonged nociceptor sensitization. I.pl. injection of dmPGE2 or carrageenan time-dependently increased EP4 levels in L4-6 DRG neurons and peripheral nerves. EP4 was expressed in almost half of IB4-binding nociceptors of L4-6 DRG. Taken together, our data suggest that stimulating the synthesis and anterograde axonal trafficking to increase EP4 availability at the axonal terminals of nociceptors is likely a novel mechanism underlying PGE2-prolonged nociceptor

  13. Cyclooxygenase-2 prostaglandins mediate anandamide-inhibitory action on nitric oxide synthase activity in the receptive rat uterus.

    PubMed

    Sordelli, Micaela S; Beltrame, Jimena S; Cella, Maximiliano; Franchi, Ana M; Ribeiro, Maria Laura

    2012-06-15

    Anandamide, an endocannabinoid, prostaglandins derived from cyclooxygenase-2 and nitric oxide synthesized by nitric oxide synthase (NOS), are relevant mediators of embryo implantation. We adopted a pharmacological approach to investigate if anandamide modulated NOS activity in the receptive rat uterus and if prostaglandins mediated this effect. As we were interested in studying the changes that occur at the maternal side of the fetal-maternal interface, we worked with uteri obtained from pseudopregnant rats. Females were sacrificed on day 5 of pseudopregnancy, the day in which implantation would occur, and the uterus was obtained. Anandamide (2 ng/kg, i.p.) inhibited NOS activity (P<0.001) and increased the levels of prostaglandin E(2) (P<0.001) and prostaglandin F(2α) (P<0.01). These effects were mediated via cannabinoid receptor type 2, as the pre-treatment with SR144528 (10 mg/kg, i.p.), a selective cannabinoid receptor type 2 antagonist, completely reverted anandamide effect on NOS activity and prostaglandin levels. The pre-treatment with a non-selective cyclooxygenase inhibitor (indomethacin 2.5mg/kg, i.p.) or with selective cyclooxygenase-2 inhibitors (meloxicam 4 mg/kg, celecoxib 3mg/kg, i.p.) reverted anandamide inhibition on NOS, suggesting that prostaglandins are derived from cyclooxygenase-2 mediated anandamide effect. Thus, anandamide levels seemed to modulate NOS activity, fundamental for implantation, via cannabinoid receptor type 2 receptors, in the receptive uterus. This modulation depends on the production of cyclooxygenase-2 derivatives. These data establish cannabinoid receptors and cyclooxygenase enzymes as an interesting target for the treatment of implantation deficiencies. PMID:22554772

  14. Progesterone receptor expression declines in the guinea pig uterus during functional progesterone withdrawal and in response to prostaglandins.

    PubMed

    Welsh, Toni N; Hirst, Jonathan J; Palliser, Hannah; Zakar, Tamas

    2014-01-01

    Progesterone withdrawal is essential for parturition, but the mechanism of this pivotal hormonal change is unclear in women and other mammals that give birth without a pre-labor drop in maternal progesterone levels. One possibility suggested by uterine tissue analyses and cell culture models is that progesterone receptor levels change at term decreasing the progesterone responsiveness of the myometrium, which causes progesterone withdrawal at the functional level and results in estrogen dominance enhancing uterine contractility. In this investigation we have explored whether receptor mediated functional progesterone withdrawal occurs during late pregnancy and labor in vivo. We have also determined whether prostaglandins that induce labor cause functional progesterone withdrawal by altering myometrial progesterone receptor expression. Pregnant guinea pigs were used, since this animal loses progesterone responsiveness at term and gives birth in the presence of high maternal progesterone level similarly to primates. We found that progesterone receptor mRNA and protein A and B expression decreased in the guinea pig uterus during the last third of gestation and in labor. Prostaglandin administration reduced while prostaglandin synthesis inhibitor treatment increased progesterone receptor A protein abundance. Estrogen receptor-1 protein levels remained unchanged during late gestation, in labor and after prostaglandin or prostaglandin synthesis inhibitor administration. Steroid receptor levels were higher in the non-pregnant than in the pregnant uterine horns. We conclude that the decreasing expression of both progesterone receptors A and B is a physiological mechanism of functional progesterone withdrawal in the guinea pig during late pregnancy and in labor. Further, prostaglandins administered exogenously or produced endogenously stimulate labor in part by suppressing uterine progesterone receptor A expression, which may cause functional progesterone withdrawal, promote

  15. Absence of shock-elicited aggression in pigeons1

    PubMed Central

    Rashotte, Michael E.; Dove, L. Duane; Looney, Thomas A.

    1974-01-01

    Two pigeons that attacked a taxidermically prepared target pigeon during a schedule of positive reinforcement for key pecking, and two that did not, were shocked through implanted electrodes in the presence of the target. Shock intensities of 2 and 4 mA, durations of 0.1 and 1.3 sec, and frequencies of 2, 6, 20, and 35 per minute were delivered across 16 sessions with 180 shocks per session. No pigeon attacked the target; one pecked the shockplug on its back. The two pigeons that had not attacked during the positive reinforcement schedules were conditioned to peck the target for food reinforcement before another 16 sessions of shock. No attack was observed in these shock sessions. During subsequent positive reinforcement of key pecking, the target was attacked by the two pigeons that had originally attacked and by one that had not. Absence of shock-elicited attack in these pigeons may be related to the parameters of the experiment or may be yet another instance of the absence of shock-elicited attack in the class Aves. At least under the present conditions, it was not possible to predict the level of attack during electric shock from the level of attack during schedules of positive reinforcement for key pecking. PMID:4856078

  16. Cognitive constraints on constituent order: Evidence from elicited pantomime

    PubMed Central

    Hall, Matthew L.; Mayberry, Rachel I.; Ferreira, Victor S.

    2014-01-01

    To what extent does human cognition influence the structure of human language? Recent experiments using elicited pantomime suggest that the prevalence of Subject-Object-Verb (SOV) order across the world's languages may arise in part because SOV order is most compatible with how we conceptually represent transitive events (Goldin-Meadow, So, Özyürek, & Mylander, 2008). However, this raises the question as to why non-SOV orders exist. Two recent studies (Meir, Lifshitz, Ilkbasaran, & Padden, 2010; Gibson et al., 2013) suggest that SOV might be suboptimal for describing events in which both the agent and patient are plausible agents (e.g. a woman pushing a boy); we call these “reversible” events. We replicate these findings using elicited pantomime and offer a new interpretation. Meir et al.'s (2010) account is framed largely in terms of constraints on comprehension, while Gibson et al.'s (2013) account involves minimizing the risk of information loss or memory degradation. We offer an alternative hypothesis that is grounded in constraints on production. We consider the implications of these findings for the distribution of constituent order in the world's spoken languages and for the structure of emerging sign languages. PMID:23792806

  17. Emotion Elicitation: A Comparison of Pictures and Films

    PubMed Central

    Uhrig, Meike K.; Trautmann, Nadine; Baumgärtner, Ulf; Treede, Rolf-Detlef; Henrich, Florian; Hiller, Wolfgang; Marschall, Susanne

    2016-01-01

    Pictures and film clips are widely used and accepted stimuli to elicit emotions. Based on theoretical arguments it is often assumed that the emotional effects of films exceed those of pictures, but to date this assumption has not been investigated directly. The aim of the present study was to compare pictures and films in terms of their capacity to induce emotions verified by means of explicit measures. Stimuli were (a) single pictures presented for 6 s, (b) a set of three consecutive pictures with emotionally congruent contents presented for 2 s each, (c) short film clips with a duration of 6 s. A total of 144 participants rated their emotion and arousal states following stimulus presentation. Repeated-measures ANOVAs revealed that the film clips and 3-picture version were as effective as the classical 1-picture method to elicit positive emotions, however, modulation toward positive valence was little. Modulation toward negative valence was more effective in general. Film clips were less effective than pictorial stimuli in producing the corresponding emotion states (all p < 0.001) and were less arousing (all p ≤ 0.02). Possible reasons for these unexpected results are discussed. PMID:26925007

  18. Eliciting spatial statistics from geological experts using genetic algorithms

    NASA Astrophysics Data System (ADS)

    Walker, Matthew; Curtis, Andrew

    2014-07-01

    A new method to obtain the statistics of a geostatistical model is introduced. The method elicits the statistical information from a geological expert directly, by iteratively updating a population of vectors of statistics, based on the expert's subjective opinion of the corresponding geological simulations. Thus, it does not require the expert to have knowledge of the mathematical and statistical details of the model. The process uses a genetic algorithm to generate new vectors. We demonstrate the methodology for a particular geostatistical model used to model rock pore-space, which simulates the spatial distribution of matrix and pores over a 2-D grid, using multipoint statistics specified by conditional probabilities. Experts were asked to use the algorithm to estimate the statistics of a given target pore-space image with known statistics; thus, their numerical rates of convergence could be calculated. Convergence was measured for all experts, showing that the algorithm can be used to find appropriate probabilities given the expert's subjective input. However, considerable and apparently irreducible residual misfit was found between the true statistics and the estimates of statistics obtained by the experts, with the root-mean-square error on the conditional probabilities typically >0.1. This is interpreted as the limit of the experts' abilities to distinguish between realizations of different spatial statistics using the algorithm. More accurate discrimination is therefore likely to require complementary elicitation techniques or sources of information independent of expert opinion.

  19. Hypoglycemic activity of withanolides and elicitated Withania somnifera.

    PubMed

    Gorelick, Jonathan; Rosenberg, Rivka; Smotrich, Avinoam; Hanuš, Lumír; Bernstein, Nirit

    2015-08-01

    Withania somnifera, known in India as Asghawhanda, is used traditionally to treat many medical problems including diabetes and has demonstrated therapeutic activity in various animal models as well as in diabetic patients. While much of W. somnifera's therapeutic activity is attributed to withanolides, their role in the anti-diabetic activity of W. somnifera has not been adequately studied. In the present study, we evaluated the anti-diabetic activity of W. somnifera extract and purified withanolides, as well as the effect of various elicitors on this activity. W. somnifera leaf and root extracts increased glucose uptake in myotubes and adipocytes in a dose dependent manner, with the leaf extract more active than the root extract. Leaf but not root extract increased insulin secretion in basal pancreatic beta cells but not in stimulated cells. Six withanolides isolated from W. somnifera were tested for anti-diabetic activity based on glucose uptake in skeletal myotubes. Withaferin A was found to increase glucose uptake, with 10μM producing a 54% increase compared with control, suggesting that withaferin A is at least partially responsible for W. somnifera's anti-diabetic activity. Elicitors applied to the root growing solutions affected the physiological state of the plants, altering membrane leakage or osmotic potential. Methyl salicylate and chitosan increased withaferin A content by 75% and 69% respectively, and extracts from elicited plants increased glucose uptake to a higher extent than non-elicited plants, demonstrating a correlation between increased content of withaferin A and anti-diabetic activity. PMID:25796090

  20. Emotion Elicitation: A Comparison of Pictures and Films.

    PubMed

    Uhrig, Meike K; Trautmann, Nadine; Baumgärtner, Ulf; Treede, Rolf-Detlef; Henrich, Florian; Hiller, Wolfgang; Marschall, Susanne

    2016-01-01

    Pictures and film clips are widely used and accepted stimuli to elicit emotions. Based on theoretical arguments it is often assumed that the emotional effects of films exceed those of pictures, but to date this assumption has not been investigated directly. The aim of the present study was to compare pictures and films in terms of their capacity to induce emotions verified by means of explicit measures. Stimuli were (a) single pictures presented for 6 s, (b) a set of three consecutive pictures with emotionally congruent contents presented for 2 s each, (c) short film clips with a duration of 6 s. A total of 144 participants rated their emotion and arousal states following stimulus presentation. Repeated-measures ANOVAs revealed that the film clips and 3-picture version were as effective as the classical 1-picture method to elicit positive emotions, however, modulation toward positive valence was little. Modulation toward negative valence was more effective in general. Film clips were less effective than pictorial stimuli in producing the corresponding emotion states (all p < 0.001) and were less arousing (all p ≤ 0.02). Possible reasons for these unexpected results are discussed. PMID:26925007

  1. Landing responses of Anopheles gambiae elicited by oxocarboxylic acids.

    PubMed

    Healy, T P; Copland, M J W; Cork, A; Przyborowska, A; Halket, J M

    2002-06-01

    A wind tunnel bioassay and video system were used to observe Anopheles gambiae Giles sensu stricto (Diptera: Culicidae) landing on glass cylinders, heated to human skin temperature (34 degrees C) and treated with aqueous solutions of oxocarboxylic acids. Six of nine compounds tested: 2-oxobutanoic, 2-oxo-3-methylbutanoic, 2-oxopentanoic, 2-oxo-3-methylpentanoic, 2-oxo-4-methylpentanoic and 2-oxohexanoic elicited significant landing responses in comparison to a water control. Landing responses appeared to be restricted to C4-C6, 2-oxocarboxylic acids. A solution of 1 microg/microL of 2-oxopentanoic acid elicited the highest level of response that was temperature dependent: significant numbers of landings occurred only within +/-2 degrees C of human skin temperature. Chemical analysis by linked gas-liquid chromatography/mass spectrometry of methyl-oxime, trimethylsilyl derivatized samples of human sweat extracts revealed the presence of 2-oxopropanoic (pyruvic) acid and three behaviourally active, branched chain acids: 2-oxo-3-methylbutanoic, 2-oxo-3-methylpentanoic and 2-oxo-4-methylpentanoic. PMID:12109705

  2. Vibrio elicits targeted transcriptional responses from copepod hosts.

    PubMed

    Almada, Amalia A; Tarrant, Ann M

    2016-06-01

    Copepods are abundant crustaceans that harbor diverse bacterial communities, yet the nature of their interactions with microbiota are poorly understood. Here, we report that Vibrio elicits targeted transcriptional responses in the estuarine copepod Eurytemora affinis We pre-treated E. affinis with an antibiotic cocktail and exposed them to either a zooplankton specialist (Vibrio sp. F10 9ZB36) or a free-living species (Vibrio ordalii 12B09) for 24 h. We then identified via RNA-Seq a total of 78 genes that were differentially expressed following Vibrio exposure, including homologs of C-type lectins, chitin-binding proteins and saposins. The response differed between the two Vibrio treatments, with the greatest changes elicited upon inoculation with V. sp. F10 We suggest that these differentially regulated genes play important roles in cuticle integrity, the innate immune response, and general stress response, and that their expression may enable E. affinis to recognize and regulate symbiotic vibrios. We further report that V. sp. F10 culturability is specifically altered upon colonization of E. affinis These findings suggest that rather than acting as passive environmental vectors, copepods discriminately interact with vibrios, which may ultimately impact the abundance and activity of copepod-associated bacteria. PMID:27056917

  3. The Effect of Thyroid Hormone, Prostaglandin E2, and Calcium Gluconate on Orthodontic Tooth Movement and Root Resorption in Rats

    PubMed Central

    Seifi, Massoud; Hamedi, Roya; Khavandegar, Zohre

    2015-01-01

    Statement of the Problem A major objective of investigators is to clarify the role of metabolites in achievement of maximum tooth movement with minimal root damage during orthodontic tooth movement (OTM). Purpose The aim of this study was to determine the effect of administration of thyroid hormone, prostaglandin E2, and calcium on orthodontic tooth movement and root resorption in rats. Materials and Method Sixty four male Wistar rats were randomly divided into 8 groups of eight rats each: 1- 20µg/kg thyroxine was injected in traperitoneally after installation of the orthodontic appliance.  2- 0.1 ml of 1 mg/ml prostaglandin E2 was injected submucosally.  3- 10% (200 mg/kg) calcium gluconate was injected.  4- Prostaglandin E2 was injected submucosally and 10% calcium was injected intraperitoneally.  5- Thyroxine was injected intraperitoneally and prostaglandin E2 was injected submucosally.  6- 20µg/kg thyroxine with calcium was injected. 7- Prostaglandin E2 was injected submucosally with calcium and thyroxine.  8- Distilled water was used in control group. The orthodontic appliances comprised of a NiTi closed coil were posteriorly connected to the right first molar and anteriorly to the upper right incisor. OTM was measured with a feeler gauge. The mid-mesial root of the first molar and the adjacent tissues were histologically evaluated. The Data were analyzed by one-way ANOVA and Student-Newman-Keuls test. Results The highest mean OTM was observed in the thyroxine and prostaglandin E2 group (Mean±SD = 0.7375±0.1359 mm) that was significantly different (p< 0.05). A significant difference (p< 0.05) in root resorption was observed between the prostaglandin E2 (0.0192±0.0198 mm2) and the other groups. Conclusion It seems that the combination of thyroxine and prostaglandin E2, with a synergistic effect, would decrease the root resorption and increase the rate of orthodontic tooth movement in rats. PMID:26106633

  4. Prostaglandin endoperoxide synthetase and the activation of benzo(a)pyrene to reactive metabolites in vivo in guinea pigs

    SciTech Connect

    Garattini, E.; Coccia, P.; Romano, M.; Jiritano, L.; Noseda, A.; Salmona, M.

    1984-11-01

    The role of prostaglandin endoperoxide synthetase in the in vivo activation of benzo(a)pyrene to reactive metabolites capable of interacting irreversibly with cellular macromolecules was studied in guinea pig liver, lung, kidney, spleen, small intestine, colon, and brain. DNA and protein covalent binding experiments were made after systemic administration of acetylsalicylic acid (200 mg/kg) followed by radiolabeled benzo(a)pyrene (4 microgram/kg). Results are compared with a control situation in which the prostaglandin endoperoxide synthetase inhibitor (acetylsalicylic acid) was not administered. No decrease in the level of DNA or protein benzo(a)pyrene-derived covalent binding was observed in any of the tissues studied.

  5. Effects of pressure overload and insulin on protein turnover in the perfused rat heart. Prostaglandins are not involved although their synthesis is stimulated by insulin.

    PubMed Central

    Smith, D M; Sugden, P H

    1987-01-01

    A modified anterogradely perfused rat heart preparation is described in which all the cardiac output passes through the coronary circulation. Such a preparation develops hypertensive aortic pressures. Hypertensive aortic pressures or insulin stimulate the rate of cardiac protein synthesis and inhibit the rate of protein degradation. Aortic pressure and insulin may be important in the regulation of cardiac nitrogen balance in vivo. By abolishing cardiac prostaglandin synthesis with 4-biphenylacetate, we were able to investigate the possible involvement of prostaglandins in the modulation of protein turnover by pressure overload or insulin. There was no evidence of any involvement. However, insulin stimulated and cycloheximide inhibited cardiac prostaglandin synthesis. These findings are consonant with an enzyme involved in prostaglandin synthesis being short-lived and prostaglandin synthesis being rapidly influenced by activators and inhibitors of protein synthesis and degradation. PMID:3307762

  6. Pharmacological inhibition of interleukin-1 activity on T cells by hydrocortisone, cyclosporine, prostaglandins, and cyclic nucleotides.

    PubMed

    Tracey, D E; Hardee, M M; Richard, K A; Paslay, J W

    1988-01-01

    The effects of a panel of hormones and pharmacological agents on the activation of T cells by a combination of interleukin-1 and phytohemagglutinin (IL-1/PHA) was studied. Pharmacological effects on various stages of IL-1/PHA-induced interleukin-2 (IL-2) production by the cloned murine thymoma cell line LBRM-33-1A5.7 were dissected using a multi-step assay procedure. A 4-h lag phase in the kinetics of IL-2 production allowed the operational definition of an early, IL-1-dependent programming stage, followed by an IL-2-production stage of the assay. A cell-washing procedure between these stages was introduced in order to distinguish IL-1 receptor antagonists from functional IL-1/PHA antagonists. Hydrocortisone and cyclosporine were potent inhibitors (active in the nM range) of both stages of IL-2 production, suggesting that neither is an IL-1 receptor antagonist. The cyclic adenosine monophosphate (cAMP)-elevating agents prostaglandin E2, dibutyryl cAMP, and theophylline inhibited IL-2 production during the early, IL-1-dependent programming stage. By contrast, prostaglandin F2 alpha and dibutyryl cyclic guanosine monophosphate did not appreciably inhibit IL-1/PHA activity. These results are discussed in relationship to the effects of these test agents in thymocyte IL-1 assays or mitogenesis assays and the implications toward understanding the mechanisms underlying IL-1/PHA activation of T cells. PMID:3258857

  7. The oral activity of delta'-tetrahydrocannabinol and its dependence on prostaglandin E2.

    PubMed Central

    Fairbairn, J. W.; Pickens, J. T.

    1979-01-01

    1 delta'-trans-Tetrahydrocannabinol (THC) is more active orally in mice than previously thought, as cataleptic responses occur at doses from 0.06 mg/kg upwards, with peak activity at 2 to 4 h after dosing. These doses and peaks correspond well with the effects in man. 2 Comparison with chlorpromazine in mice shows that chlorpromazine and THC are equipotent as cataleptics during the first 2 h after dosing; thereafter the THC activity increases to a peak when it is 5.67 times as active as chlorpromazine. 3 The cataleptic effect of THC is abolished by aspirin, indomethacine, diffunisal and phenylbutazone which inhibit the biosynthesis of prostaglandins and is restored by exogenous prostaglandin E2 (PGE2) but not PGE1 and PGF2 alpha. This suggests that the effect of THC depends upon the presence of PGE2. 4 In contrast, the cataleptic effect of chlorpromazine is not affected by pretreatment with aspirin. 5 THC is very much less active intraperitoneally than orally; our results suggest this is not due to poor absorption or extraction into fat depots. 6 Cannabidiol has no cataleptic effect. PMID:574040

  8. Development of pH-Independent Drug Release Formulation Using Lipocalin-Type Prostaglandin D Synthase.

    PubMed

    Mizoguchi, Masashi; Nakatsuji, Masatoshi; Takano, Junichi; Ishibashi, Osamu; Wada, Koichi; Inui, Takashi

    2016-09-01

    The purpose of this study was to develop a pH-independent drug release formulation using lipocalin-type prostaglandin D synthase, a member of the lipocalin superfamily, with the function of forming complexes together with various small lipophilic molecules. Dipyridamole, a poorly water-soluble drug, showing a pH-dependent solubility profile, was used as the model drug. The solubilization of dipyridamole was achieved by a simple complex formulation method with lipocalin-type prostaglandin D synthase. The complex formulation was produced successfully by spray drying, and the obtained powder formulation showed complete dissolution in fasted-state simulated gastric fluid (pH, 1.6) and phosphate-buffered solution (pH, 6.8). In addition, the potential stability of the complex formulation was assessed, and the dissolution profile of the produced powder at pH 6.8 was maintained after 4-week storage under several storage conditions. Furthermore, a pharmacokinetic study using hypochlorhydria model rats was performed to verify the improvement of the intestinal absorption behavior, and eventually the complex formulation overcame the problematic absorption profile of dipyridamole in the elevated gastric pH conditions. These results, taken together, demonstrate that the use of this well-designed drug-delivery carrier is feasible for the development of pH-independent drug release formulations. PMID:26886322

  9. Prostaglandin control of renal circulation in the unanesthetized dog and baboon

    NASA Technical Reports Server (NTRS)

    Swain, J. A.; Vatner, S. F.; Heyndrickx, G. R.; Boettcher, D. H.

    1975-01-01

    Effects of indomethacin and meclofenamate, inhibitors of prostaglandin synthesis, were evaluated in the regulation of renal blood flow in conscious and anesthetized dogs and in tranquilized baboons, instrumented with arterial pressure catheters and renal blood flow probes. Indomethacin, 10 mg/kg, did not alter renal blood flow or resistance significantly in the conscious dog. In the anesthetized dog, however, indomethacin caused a reduction in renal blood flow and an elevation of renal vascular resistance. Meclofenamate, 4 mg/kg, reduced renal flow and increased renal vascular resistance in conscious dogs. In conscious dogs and tranquilized primates, indomethacin and meclofenamate reduced the reactive hyperemia in the renal bed. Methoxamine and angiotensin II infused in graded doses induced significantly greater renal vasoconstriction in conscious dogs in the presence of indomethacin. Thus, in the conscious animal, prostaglandins appear to play only a minor part in the control of renal circulation at rest, but they are of greater importance in mediating the renal responses to reactive hyperemia and to vasoconstriction.

  10. Neutrophils mediate Salmonella Typhimurium clearance through the GBP4 inflammasome-dependent production of prostaglandins

    PubMed Central

    Tyrkalska, Sylwia D.; Candel, Sergio; Angosto, Diego; Gómez-Abellán, Victoria; Martín-Sánchez, Fátima; García-Moreno, Diana; Zapata-Pérez, Rubén; Sánchez-Ferrer, Álvaro; Sepulcre, María P.; Pelegrín, Pablo; Mulero, Victoriano

    2016-01-01

    Inflammasomes are cytosolic molecular platforms that alert the immune system about the presence of infection. Here we report that zebrafish guanylate-binding protein 4 (Gbp4), an IFNγ-inducible GTPase protein harbouring a C-terminal CARD domain, is required for the inflammasome-dependent clearance of Salmonella Typhimurium (ST) by neutrophils in vivo. Despite the presence of the CARD domain, Gbp4 requires the universal inflammasome adaptor Asc for mediating its antibacterial function. In addition, the GTPase activity of Gbp4 is indispensable for inflammasome activation and ST clearance. Mechanistically, neutrophils are recruited to the infection site through the inflammasome-independent production of the chemokine (CXC motif) ligand 8 and leukotriene B4, and then mediate bacterial clearance through the Gbp4 inflammasome-dependent biosynthesis of prostaglandin D2. Our results point to GBPs as key inflammasome adaptors required for prostaglandin biosynthesis and bacterial clearance by neutrophils and suggest that transient activation of the inflammasome may be used to treat bacterial infections. PMID:27363812

  11. A Novel Selective Prostaglandin E2 Synthesis Inhibitor Relieves Pyrexia and Chronic Inflammation in Rats.

    PubMed

    Sugita, Ryusuke; Kuwabara, Harumi; Sugimoto, Kotaro; Kubota, Kazufumi; Imamura, Yuichiro; Kiho, Toshihiro; Tengeiji, Atsushi; Kawakami, Katsuhiro; Shimada, Kohei

    2016-04-01

    Prostaglandin E2 (PGE2) is a terminal prostaglandin in the cyclooxygenase (COX) pathway. Inhibition of PGE2 production may relieve inflammatory symptoms such as fever, arthritis, and inflammatory pain. We report here the profile of a novel selective PGE2 synthesis inhibitor, compound A [N-[(1S,3S)-3-carbamoylcyclohexyl]-1-(6-methyl-3-phenylquinolin-2-yl)piperidine-4-carboxamide], in animal models of pyrexia and inflammation. The compound selectively suppressed the synthesis of PGE2 in human alveolar adenocarcinoma cell line A549 cells and rat macrophages. In the lipopolysaccharide-induced pyrexia model, this compound selectively reduced PGE2 production in cerebrospinal fluid and showed an anti-pyretic effect. In the adjuvant-induced arthritis model, compound A therapeutically decreased foot swelling in the established arthritis. Our data demonstrates that selective suppression of PGE2 synthesis shows anti-pyretic and anti-inflammatory effects, suggesting that selective PGE2 synthesis inhibitors can be applied as an alternative treatment to nonsteroidal, anti-inflammatory drugs (NSAIDs) or COX-2-selective inhibitors. PMID:26923147

  12. [Inhibition of initial puerperal and postabortion lactation using oral prostaglandin E2 (Dinoprostone)].

    PubMed

    Berić, B; Mitreski, A; Kuzmancev, O; Curcić, A; Ilić, V; Vukelić, J; Budakov, D

    1992-01-01

    Authors present their experience in oral administration of Prostaglandin E2 (Dinoproston, Upjohn) during postpartal and postabortal period (à 0.5 mg after legal pregnancy interruption) in suppression of lactation. Indications for postpartal lactation suppression were such as: stillbirth, postpartal neonatal death and maternal negative attitude towards breast feeding. The patients in whom the suppression of lactation was applied were of generative age (18-40 years) either primiparas or multiparas. All were delivered vaginally with no extra intrapartal or postpartal complications being the same in legal pregnancy interruptions which were performed by application of intravaginal, intracervical and intramuscular Prostaglandin preparations. The patients were administered 1 tbl od 0.5 mg Dinoproston preparation every 6-7 hours, 48 h after the delivery, i.e. 2 tbl in total (after meal). This method of lactation suppression was applied in 50 patients during 1990. Satisfactory results were achieved in all cases, while negative side effects and complications were not noted. Oral administration of PGE2 was found very efficient in postpartal and postabortal lactation suppression while compared with previously applied methods such as Estrogen-Testosterone preparation, i.e. small doses of Bromergon applied during 10-14 days. Oral administration of PG2 is more efficient and in a certain way more comfortable in relation to the previously applied methods. PMID:1344441

  13. Cervical dilatation in late first trimester termination by prostaglandin, hylase and isogel.

    PubMed

    Mandlekar, A V; Ganguli, A C; Krishna, U R; Purandare, V N

    1981-04-01

    Pre-operative dilatation of the cervix was attempted in 223 cases prior to vacuum aspiration in patients seeking late first trimester termination beyond ten weeks. 15 Me PGF2a was used in the form of vaginal suppositories, intramuscular and intracervical injections. Dilatation of cervix of 10 mm or more was achieved within 4 hours in 86% cases with intra-cervical injections. Gastro-intestinal disturbances caused by intra-muscular injections could be avoided by intra-cervical injections, as the amount of prostaglandin required was only 100 ugm, but the success rate was significantly lower. The success with multiple dose suppositories was 80%. There was no significant difference in the success with 1.5 mgm or 1.0 mgm dosage, but the side effects were significantly higher with 1.5 mgm suppositories. Intra-cervical Hylase did not dilate the cervix but successfully softened it within 5 minutes to make metallic dilatation simple. The hygroscopic Isogel tents achieved dilatation of 10 mm or more in 73% of the patients in 12 hours. The tents as well as intra-cervical prostaglandin injection had the disadvantage of requiring an additional theatre procedure prior to suction curettage. PMID:7025067

  14. A dynamic Asp-Arg interaction is essential for catalysis in microsomal prostaglandin E2 synthase.

    PubMed

    Brock, Joseph S; Hamberg, Mats; Balagunaseelan, Navisraj; Goodman, Michael; Morgenstern, Ralf; Strandback, Emilia; Samuelsson, Bengt; Rinaldo-Matthis, Agnes; Haeggström, Jesper Z

    2016-01-26

    Microsomal prostaglandin E2 synthase type 1 (mPGES-1) is responsible for the formation of the potent lipid mediator prostaglandin E2 under proinflammatory conditions, and this enzyme has received considerable attention as a drug target. Recently, a high-resolution crystal structure of human mPGES-1 was presented, with Ser-127 being proposed as the hydrogen-bond donor stabilizing thiolate anion formation within the cofactor, glutathione (GSH). We have combined site-directed mutagenesis and activity assays with a structural dynamics analysis to probe the functional roles of such putative catalytic residues. We found that Ser-127 is not required for activity, whereas an interaction between Arg-126 and Asp-49 is essential for catalysis. We postulate that both residues, in addition to a crystallographic water, serve critical roles within the enzymatic mechanism. After characterizing the size or charge conservative mutations Arg-126-Gln, Asp-49-Asn, and Arg-126-Lys, we inferred that a crystallographic water acts as a general base during GSH thiolate formation, stabilized by interaction with Arg-126, which is itself modulated by its respective interaction with Asp-49. We subsequently found hidden conformational ensembles within the crystal structure that correlate well with our biochemical data. The resulting contact signaling network connects Asp-49 to distal residues involved in GSH binding and is ligand dependent. Our work has broad implications for development of efficient mPGES-1 inhibitors, potential anti-inflammatory and anticancer agents. PMID:26755582

  15. Chromosomal organization of the inducible and constitutive prostaglandin synthase/cyclooxygenase genes in mouse

    SciTech Connect

    Ping Zi Wen; Warden C.; Fletcher, B.S.; Kujubu, D.A.; Herschman, H.R.; Lusis, A.J. )

    1993-02-01

    Two distinct prostaglandin synthase/cyclooxygenase (PGS/COS) enzymes have recently been recognized. One (EC 1.14.00.1) is largely constitutive and has been characterized in a variety of species, whereas the other (also known as TIS10) is inducible by mitogens and inhibitable by glucocorticoids. Along with activation of phospholipase A2, the latter PGS/COS is likely to mediate ligand-induced prostaglandin production in a variety of cell types. The two enzymes have similar gene structures and activities. There is accumulating evidence that PGS/COX activity may play a role in inflammatory diseases. For example, PGS/COX expression is upregulated in inflammatory joint diseases and is genetically controlled. As part of an effort to examine genetic factors regulating PGS/COX expression and the possible involvement of the enzymes in mouse models of inflammatory disorders, we report here the chromosomal mapping of the genes for the constitutive and regulated PGS/COX enzymes. We will refer to the constitutive enzyme as Pgs-1 and the inducible enzyme as Pgs-2. 14 refs., 1 tab.

  16. Suppression of the cutaneous immune response following topical application of the prostaglandin PGE2

    SciTech Connect

    Rheins, L.A.; Barnes, L.; Amornsiripanitch, S.; Collins, C.E.; Nordlund, J.J.

    1987-04-15

    UVB irradiation (290-320 nm) and topical applications of arachidonic acid (AA) in mice decrease the number of identifiable Langerhans cells and alter the cutaneous immune response. Application of contact allergens such as dinitrofluorobenzene (DNFB) to irradiated or AA-treated skin induces antigen-specific tolerance. Indomethacin (IM), a cyclooxygenase inhibitor, administered orally to mice prior to UVB irradiation or prior to the topical application of arachidonic acid, abrogates suppression of contact hypersensitivity (CHS) to DNFB. This suggests a byproduct of arachidonic acid generated through the cyclooxygenase pathway may be involved in the immune suppression. Topical application of various prostaglandins (PGE2, PGD2, PGF2 alpha, and CTXA2) did not cause alterations in the population density of the identifiable Ia+ dendritic Langerhans cells. PGE2, but no other tested agent, produced a suppression of the CHS response to DNFB. These observations suggests that of the various prostaglandins, PGE2 might be one of several biochemical signals which mediate the suppression of contact hypersensitivity reactions following ultraviolet radiation exposure. However, the mechanisms by which PGE2 produces its suppressive effects have not been identified.

  17. Free radical oxidation of (E)-retinoic acid by prostaglandin H synthase.

    PubMed

    Samokyszyn, V M; Chen, T; Maddipati, K R; Franz, T J; Lehman, P A; Lloyd, R V

    1995-01-01

    Cooxidative metabolism of all-trans (E)-retinoic acid (RA) by prostaglandin H synthase was investigated employing ram seminal vesicle microsomes (RSVM) or purified, RSVM-derived enzyme. RA was shown to undergo hydroperoxide [H2O2 or 5-phenyl-4-penten-1-yl hydroperoxide (PPHP)]- or arachidonic acid-dependent cooxidation by microsomal prostaglandin H (PGH) synthase as evidenced by UV spectroscopic analysis of reaction mixtures. Cooxidation of RA by microsomal or purified PGH synthase, using PPHP as substrate, was characterized by uptake of dioxygen which was first order with respect to enzyme concentration. Dioxygen uptake was inhibited by the peroxidase reducing substrate 2-methoxyphenol. In addition, O2 uptake was inhibited by the spin trap nitrosobenzene. ESR spin trapping studies, using alpha-phenyl-N-tert-butylnitrone (PBN) as the spin trap, demonstrated the formation of RA-PBN adducts, characterized by hyperfine coupling constants of alpha H = 3.2 G and alpha N = 15.8 G. Reverse phase HPLC analysis of reaction mixtures demonstrated the formation of 4-hydroxy-RA, 5,6-epoxy-RA, 4-oxo-RA, (13Z)-retinoic acid, and other geometric isomers which were identified on the basis of cochromatography with synthetic standards, UV spectroscopy, and/or mass spectrometry. Mechanisms are proposed for the hydroperoxide-dependent, PGH synthase-catalyzed oxidation of RA that are consistent with these results. PMID:7548765

  18. In vivo investigations on luteotropic activity of prostaglandins during early diestrus in nonpregnant bitches.

    PubMed

    Janowski, Tomasz; Fingerhut, Julia; Kowalewski, Mariusz P; Zduńczyk, Sławomir; Domosławska, Anna; Jurczak, Andrzej; Boos, Alois; Schuler, Gerhard; Hoffmann, Bernd

    2014-10-01

    The aim of this study was to test for the postulated luteotropic effect of prostaglandin E2 during early diestrus in the dog in an in vivo study. This study was performed on 30 bitches which were randomly assigned to a treatment group (TG) and a control group. Starting on the day of ovulation (Day 0), dogs of the TG were treated for 5, 10, 20, or 30 days with 10 mg firocoxib/kg body weight per day (Previcox, a selective PTGS2 inhibitor) and ovariohysterectomized for collection of corpora lutea on the last day of treatment. Similarly, dogs of the control group were ovariohysterectomized on Days 0, 5, 10, 20, and 30. Blood samples for progesterone measurement were collected every second day; additionally, the area of luteal cell nuclei and the expression of 3β-hydroxysteroid-dehydrogenase at the mRNA and the protein levels were assessed. Mean P4 concentrations were lower in TGs; however, a significant difference was only observed on Day 10. This observation is in line with the finding that treatment with firocoxib reduced expression of 3β-hydroxysteroid-dehydrogenase mRNA and protein (P < 0.05) and the area of luteal cell nuclei (P < 0.05). The results of this study further point to the postulated luteotropic function of prostaglandin E2. PMID:25115648

  19. Effect of diet on hyperthermia-induced cell lethality and prostaglandin release.

    PubMed

    Wainberg, R H; Walden, T L; Stebler, B A; Yatvin, M B

    1991-05-01

    Hyperthermia-induced cell lethality is thought to be mediated through injury to the cell membrane. Membrane perturbation results in the release of prostaglandins (PG) and leukotrienes (LT). These compounds are potent biological mediators and may modify the tumor microenvironment and therapeutic efficacy. Membrane composition and PG/LT release are influenced by the dietary fatty acids. The relationship between these variables and response to hyperthermia was examined in vitro using murine P388 leukemia cells grown as an ascites in mice provided either saturated fatty acid diet (SFA; 16% beef tallow) or unsaturated fatty acid diet (UFA; 16% safflower oil). Cells were harvested and exposed in vitro to either 37 degrees C or 43.5 degrees C for periods up to 2 hours. Hyperthermic exposure for 2 hours resulted in 40% cell lethality in SFA cells and 55% in UFA cells. The phospholipid and total cholesterol content was higher (33% and 50% respectively) in the UFA versus the SFA cells. Hyperthermia produced a six-fold increase in prostaglandin E2 PGE2 release by SFA cells and a 4.5-fold increase by UFA cells. No LTC4 was detected. Alteration of dietary fat affects cell lethality and PG release following hyperthermic treatment. The increase in phospholipid and cholesterol content of UFA cells may be a response to reduced membrane fluidity. PMID:1862229

  20. Modulation of Leishmania (L.) amazonensis Growth in Cultured Mouse Macrophages by Prostaglandins and Platelet Activating Factor

    PubMed Central

    Lonardoni, M. V. C.; Barbieri, C. L.; Russo, M.

    1994-01-01

    The role of endogenously synthesized PAF and prostaglandins on the infection of mouse macrophages by Letsbmanta (L.) amazonensis was investigated, as well as the possible correlation between the effects of these inflammatory mediators with nitric oxide production. It was found that pretreatment of macrophages with 10−5 M of the PAF antagonists, BN-52021 or WEB-2086, increased macrophage infection by 17 and 59%, respectively. The cyclooxygenase inhibitor, indomethacin (10 μg/ml), induced a significant inhibition which was reversed by addition of PGE (10-3 M) to the culture medium. These results suggested that the infection of macrophages by leisbmanla is inhibited by PAF and enhanced by prostaglandins and that these mediators are produced by macrophages during this infection. This was confirmed by addition of these mediators to the culture medium before infection; PAF (10−6, 10−9 and 10−12M) reduced significantly the infection whereas PGE2 (10−5 M) induced a marked enhancement. This effect of exogenous PAF on macrophage infection was reversed by the two PAF antagonists used in this study as well as by the inhibitor of nitric oxide synthesis, L-arginine methyl ester (100 mM). Taken together the data suggest that endogenous production of PAF and PGE2 exert opposing effects on Lesbmana–macrophage interaction and that nitric oxide may be involved in the augmented destruction of parasites induced by PAF. PMID:18472932

  1. Cervical dilatation with prostaglandin analogues prior to vaginal termination of first trimester pregnancy in nulliparous patients.

    PubMed

    Karim, S M; Choo, H T; Cheng, P

    1975-04-01

    Dilatation of the cervix with prostaglandin analogues prior to vaginal termination of pregnancy was attempted in 125 nulliparous women in the first trimester of pregnancy. The patients were divided into five groups (25 in each group) and given a single extra-amniotic dose of one of the following prostaglandin analogues 14-16 hours prior to the evacuation of the uterus by vacuum aspiration. (Group A) 15 (S) 15 methyl PGE2 (free acid); (Group B) 15 (S) 15 methyl PGE2 methyl ester; (Group C) 15 (S) 15 methyl PGF2alpha (free acid); (Group D) 15 (S) 15 methyl PGF2alpha methyl ester and(Group E) a mixture of 15 (S) 15 methyl PGE2methyl ester and 15 (S) 15 methyl PGF2alpha methyl ester. Evacuation of the uterus without mechanical dilatation of the cervix was possible in 111 (90%) of the patients. In an additional 10 patients (8%) there was some degree of cervical dilatation and further mechanical dilatation could be performed easily. With the combination of 15 (S) 15 methyl PGE2 methyl ester and 15 (S) 15 methyl PGF2alpha methyl ester the incidence of gastrointestinal side effects and pyrexia were considerably reduced. PMID:1153813

  2. Neutrophils mediate Salmonella Typhimurium clearance through the GBP4 inflammasome-dependent production of prostaglandins.

    PubMed

    Tyrkalska, Sylwia D; Candel, Sergio; Angosto, Diego; Gómez-Abellán, Victoria; Martín-Sánchez, Fátima; García-Moreno, Diana; Zapata-Pérez, Rubén; Sánchez-Ferrer, Álvaro; Sepulcre, María P; Pelegrín, Pablo; Mulero, Victoriano

    2016-01-01

    Inflammasomes are cytosolic molecular platforms that alert the immune system about the presence of infection. Here we report that zebrafish guanylate-binding protein 4 (Gbp4), an IFNγ-inducible GTPase protein harbouring a C-terminal CARD domain, is required for the inflammasome-dependent clearance of Salmonella Typhimurium (ST) by neutrophils in vivo. Despite the presence of the CARD domain, Gbp4 requires the universal inflammasome adaptor Asc for mediating its antibacterial function. In addition, the GTPase activity of Gbp4 is indispensable for inflammasome activation and ST clearance. Mechanistically, neutrophils are recruited to the infection site through the inflammasome-independent production of the chemokine (CXC motif) ligand 8 and leukotriene B4, and then mediate bacterial clearance through the Gbp4 inflammasome-dependent biosynthesis of prostaglandin D2. Our results point to GBPs as key inflammasome adaptors required for prostaglandin biosynthesis and bacterial clearance by neutrophils and suggest that transient activation of the inflammasome may be used to treat bacterial infections. PMID:27363812

  3. 2-methoxycinnamaldehyde reduces IL-1beta-induced prostaglandin production in rat cerebral endothelial cells.

    PubMed

    Guo, Jian-You; Huo, Hai-Ru; Yang, Yuan-Xiao; Li, Cang-Hai; Liu, Hong-Bin; Zhao, Bao-Sheng; Li, Lan-Fang; Ma, Yue-Ying; Guo, Shu-Ying; Jiang, Ting-Liang

    2006-11-01

    Prostaglandin E2 (PGE2) works as a common final mediator of the febrile. Guizhi-Tang, one of the most famous traditional Chinese medical formula used to treat influenza, common cold and other pyretic conditions, was previously reported to reduce the production of PGE 2 in rats. 2-Methoxycinnamaldehyde is a principle compound isolated from Guizhi-Tang. The aim of the present study was to investigate the effects of 2-methoxycinnamaldehyde on PGE2 production of rat cerebral endothelial cells (CECs). 2-Methoxycinnamaldehyde dose-dependently inhibited interleukin (IL)-1beta-induced PGE2 production in CECs with IC50 values of 174 microM. IL-1beta stimulation increased the protein, activity and mRNA expression of cyclooxygenase (COX)-2 but not COX-1. 2-Methoxycinnamaldehyde reduced IL-1beta-induced protein and activity of COX-2, but did not influence the COX-2 mRNA expression. Our results show that prostaglandin production in CECs during stimulated conditions is sensitive to inhibition by 2-methoxycinnamaldehyde and suggest that 2-methoxycinnamaldehyde may reduce COX-2 protein level and activity but not COX-2 mRNA. PMID:17077517

  4. Binding of thromboxane A2/prostaglandin H2 agonists to human platelets.

    PubMed Central

    Halushka, P. V.; Kochel, P. J.; Mais, D. E.

    1987-01-01

    The competition of [125I]-9, 11 dimethylmethano-11, 12 methano-16-(3-iodo-4-hydroxyphenyl)-13, 14-dihydro-13-aza 15 alpha beta-omega-tetranor-thromboxane A2 ([125I]-PTA-OH), a thromboxane A2/prostaglandin H2 receptor antagonist, with a series of thromboxane A2/prostaglandin H2 (TXA2/PGH2) mimetics for binding to the putative TXA2/PGH2 receptor in washed human platelets was studied. The rank order potency for the series of mimetics to compete with [125I]-PTA-OH for binding was compared with their rank order potency for induction of platelet aggregation. The rank order potency for the mimetics to compete with [125I]-PTA-OH for binding was ONO-11113 greater than SQ-26655 greater than U44069 greater than U46619 = 9, 11-azo PGH2 greater than MB28767. This rank order potency was highly correlated with their rank order potency for inducing platelet aggregation (r = 0.992). Changes in the intra or extracellular concentrations of Na+ did not have a significant effect on the competition between U46619 and [125I]-PTA-OH for binding to the putative receptor. In summary, it appears that these TXA2/PGH2 mimetics activate human platelets through the putative TXA2/PGH2 receptor. PMID:3594077

  5. Prostaglandin E2 differentially modulates the central control of eupnoea, sighs and gasping in mice

    PubMed Central

    Koch, Henner; Caughie, Cali; Elsen, Frank P; Doi, Atsushi; Garcia, Alfredo J; Zanella, Sebastien; Ramirez, Jan-Marino

    2015-01-01

    Prostaglandins are important regulators of autonomic functions in the mammalian organism. Here we demonstrate in vivo that prostaglandin E2 (PGE2) can differentially increase the frequency of eupnoea (normal breathing) and sighs (augmented breaths) when injected into the preBötzinger complex (preBötC), a medullary area that is critical for breathing. Low concentrations of PGE2 (100–300 nm) increased the sigh frequency, while higher concentrations (1–2 μm) were required to increase the eupnoeic frequency. The concentration-dependent effects were similarly observed in the isolated preBötC. This in vitro preparation also revealed that riluzole, a blocker of the persistent sodium current (INap), abolished the modulatory effect on sighs, while flufenamic acid, an antagonist for the calcium-activated non-selective cation conductance (ICAN) abolished the effect of PGE2 on fictive eupnoea at higher concentrations. At the cellular level PGE2 significantly increased the amplitude and frequency of intrinsic bursting in inspiratory neurons. By contrast PGE2 affected neither excitatory nor inhibitory synaptic transmission. We conclude that PGE2 differentially modulates sigh, gasping and eupnoeic activity by differentially increasing INap and ICAN currents in preBötC neurons. PMID:25556802

  6. Neuroprotection by selective allosteric potentiators of the EP2 prostaglandin receptor

    PubMed Central

    Jiang, Jianxiong; Ganesh, Thota; Du, Yuhong; Thepchatri, Pahk; Rojas, Asheebo; Lewis, Iestyn; Kurtkaya, Serdar; Li, Lian; Qui, Min; Serrano, Geidy; Shaw, Renee; Sun, Aiming; Dingledine, Ray

    2010-01-01

    Activation of the Gαs-coupled EP2 receptor for prostaglandin E2 (PGE2) promotes cell survival in several models of tissue damage. To advance understanding of EP2 functions, we designed experiments to develop allosteric potentiators of this key prostaglandin receptor. Screens of 292,000 compounds identified 93 that at 20 μM (i) potentiated the cAMP response to a low concentration of PGE2 by > 50%; (ii) had no effect on EP4 or β2 adrenergic receptors, the cAMP assay itself, or the parent cell line; and (iii) increased the potency of PGE2 on EP2 receptors at least 3-fold. In aqueous solution, the active compounds are largely present as nanoparticles that appear to serve as active reservoirs for bioactive monomer. From 94 compounds synthesized or purchased, based on the modification of one hit compound, the most active increased the potency of PGE2 on EP2 receptors 4- to 5-fold at 10 to 20 μM and showed substantial neuroprotection in an excitotoxicity model. These small molecules represent previously undescribed allosteric modulators of a PGE2 receptor. Our results strongly reinforce the notion that activation of EP2 receptors by endogenous PGE2 released in a cell-injury setting is neuroprotective. PMID:20080612

  7. Microsomal prostaglandin E synthase-1 protects against Fas-induced liver injury.

    PubMed

    Yao, Lu; Chen, Weina; Han, Chang; Wu, Tong

    2016-06-01

    Microsomal prostaglandin E synthase-1 (mPGES-1) is the terminal enzyme for the synthesis of prostaglandin E2 (PGE2), a proproliferative and antiapoptotic lipid molecule important for tissue regeneration and injury repair. In this study, we developed transgenic (Tg) mice with targeted expression of mPGES-1 in the liver to assess Fas-induced hepatocyte apoptosis and acute liver injury. Compared with wild-type (WT) mice, the mPGES-1 Tg mice showed less liver hemorrhage, lower serum alanine transaminase (ALT) and aspartate transaminase (AST) levels, less hepatic necrosis/apoptosis, and lower level of caspase cascade activation after intraperitoneal injection of the anti-Fas antibody Jo2. Western blotting analysis revealed increased expression and activation of the serine/threonine kinase Akt and associated antiapoptotic molecules in the liver tissues of Jo2-treated mPGES-1 Tg mice. Pretreatment with the mPGES-1 inhibitor (MF63) or the Akt inhibitor (Akt inhibitor V) restored the susceptibility of the mPGES-1 Tg mice to Fas-induced liver injury. Our findings provide novel evidence that mPGES-1 prevents Fas-induced liver injury through activation of Akt and related signaling and suggest that induction of mPGES-1 or treatment with PGE2 may represent important therapeutic strategy for the prevention and treatment of Fas-associated liver injuries. PMID:27102561

  8. Prostaglandin D2 inhibits wound-induced hair follicle neogenesis through the receptor, Gpr44.

    PubMed

    Nelson, Amanda M; Loy, Dorothy E; Lawson, John A; Katseff, Adiya S; Fitzgerald, Garret A; Garza, Luis A

    2013-04-01

    Prostaglandins (PGs) are key inflammatory mediators involved in wound healing and regulating hair growth; however, their role in skin regeneration after injury is unknown. Using wound-induced hair follicle neogenesis (WIHN) as a marker of skin regeneration, we hypothesized that PGD2 decreases follicle neogenesis. PGE2 and PGD2 were elevated early and late, respectively, during wound healing. The levels of WIHN, lipocalin-type prostaglandin D2 synthase (Ptgds), and its product PGD2 each varied significantly among background strains of mice after wounding, and all correlated such that the highest Ptgds and PGD2 levels were associated with the lowest amount of regeneration. In addition, an alternatively spliced transcript variant of Ptgds missing exon 3 correlated with high regeneration in mice. Exogenous application of PGD2 decreased WIHN in wild-type mice, and PGD2 receptor Gpr44-null mice showed increased WIHN compared with strain-matched control mice. Furthermore, Gpr44-null mice were resistant to PGD2-induced inhibition of follicle neogenesis. In all, these findings demonstrate that PGD2 inhibits hair follicle regeneration through the Gpr44 receptor and imply that inhibition of PGD2 production or Gpr44 signaling will promote skin regeneration. PMID:23190891

  9. Prostaglandin D2 inhibits wound-induced hair follicle neogenesis through the receptor, Gpr44

    PubMed Central

    Nelson, Amanda M.; Loy, Dorothy E.; Lawson, John A.; Katseff, Adiya S.; FitzGerald, Garret A.; Garza, Luis A.

    2012-01-01

    Prostaglandins (PGs) are key inflammatory mediators involved in wound healing and regulating hair growth; however, their role in skin regeneration after injury is unknown. Using wound-induced hair follicle neogenesis (WIHN) as a marker of skin regeneration, we hypothesized that PGD2 decreases follicle neogenesis. PGE2 and PGD2 were elevated early and late respectively during wound healing. The levels of WIHN, lipocalin-type prostaglandin D2 synthase (Ptgds) and its product PGD2 each varied significantly among background strains of mice after wounding and all correlated such that the highest Ptgds and PGD2 levels were associated with the lowest amount of regeneration. Additionally, an alternatively spliced transcript variant of Ptgds missing exon 3 correlated with high regeneration in mice. Exogenous application of PGD2 decreased WIHN in wild type mice and PGD2 receptor Gpr44 null mice showed increased WIHN compared to strain-matched control mice. Furthermore, Gpr44 null mice were resistant to PGD2-induced inhibition of follicle neogenesis. In all, these findings demonstrate that PGD2 inhibits hair follicle regeneration through the Gpr44 receptor and imply that inhibition of PGD2 production or Gpr44 signaling will promote skin regeneration. PMID:23190891

  10. Aspirin inhibits interleukin 1-induced prostaglandin H synthase expression in cultured endothelial cells

    SciTech Connect

    Wu, K.K.; Sanduja, R.; Tsai, A.L.; Ferhanoglu, B.; Loose-Mitchell, D.S. )

    1991-03-15

    Prostaglandin H (PGH) synthase is a key enzyme in the biosynthesis of prostaglandins, thromboxane, and prostacyclin. In cultured human umbilical vein endothelial cells, interleukin 1 (IL-1) is known to induce the synthesis of this enzyme, thereby raising the level of PGH synthase protein severalfold over the basal level. Pretreatment with aspirin at low concentrations inhibited more than 60% of the enzyme mass and also the cyclooxygenase activity in IL-1-induced cells with only minimal effects on the basal level of the synthase enzyme in cells without IL-1. Sodium salicylate exhibited a similar inhibitory action whereas indomethacin had no apparent effect. Similarly low levels of aspirin inhibited the increased L-({sup 35}S)methionine incorporation into PGH synthase that was induced by IL0-1 and also suppressed expression of the 2.7-kilobase PGH synthase mRNA. These results suggest that in cultured endothelial cells a potent inhibition of eicosanoid biosynthetic capacity can be effected by aspirin or salicylate at the level of PGH synthase gene expression. The aspirin effect may well be due to degradation of salicylate.

  11. Cysteamine and prostaglandin F2 beta stimulate rat gastric mucin release

    SciTech Connect

    Lamont, J.T.; Ventola, A.S.; Maull, E.A.; Szabo, S.

    1983-02-01

    Gastric mucin glycoproteins form an adherent gel over the surface epithelium that is thought to protect the stomach against chemical and physical damage. The purpose of this study was to measure the release of mucin glycoproteins from rat stomach after treatment with cysteamine and prostaglandin F2 beta, two structurally unrelated drugs that have been shown to protect the stomach against the noxious effects of alcohol and other damaging agents. Gastric mucin was separated into soluble (washout) and insoluble (adherent) phases before colorimetric quantitation of total mucin, protein-bound hexose, and sialic acid. Cysteamine produced a dose-dependent increase in release of soluble and gel mucin. Prostaglandin F2 beta caused a dose-dependent release of hexose-containing mucin but had no effect on sialic acid-containing glycoproteins. Sepharose 4B chromatography of both the soluble and adherent mucus revealed that greater than 90% was a high molecular weight glycoprotein fraction. N-Ethylmaleimide, a known inhibitor of cytoprotection by cysteamine, had no effect on mucin secretion. Similarly, indomethacin inhibited mucin secretion by cysteamine but did not significantly influence cytoprotection. Thus the secretion of mucin by cytoprotective agents is unlikely by itself to explain the ability of the stomach to resist chemical or physical damage.

  12. Modulation of ligand-mediated human red cell agglutinability by prostaglandins

    SciTech Connect

    McLawhon, R.W.; Marikovsky, Y.; Weinstein, R.S.

    1986-03-01

    Ethanol induces the transformation of human red cells from bioconcave discs to echinocytes in vitro. In addition, they have observed that ethanol can enhance the agglutination of red cells by the plant lectin wheat germ agglutinin or poly-L-lysine. Incubation of washed human red cells with 5 and 10% ethanol (v/v) in phosphate buffered saline, pH 7.3 at 25/sup 0/C produced a 30% increase in ligand-mediated agglutinability within 12 min. Simultaneous addition of ethanol and one of the following prostaglandin derivatives, PGE/sub 1/, pge/sub 2/, pgf/sub 2/-alpha, or PGl/sub 2/ (10/sup -9/ to 5 x 10/sup -7/ M) prevented the shape-associated increases in red cell agglutinability. Thromboxane-B/sub 2/ had no effect on agglutinability. Prostaglandins did not prevent ethanol-induced red cell shape transformations per se under identical experimental conditions. As intragastric administration of 100% ethanol results in the formation of spiculated red cell thrombi in postcapillary venules of rat gastric mucosa, they postulate that the cytoprotective role of prostanoids in preventing mucosal ulceration may be due in part to their capacity to inhibit intravascular ligand mediated red cell agglutination, hemostasis, and their sequelae, epithelial necrosis. Moreover, the data suggest that ethanol-induced red cell shape transformations and ligand-mediated agglutination represent two distinct and independent biological phenomena.

  13. Lung prostaglandin H synthase and mixed-function oxidase metabolism of nicotine.

    PubMed

    Mattammal, M B; Lakshmi, V M; Zenser, T V; Davis, B B

    1987-09-01

    Nicotine, a major constituent of cigarette smoke, was metabolized by lung microsomes to an aqueous soluble metabolite after addition of arachidonic acid. Similar results were observed with ram seminal vesicle microsomes. Metabolism was inhibited by indomethacin, propylthiouracil and methimazole but not glutathione. Data are consistent with metabolism being catalyzed by the hydroperoxidase activity of prostaglandin H synthase. The product was identified by mass spectrometry as 3-(2,3-dihydro-1-methyl-2-pyrrolyl)pyridine. Addition of NADPH resulted in formation of a different aqueous soluble product and also an organic extractable product. NADPH-dependent products were inhibited by 2-[(2,4-dichloro-6-phenyl)phenoxy]ethylamine, suggesting mixed-function oxidase catalyzed metabolism. The organic soluble product was identified as cotinine. Cotinine formation was inhibited by glutathione. 3-(2,3-dihydro-1-methyl-2-pyrrolyl)Pyridine was identified in urine from rabbits administered nicotine and from a male cigarette smoker. The amount of peroxidatic product in urine from rabbit and humans was 15 and 6%, respectively, that observed for cotinine. Thus, peroxidation represents a new metabolic pathway for nicotine which involves the peroxidatic activity of prostaglandin H synthase. PMID:3116198

  14. A dynamic Asp–Arg interaction is essential for catalysis in microsomal prostaglandin E2 synthase

    PubMed Central

    Brock, Joseph S.; Hamberg, Mats; Balagunaseelan, Navisraj; Goodman, Michael; Morgenstern, Ralf; Strandback, Emilia; Samuelsson, Bengt; Rinaldo-Matthis, Agnes; Haeggström, Jesper Z.

    2016-01-01

    Microsomal prostaglandin E2 synthase type 1 (mPGES-1) is responsible for the formation of the potent lipid mediator prostaglandin E2 under proinflammatory conditions, and this enzyme has received considerable attention as a drug target. Recently, a high-resolution crystal structure of human mPGES-1 was presented, with Ser-127 being proposed as the hydrogen-bond donor stabilizing thiolate anion formation within the cofactor, glutathione (GSH). We have combined site-directed mutagenesis and activity assays with a structural dynamics analysis to probe the functional roles of such putative catalytic residues. We found that Ser-127 is not required for activity, whereas an interaction between Arg-126 and Asp-49 is essential for catalysis. We postulate that both residues, in addition to a crystallographic water, serve critical roles within the enzymatic mechanism. After characterizing the size or charge conservative mutations Arg-126–Gln, Asp-49–Asn, and Arg-126–Lys, we inferred that a crystallographic water acts as a general base during GSH thiolate formation, stabilized by interaction with Arg-126, which is itself modulated by its respective interaction with Asp-49. We subsequently found hidden conformational ensembles within the crystal structure that correlate well with our biochemical data. The resulting contact signaling network connects Asp-49 to distal residues involved in GSH binding and is ligand dependent. Our work has broad implications for development of efficient mPGES-1 inhibitors, potential anti-inflammatory and anticancer agents. PMID:26755582

  15. Pyometra in Bitches Induces Elevated Plasma Endotoxin and Prostaglandin F2α Metabolite Levels

    PubMed Central

    Hagman, R; Kindahl, H; Lagerstedt, A-S

    2006-01-01

    Endotoxemia in bitches with pyometra can cause severe systemic effects directly or via the release of inflammatory mediators. Plasma endotoxin concentrations were measured in ten bitches suffering from pyometra with moderately to severely deteriorated general condition, and in nine bitches admitted to surgery for non-infectious reasons. Endotoxin samples were taken on five occasions before, during and after surgery. In addition, urine and uterine bacteriology was performed and hematological, blood biochemical parameters, prostaglandin F2α metabolite 15-ketodihydro-PGF2α (PG-metabolite), progesterone and oestradiol (E2-17β) levels were analysed. The results confirm significantly increased plasma levels of endotoxin in bitches with pyometra and support previous reports of endotoxin involvement in the pathogenesis of the disease. Plasma concentrations of PG-metabolite were elevated in pyometra bitches and provide a good indicator of endotoxin release since the concentrations were significantly correlated to the endotoxin levels and many other hematological and chemistry parameters. The γ-globulin serum protein electrophoresis fraction and analysis of PG-metabolite can be valuable in the diagnosis of endotoxin involvement if a reliable, rapid and cost-effective test for PG-metabolite analysis becomes readily available in the future. Treatment inhibiting prostaglandin biosynthesis and related compounds could be beneficial for bitches suffering from pyometra. PMID:16722306

  16. [Prostaglandin E-2 in cyanotic heart defects in newborn (author's transl)].

    PubMed

    Beitzke, A

    1981-09-01

    14 newborn babies with pulmonary atresia (4) or transposition (TGA) (8) received Prostaglandin E2 infusions to correct their hypoxia and acidosis. 12 out of 10 patients were infused before diagnostic catheterization and creation of an interatrial communication by balloon atrioseptostomy. Infusions were stopped after septostomy in patients with transposition and prolonged up to palliative surgery in pulmonary atresia patients. All patients whose treatment was started in the first four days of life had a highly significant rise of their paO2. The only non-responder was a patient with TGA after septostomy who was a non-mixer and seven days old. Typical side effects of PGE2 were seen in two-thirds of all cases. One patient with TGA needed ductus ligation after PGE2 withdrawal because of congestive heart failure due to prolonged ductus patency. We conclude that prostaglandins of the E-type can safely be used in all cases of TGA with hypoxia and acidosis who are awaiting catheterization. Even when an adequate interatrial communication does not yet exist PGE2 seems to bring good oxygenation by opening the ductus. Used up to a maximum of 32 hours infusion-time heart failure was not seen. PMID:7289432

  17. Prostaglandin E2 induces expression of MAPK phosphatase 1 (MKP-1) in airway smooth muscle cells.

    PubMed

    Rumzhum, Nowshin N; Ammit, Alaina J

    2016-07-01

    Prostaglandin E2 (PGE2) is a prostanoid with diverse actions in health and disease. In chronic respiratory diseases driven by inflammation, PGE2 has both positive and negative effects. An enhanced understanding of the receptor-mediated cellular signalling pathways induced by PGE2 may help us separate the beneficial properties from unwanted actions of this important prostaglandin. PGE2 is known to exert anti-inflammatory and bronchoprotective actions in human airways. To date however, whether PGE2 increases production of the anti-inflammatory protein MAPK phosphatase 1 (MKP-1) was unknown. We address this herein and use primary cultures of human airway smooth muscle (ASM) cells to show that PGE2 increases MKP-1 mRNA and protein upregulation in a concentration-dependent manner. We explore the signalling pathways responsible and show that PGE2-induces CREB phosphorylation, not p38 MAPK activation, in ASM cells. Moreover, we utilize selective antagonists of EP2 (PF-04418948) and EP4 receptors (GW 627368X) to begin to identify EP-mediated functional outcomes in ASM cells in vitro. Taken together with earlier studies, our data suggest that PGE2 increases production of the anti-inflammatory protein MKP-1 via cAMP/CREB-mediated cellular signalling in ASM cells and demonstrates that EP2 may, in part, be involved. PMID:27108790

  18. Effects of prostaglandin inhibition on intrarenal hemodynamics in acutely saline-loaded rats.

    PubMed

    Düsing, R; Melder, B; Kramer, H J

    1977-09-01

    We studied the effect of inhibition of the prostaglandin (PG)-synthesizing enzyme system in female Sprague-Dawley rats following acute expansion of the extracellular fluid volume (ECV). In 57 conscious rats expansion of the ECV with isotonic saline corresponding to an increase in body weight of 10% was induced. Prior to ECV expansion 31 rats received indomethacin (10 mg/kg of body wt) by stomach tube. In six non-ECV-expanded rats indomethacin had no effect on glomerular filtration rate (GFR) and renal plasma flow (RPF). In ECV-expanded rats pretreated with indomethacin, GFR was unaltered but 125I-hippuran clearance decreased, and filtration fraction significantly increased. Intrarenal 86Rb distribution was similar in control and ECV-expanded rats. Indomethacin caused a slight increase in relative cortical 86 RB activity in non-ECV-expanded rats, but had no effect on intrarenal 86Rb distribution in ECV-expanded rats. No difference in intracortical glomerular perfusion was noted between control and ECV-expanded rats. In indomethacin-treated ECV-expanded rats an increase in relative inner cortical perfusion was observed. Absolute perfusion remained unaltered. Thus the decrease in total RPF was entirely due to decreased perfusion of outer cortical nephrons. Renal prostaglandins therefore may play a permissive role for physical factors to promote renal sodium excretion in acute ECV expansion via changes in intrarenal hemodynamics. PMID:890884

  19. Stimulation of prolactin synthesis and of adenosine 3':5'-cyclic phosphate formation by prostaglandins and thyroliberin in cultured rat pituitary cells.

    PubMed Central

    Gautvik, K M; Kriz, M

    1976-01-01

    1. The effects of prostaglandins E2 and F2alpha on prolactin synthesis were examined in a clonal strain of rat pituitary tumour cells, and compared with those of thyroliberin. 2. The prostaglandins and thyroliberin gave a dose-related and time-dependent stimulation of prolactin synthesis. The maximal effects (about twofold increases) were observed after 54h of treatment with 25nM-prostaglandin E2 and 2.5nM-prostaglandin F2alpha. A similar stimulation of prolactin synthesis was observed after 250nM-thyroliberin. The combined treatment with prostaglandins and thyroliberin did not increase prolactin synthesis over and above that obtained with each compound alone. 3. After removal of prostaglandins E2 and F2alpha there was a complete reversal of prolactin synthesis to pre-stimulation values 18h later (t1/2less than or equal to 9h). The rapid reversible effect of prostaglandins was in contrast with that of thyroliberin, where prolactin synthesis returned to control values with a t1/2 of about 42 h. 4. Prostaglandin E2 (5mum) and thyroliberin (5mum) increased cellular concentrations of cyclic AMP eight- and four-fold respectively. Maximal effects were observed after 2-5min of incubation. The increases in cyclic AMP were biphasic; normal values were obtained 60 min after the start of incubation with prostaglandin E2 or thyroliberin. 5. The dose/response curve showed that prostaglandin E2 caused maximal increase of cyclic AMP at 50nM. Concentrations of prostagland in E2 that caused half-maximal stimulation of cyclic AMP accumulation and of prolactin synthesis were 4 and 5nM respectively. 6. Combined treatment with prostaglandin E2 and thyroliberin in concentrations that separately caused maximal cyclic AMP increases did not result in a further increase in this cyclic nucleotide. 7. These results are consistent with a role of cyclic AMP in mediating the effects or prostaglandins and thyroliberin on prolactin synthesis. However, if cyclic AMP is involved as a common

  20. Reliance on luck: identifying which achievement goals elicit superstitious behavior.

    PubMed

    Hamerman, Eric J; Morewedge, Carey K

    2015-03-01

    People often resort to superstitious behavior to facilitate goal achievement. We examined whether the specific type of achievement goal pursued influences the propensity to engage in superstitious behavior. Across six studies, we found that performance goals were more likely than learning goals to elicit superstitious behavior. Participants were more likely to engage in superstitious behavior at high than at low levels of chronic performance orientation, but superstitious behavior was not influenced by chronic learning orientation (Studies 1 and 2). Similarly, participants exhibited stronger preferences for lucky items when primed to pursue performance goals rather than learning goals (Studies 3 and 4). As uncertainty of goal achievement increased, superstitious behavior increased when participants pursued performance goals but not learning goals (Study 5). Finally, assignment to use a lucky (vs. unlucky) item resulted in greater confidence of achieving performance goals but not learning goals (Study 6). PMID:25617118

  1. PROBES: a framework for probability elicitation from experts.

    PubMed Central

    Lau, A. H.; Leong, T. Y.

    1999-01-01

    A decision analytic model represents uncertainties as probability distributions. These distributions are hard to assess especially for large and dynamic models. We propose an integrated framework that facilitates elicitation of the relevant probability distributions for dynamic decision models from the domain experts. The experts usually use some judgmental heuristics to aid probability assessments; the resulting distributions may be proned to cognitive biases. Our framework aims to minimize the effects of these biases and to improve the quality of decisions made. We have implemented a prototype system of the framework and evaluated its effectiveness via a case study in the follow-up management of colorectal cancer patients after curative surgery. Preliminary results demonstrate the practical promise of the framework. Images Figure 4 PMID:10566369

  2. Small‐molecule elicitation of microbial secondary metabolites

    PubMed Central

    Pettit, Robin K.

    2011-01-01

    Summary Microbial natural products continue to be an unparalleled resource for pharmaceutical lead discovery, but the rediscovery rate is high. Bacterial and fungal sequencing studies indicate that the biosynthetic potential of many strains is much greater than that observed by fermentation. Prodding the expression of such silent (cryptic) pathways will allow us to maximize the chemical diversity available from microorganisms. Cryptic metabolic pathways can be accessed in the laboratory using molecular or cultivation‐based approaches. A targeted approach related to cultivation‐based methods is the application of small‐molecule elicitors to specifically affect transcription of secondary metabolite gene clusters. With the isolation of the novel secondary metabolites lunalides A and B, oxylipins, cladochromes F and G, nygerone A, chaetoglobosin‐542, ‐540 and ‐510, sphaerolone, dihydrosphaerolone, mutolide and pestalone, and the enhanced production of known secondary metabolites like penicillin and bacitracin, chemical elicitation is proving to be an effective way to augment natural product libraries. PMID:21375710

  3. Eliciting design patterns for e-learning systems

    NASA Astrophysics Data System (ADS)

    Retalis, Symeon; Georgiakakis, Petros; Dimitriadis, Yannis

    2006-06-01

    Design pattern creation, especially in the e-learning domain, is a highly complex process that has not been sufficiently studied and formalized. In this paper, we propose a systematic pattern development cycle, whose most important aspects focus on reverse engineering of existing systems in order to elicit features that are cross-validated through the use of appropriate, authentic scenarios. However, an iterative pattern process is proposed that takes advantage of multiple data sources, thus emphasizing a holistic view of the teaching learning processes. The proposed schema of pattern mining has been extensively validated for Asynchronous Network Supported Collaborative Learning (ANSCL) systems, as well as for other types of tools in a variety of scenarios, with promising results.

  4. Elicitation: a tool for enriching the bioactive composition of foods.

    PubMed

    Baenas, Nieves; García-Viguera, Cristina; Moreno, Diego A

    2014-01-01

    Elicitation is a good strategy to induce physiological changes and stimulate defense or stress-induced responses in plants. The elicitor treatments trigger the synthesis of phytochemical compounds in fruits, vegetables and herbs. These metabolites have been widely investigated as bioactive compounds responsible of plant cell adaptation to the environment, specific organoleptic properties of foods, and protective effects in human cells against oxidative processes in the development of neurodegenerative and cardiovascular diseases and certain types of cancer. Biotic (biological origin), abiotic (chemical or physical origin) elicitors and phytohormones have been applied alone or in combinations, in hydroponic solutions or sprays, and in different selected time points of the plant growth or during post-harvest. Understanding how plant tissues and their specific secondary metabolic pathways respond to specific treatments with elicitors would be the basis for designing protocols to enhance the production of secondary metabolites, in order to produce quality and healthy fresh foods. PMID:25255755

  5. Ontological leveling and elicitation for complex industrial transactions

    SciTech Connect

    Phillips, L.R.; Goldsmith, S.Y.; Spires, S.V.

    1998-11-01

    The authors present an agent-oriented mechanism that uses a central ontology as a means to conduct complex distributed transactions. This is done by instantiating a template object motivated solely by the ontology, then automatically and explicitly linking each temple element to an independently constructed interface component. Validation information is attached directly to the links so that the agent need not know a priori the semantics of data validity, merely how to execute a general validation process to satisfy the conditions given in the link. Ontological leveling is critical: all terms presented to informants must be semantically coherent within the central ontology. To illustrate this approach in an industrial setting, they discuss an existing implementation that conducted international commercial transactions on the World-Wide Web. Agents operating within a federated architecture construct, populate by Web-based elicitation, and manipulate a distributed composite transaction object to effect transport of goods over the US/Mexico border.

  6. Promoting environmental sustainability via an expert elicitation process

    SciTech Connect

    Swor, Tom; Canter, Larry

    2011-09-15

    Environmental sustainability (ES) planning was applied to the 981-mile, commercially navigable Ohio River. Navigation improvement needs were identified within the broad study along with actions to restore aquatic and riparian ecological resources to a higher state of sustainability. The actions were identified via an Expert Elicitation Process (EEP) involving aquatic and riparian/terrestrial experts knowledgeable of Ohio River resources. The received information was synthesized into goals for the selected resources (Valued Ecosystem Components - or VECs), actions or measures to attain the goals, and monitoring to evaluate conditions. Finally, 26 types of ES actions were identified and classified into three ES alternatives. These alternatives were then evaluated relative to key decision criteria, and such evaluations, based on pertinent decision criteria, were also conducted for four navigation improvement alternatives. Finally, the best combination of ES and navigation alternatives was identified. The key lessons derived from this use of EEP were that: (1) EEP can support the preliminary identification of ES measures; however, more detailed study of specific designs and cost evaluations will be necessary; (2) the method promotes collaboration between key scientists and policymakers from governmental agencies and private sectors, and such collaboration will ultimately provide the foundation for implementation of sustainability actions; and (3) an effective EEP does not occur by accident, it requires careful planning, implementation, and documentation. - Research Highlights: > Use of an Expert Elicitation Process (EEP) is demonstrated in this study. > EEP was used to identify Environmental Sustainability (ES) needs for the Ohio River. > EEP helped develop consensus among resource experts on ES needs. > EEP promotes collaboration to identify and contribute to common resource goals. > EEP may be used in assessing cumulative effects and formulating restoration plans.

  7. Noncanonical Roles of the Immune System in Eliciting Oncogene Addiction

    PubMed Central

    Casey, Stephanie C.; Bellovin, David I.; Felsher, Dean W.

    2013-01-01

    Summary Cancer is highly complex. The magnitude of this complexity makes it highly surprising that even the brief suppression of an oncogene can sometimes result in rapid and sustained tumor regression illustrating that cancers can be “oncogene addicted” [1-10]. The essential implication is that oncogenes may not only fuel the initiation of tumorigenesis, but in some cases necessarily their surfeit of activation is paramaount to maintain a neoplastic state [11]. Oncogene suppression acutely restores normal physiological programs that effectively overrides secondary genetic events and a cancer collapses [12,13]. Oncogene addiction is mediated both through both tumor intrinsic cell-autonomous mechanisms including proliferative arrest, apoptosis, differentiation and cellular senescence [1,2,4,12] but also host-dependent mechanisms that interact with these tumor intrinsic programs [14,15]. Notably, oncogene inactivation elicits a host immune response that involves specific immune effectors and cytokines that facilitate a remodeling of the tumor microenvironment including the shut down of angiogenesis and the induction of cellular senescence of tumor cells [16]. Hence, immune effectors are critically involved in tumor initiation and prevention [17-19] and progression [20], but also appear to be essential to tumor regression upon oncogene inactivation [21-23]. The understanding how the inactivation of an oncogene elicits a systemic signal in the host that prompts a deconstruction of a tumor could have important implications. The combination of oncogene-targeted therapy together with immunomodulatory therapy may be ideal for the development of both a robust tumor intrinsic as well as immunological effectively leading to sustained tumor regression. PMID:23571026

  8. Knowledge elicitation techniques and application to nuclear plant maintenance

    NASA Astrophysics Data System (ADS)

    Doyle, E. Kevin

    The new millennium has brought with it the opportunity of global trade which in turn requires the utmost in efficiency from each individual industry. This includes the nuclear power industry, a point which was emphasized when the electrical generation industry began to be de regulated across North America the late 1990s and re-emphasized when the northeast power grid of North America collapsed in the summer of 2003. This dissertation deals with reducing the cost of the maintenance function of Candu nuclear power plants and initiating a strong link between universities and the Canadian nuclear industry. Various forms of RCM (reliability-centred maintenance) have been the tools of choice in industry for improving the maintenance function during the last 20 years. In this project, pilot studies, conducted at Bruce Power between 1999 and 2005, and reported on in this dissertation, lay out a path to implement statistical improvements as the next step after RCM in reducing the cost of the maintenance. Elicitation protocols, designed for the age group being elicited, address the much-documented issue of a lack of data. Clear, graphical, inferential statistical interfaces are accentuated and developed to aid in building the teams required to implement the various methodologies and to help in achieving funding targets. Graphical analysis and Crow/AMSAA (army materials systems analysis activity) plots are developed and demonstrated from the point of view of justifying the expenditures of cost reduction efforts. This dissertation ultimately speaks to the great opportunity being presented by this approach at this time: of capturing the baby-boom generation's huge pool of knowledge before those people retire. It is expected that the protocols and procedures referenced here will have applicability across the many disciplines where collecting expert information from a similar age group is required.

  9. Tactile stimulation of the oropharynx elicits sympathoexcitation in conscious humans

    PubMed Central

    Muller, Matthew D.; Mast, Jessica L.; Cui, Jian; Heffernan, Matthew J.; McQuillan, Patrick M.

    2013-01-01

    Tactile stimulation of the oropharynx (TSO) elicits the gag reflex and increases heart rate (HR) and mean arterial pressure (MAP) in anesthetized patients. However, the interaction between upper-airway defense reflexes and the sympathetic nervous system has not been investigated in conscious humans. In Experiment 1, beat-by-beat measurements of HR, MAP, muscle sympathetic nerve activity (MSNA), and renal vascular resistance (RVR) were measured during TSO and tactile stimulation of the hard palate (Sham) in the supine posture. In Experiment 2, TSO was performed before (pre) and after (post) inhalation of 4% lidocaine via nebulizer. Rate pressure product (RPP) was determined. Compared with Sham, TSO elicited the gag reflex and increased RPP [absolute change (Δ)36 ± 6 vs. 17 ± 5%], MSNA (Δ122 ± 39 vs. 19 ± 19%), and RVR (Δ55 ± 11 vs. 4 ± 4%). This effect occurred within one to two cardiac cycles of TSO. The ΔMAP (12 ± 3 vs. 6 ± 1 mmHg) and the ΔHR (10 ± 3 vs. 3 ± 3 beats/min) were also greater following TSO compared with Sham. Lidocaine inhalation blocked the gag reflex and attenuated increases in MAP (Δpre: 16 ± 2; Δpost: 5 ± 2 mmHg) and HR (Δpre: 12 ± 3; Δpost: 2 ± 2 beats/min) in response to TSO. When mechanically stimulated, afferents in the oropharynx not only serve to protect the airway but also cause reflex increases in MSNA, RVR, MAP, and HR. An augmented sympathoexcitatory response during intubation and laryngoscopy may contribute to perioperative cardiovascular morbidity and mortality. PMID:23599399

  10. Outer membrane vesicles displaying engineered glycotopes elicit protective antibodies.

    PubMed

    Chen, Linxiao; Valentine, Jenny L; Huang, Chung-Jr; Endicott, Christine E; Moeller, Tyler D; Rasmussen, Jed A; Fletcher, Joshua R; Boll, Joseph M; Rosenthal, Joseph A; Dobruchowska, Justyna; Wang, Zhirui; Heiss, Christian; Azadi, Parastoo; Putnam, David; Trent, M Stephen; Jones, Bradley D; DeLisa, Matthew P

    2016-06-28

    The O-antigen polysaccharide (O-PS) component of lipopolysaccharides on the surface of gram-negative bacteria is both a virulence factor and a B-cell antigen. Antibodies elicited by O-PS often confer protection against infection; therefore, O-PS glycoconjugate vaccines have proven useful against a number of different pathogenic bacteria. However, conventional methods for natural extraction or chemical synthesis of O-PS are technically demanding, inefficient, and expensive. Here, we describe an alternative methodology for producing glycoconjugate vaccines whereby recombinant O-PS biosynthesis is coordinated with vesiculation in laboratory strains of Escherichia coli to yield glycosylated outer membrane vesicles (glycOMVs) decorated with pathogen-mimetic glycotopes. Using this approach, glycOMVs corresponding to eight different pathogenic bacteria were generated. For example, expression of a 17-kb O-PS gene cluster from the highly virulent Francisella tularensis subsp. tularensis (type A) strain Schu S4 in hypervesiculating E. coli cells yielded glycOMVs that displayed F. tularensis O-PS. Immunization of BALB/c mice with glycOMVs elicited significant titers of O-PS-specific serum IgG antibodies as well as vaginal and bronchoalveolar IgA antibodies. Importantly, glycOMVs significantly prolonged survival upon subsequent challenge with F. tularensis Schu S4 and provided complete protection against challenge with two different F. tularensis subsp. holarctica (type B) live vaccine strains, thereby demonstrating the vaccine potential of glycOMVs. Given the ease with which recombinant glycotopes can be expressed on OMVs, the strategy described here could be readily adapted for developing vaccines against many other bacterial pathogens. PMID:27274048

  11. Nest sanitation elicits egg discrimination in cuckoo hosts.

    PubMed

    Yang, Canchao; Chen, Min; Wang, Longwu; Liang, Wei; Møller, Anders Pape

    2015-11-01

    Nest sanitation is a nearly universal behavior in birds, while egg discrimination is a more specific adaptation that has evolved to counter brood parasitism. These two behaviors are closely related with nest sanitation being the ancestral behavior, and it has been hypothesized to constitute a preadaptation for egg discrimination. However, previous studies found little evidence to support this hypothesis. Here, we conducted an empirical test of the association between nest sanitation and egg discrimination in the barn swallow (Hirundo rustica) by inserting a single non-mimetic model egg or a non-mimetic model egg plus half a peanut shell into host nests. Compared to the rejection rate of single model eggs, barn swallows significantly increased egg rejection frequency if a half peanut shell was simultaneously introduced. Our result for the first time shows the impact of nest sanitation on egg discrimination and demonstrates that nest sanitation can elicit egg discrimination in hosts of brood parasites. This study provided evidence for nest sanitation being a preadaptation to egg discrimination by facilitating egg rejection, thereby significantly advancing our understanding of avian cognition of foreign objects. Furthermore, we suggest that egg discrimination behavior in many accepters and intermediate rejecters may be lost or diluted. Such egg discrimination can be elicited and restored after nest sanitation, implying a sensitive and rapid phenotypic response to increased risk of parasitism. Our study offers a novel perspective for investigating the role of so-called intermediate rejecter individuals or species in the long-term coevolutionary cycle between brood parasites and their hosts. PMID:26160343

  12. Cripto-1 vaccination elicits protective immunity against metastatic melanoma

    PubMed Central

    Ligtenberg, M. A.; Witt, K.; Galvez-Cancino, F.; Sette, A.; Lundqvist, A.; Lladser, A.; Kiessling, R.

    2016-01-01

    ABSTRACT Metastatic melanoma is a fatal disease that responds poorly to classical treatments but can be targeted by T cell-based immunotherapy. Cancer vaccines have the potential to generate long-lasting cytotoxic CD8+ T cell responses able to eradicate established and disseminated tumors. Vaccination against antigens expressed by tumor cells with enhanced metastatic potential represents a highly attractive strategy to efficiently target deadly metastatic disease. Cripto-1 is frequently over-expressed in human carcinomas and melanomas, but is expressed only at low levels on normal differentiated tissues. Cripto-1 is particularly upregulated in cancer-initiating cells and is involved in cellular processes such as cell migration, invasion and epithelial–mesenchymal transition, which are hallmarks of aggressive cancer cells able to initiate metastatic disease. Here, we explored the potential of Cripto-1 vaccination to target metastatic melanoma in a preclinical model. Cripto-1 was overexpressed in highly metastatic B16F10 cells as compared to poorly metastatic B16F1 cells. Moreover, B16F10 cells grown in sphere conditions to enrich for cancer stem cells (CSC) progressively upregulated cripto1 expression. Vaccination of C57Bl/6 mice with a DNA vaccine encoding mouse Cripto-1 elicited a readily detectable/strong cytotoxic CD8+ T cell response specific for a H-2 Kb-restricted epitope identified based on its ability to bind H-2b molecules. Remarkably, Cripto-1 vaccination elicited a protective response against lung metastasis and subcutaneous challenges with highly metastatic B16F10 melanoma cells. Our data indicate that vaccination against Cripto-1 represents a novel strategy to be tested in the clinic.

  13. Effects of Long-Term Daily Administration of Prostaglandin-E2 on Maintaining Elevated Proximal Tibial Metaphyseal Cancellous Bone Mass in Male Rats

    NASA Technical Reports Server (NTRS)

    Ke, Hua Zhu; Jee, Webster S. S.; Mori, Satoshi; Li, Xiao Jian; Kimmel, Donald B.

    1992-01-01

    The effects of long-term prostaglandin E(sub 2) (PGE(sub 2)) on cancellous bone in proximal tibial metaphysis were studied in 7 month old male Sprague-Dawley rats given daily subcutaneous injections of 0, 1, 3, and 6 mg PGE(sub 2)/kg/day and sacrificed after 60, 120, and 180 days. Histomorphometric analyses were performed on double fluorescent-labeled undecalcified bone specimens. After 60 days of treatment, PGE(sub 2) produced diffusely labeled trabecular bone area, increased trabecular bone area, eroded and labeled trabecular perimeter, mineral apposition rate, and bone formation rate at all dose levels when compared with age-matched controls. In rats given PGE(sub 2) for longer time periods (120 and 180 days), trabecular bone area, diffusely labeled trabecular bone area, labeled perimeter, mineral apposition, and bone formation rates were sustained at the elevated levels achieved earlier at 60-day treatment. The eroded perimeter continued to increase until 120 days, then plateau. The observation that continuous systemic PGE(sub 2) administration to adult male rats elevated metaphyseal cancellous bone mass to 3.5-fold of the control level within 60 days and maintained it for another 120 days indicates that the powerful skeletal anabolic effects of PGE2 can be sustained with continuous administration .

  14. Prostaglandin A2 influences gene expression in an established insect cell line (BCIRL-HzAm1) cells

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Prostaglandins (PGs) and other eicosanoids are oxygenated metabolites of arachidonic acid and two other C20 polyunsaturated fatty acids. While most well studied in mammals, PGs exert important actions in insects and virtually all other invertebrates. We have been researching the mechanisms of PG a...

  15. A Hereditary Enteropathy Caused by Mutations in the SLCO2A1 Gene, Encoding a Prostaglandin Transporter

    PubMed Central

    Esaki, Motohiro; Hirano, Atsushi; Kubokura, Naoya; Asano, Kouichi; Kochi, Shuji; Yanai, Shunichi; Fuyuno, Yuta; Shimamura, Katsuyoshi; Hosoe, Naoki; Ogata, Haruhiko; Watanabe, Takashi; Aoyagi, Kunihiko; Ooi, Hidehisa; Watanabe, Kenji; Yasukawa, Shigeyoshi; Hirai, Fumihito; Matsui, Toshiyuki; Iida, Mitsuo; Yao, Tsuneyoshi; Hibi, Toshifumi; Kosaki, Kenjiro; Kanai, Takanori; Kitazono, Takanari; Matsumoto, Takayuki

    2015-01-01

    Previously, we proposed a rare autosomal recessive inherited enteropathy characterized by persistent blood and protein loss from the small intestine as chronic nonspecific multiple ulcers of the small intestine (CNSU). By whole-exome sequencing in five Japanese patients with CNSU and one unaffected individual, we found four candidate mutations in the SLCO2A1 gene, encoding a prostaglandin transporter. The pathogenicity of the mutations was supported by segregation analysis and genotyping data in controls. By Sanger sequencing of the coding regions, 11 of 12 other CNSU patients and 2 of 603 patients with a diagnosis of Crohn’s disease were found to have homozygous or compound heterozygous SLCO2A1 mutations. In total, we identified recessive SLCO2A1 mutations located at seven sites. Using RT-PCR, we demonstrated that the identified splice-site mutations altered the RNA splicing, and introduced a premature stop codon. Tracer prostaglandin E2 uptake analysis showed that the mutant SLCO2A1 protein for each mutation exhibited impaired prostaglandin transport. Immunohistochemistry and immunofluorescence analyses revealed that SLCO2A1 protein was expressed on the cellular membrane of vascular endothelial cells in the small intestinal mucosa in control subjects, but was not detected in affected individuals. These findings indicate that loss-of-function mutations in the SLCO2A1 gene encoding a prostaglandin transporter cause the hereditary enteropathy CNSU. We suggest a more appropriate nomenclature of “chronic enteropathy associated with SLCO2A1 gene” (CEAS). PMID:26539716

  16. Lipid Classes, Fatty Acid Composition, and Glycerolipid Molecular Species of the Red Alga Gracilaria vermiculophylla, a Prostaglandin-Producing Seaweed.

    PubMed

    Honda, Masaki; Ishimaru, Takashi; Itabashi, Yutaka

    2016-01-01

    The red alga Gracilaria vermiculophylla is a well-known producer of prostaglandins, such as PGE2 and PGF2α. In this study, the characteristics of glycerolipids as substrates of prostaglandin production were clarified, and the lipid classes, fatty acid composition, and glycerolipid molecular species were investigated in detail. The major lipid classes were monogalactosyldiacylglycerol (MGDG), digalactosyldiacylglycerol (DGDG), and sulfoquinovosyldiacylglycerol (SQDG), as well as phosphatidylcholine (PC), which accounted for 43.0% of the total lipid profile. Arachidonic acid (20:4n-6), a prostaglandin precursor, and palmitic acid (16:0) were the predominant fatty acids in the total lipid profile. The 20:4n-6 content was significantly high in MGDG and PC (more than 60%), and the 16:0 content was significantly high in DGDG and SQDG (more than 50%). Chiral-phase high-performance liquid chromatography determined that fatty acids were esterified at the sn-1 and sn-2 positions of those lipids. The main glycerolipid molecular species were 20:4n-6/20:4n-6 (sn-1/sn-2) for MGDG (56.5%) and PC (40.0%), and 20:4n-6/16:0 for DGDG (75.4%) and SQDG (58.4%). Thus, it was considered that the glycerolipid molecular species containing one or two 20:4n-6 were the major substrates for prostaglandin production in G. vermiculophylla. PMID:27581490

  17. Control of cell cycle by metabolites of prostaglandin D2 through a non-cAMP mediated mechanism

    NASA Technical Reports Server (NTRS)

    Hughes-Fulford, M.; Fukushima, M.

    1993-01-01

    The dehydration products of PGD2, 9-deoxy-9 prostaglandin D2(PGJ2), 9-deoxy-delta 9, delta 12, delta 13 dehydroprostaglandin D2 (delta 12 PGJ2), and PGA2 all contain an unsaturated cyclopentenone structure which is characteristic of prostaglandins which effectively inhibit cell growth. It has been suggested that the action of the inhibitory prostaglandins may be through a cAMP mechanism. In this study, we use S49 wild type (WT) and adenylate cyclase variant (cyc-) cells to show that PGD2 and PGJ2 are not acting via a cyclic AMP mechanism. First, the increase in cyclic AMP in wild type S-49 cells is not proportional to its effects on DNA synthesis. More importantly, when S-49 cyc- cells were exposed to PGJ2, the adenylate cyclase (cyc-) mutant had decreased DNA synthesis with no change in its nominal cAMP content. Short-term (2 hours or less) exposure of the cyc- cells to prostaglandin J2 caused an inhibition of DNA synthesis. PGJ2 caused cytolysis at high concentrations. Long-term exposure (>14 hrs) of the cells to PGJ2, delta 12PGJ2 or delta 12, delta 14PGJ2 caused a cell cycle arrest in G1 demonstrating a cell cycle specific mechanism of action for growth inhibition by naturally occurring biological products independent of cAMP.

  18. Rapid induction of gene expression in the corpus luteum following in vivo treatment with prostaglandin F2 alpha

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The pulsatile uterine secretion of prostaglandin F2 alpha (PGF) triggers the regression of the corpus luteum (CL). Research from many laboratories has identified the early intracellular signaling events initiated by PGF (for example, activation of phospholipases, increased intracellular calcium, an...

  19. INFLUENCE OF CORTISOL ON PROSTAGLANDIN SYNTHESIS BY FETAL MEMBRANES, PLACENTA, AND UTERUS OF PREGNANT RABBITS (JOURNAL VERSION)

    EPA Science Inventory

    Two experiments were designed to assess the effects of cortisol on prostaglandin-forming cyclooxygenase in 4 gestational tissues of rabbits. Cortisol treatment (12 mg/kg body wt/h) was initiated on day 21 of pregnancy and continued for a 24-h period. In cortisol-treated rabbits, ...

  20. Echinacea Species and Alkamides Inhibit Prostaglandin E2 Production in RAW264.7 Mouse Macrophage Cells

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Inhibition of prostaglandin E2 production in lipopolysaccharide-stimulated RAW264.7 mouse macrophage cells was assessed with an enzyme immunoassay following treatments with Echinacea extracts or synthesized alkamides. Results indicated that ethanol extracts from E. angustifolia, E. pallida, E. simu...

  1. Development of a scintillation proximity binding assay for high-throughput screening of hematopoietic prostaglandin D2 synthase.

    PubMed

    Meleza, Cesar; Thomasson, Bobbie; Ramachandran, Chidambaram; O'Neill, Jason W; Michelsen, Klaus; Lo, Mei-Chu

    2016-10-15

    Prostaglandin D2 synthase (PGDS) catalyzes the isomerization of prostaglandin H2 (PGH2) to prostaglandin D2 (PGD2). PGD2 produced by hematopoietic prostaglandin D2 synthase (H-PGDS) in mast cells and Th2 cells is proposed to be a mediator of allergic and inflammatory responses. Consequently, inhibitors of H-PGDS represent potential therapeutic agents for the treatment of inflammatory diseases such as asthma. Due to the instability of the PGDS substrate PGH2, an in-vitro enzymatic assay is not feasible for large-scale screening of H-PGDS inhibitors. Herein, we report the development of a competition binding assay amenable to high-throughput screening (HTS) in a scintillation proximity assay (SPA) format. This assay was used to screen an in-house compound library of approximately 280,000 compounds for novel H-PGDS inhibitors. The hit rate of the H-PGDS primary screen was found to be 4%. This high hit rate suggests that the active site of H-PGDS can accommodate a large diversity of chemical scaffolds. For hit prioritization, these initial hits were rescreened at a lower concentration in SPA and tested in the LAD2 cell assay. 116 compounds were active in both assays with IC50s ranging from 6 to 807 nM in SPA and 82 nM to 10 μM in the LAD2 cell assay. PMID:27485270

  2. Prostaglandin A2 significantly alters gene expression in an established insect cell line (BCIRL-HzAM1)

    Technology Transfer Automated Retrieval System (TEKTRAN)

    In previous work to determine the biochemical mechanisms of prostaglandin (PG) action in insect cells, we found that PGA1 and PGE1 influenced the expression of genes encoding proteins important for a variety of cellular functions. In the present study, we exposed the same cell line, BCIRL-HzAM1, to...

  3. Regulation of cyclic AMP metabolism by prostaglandins in rabbit cortical collecting tubule cells

    SciTech Connect

    Sonnenburg, W.K.

    1987-01-01

    In the rabbit cortical collecting tubule (RCCT), prostaglandin E/sub 1/ (PGE/sub 1/) and prostaglandin E/sub 2/ (PGE/sub 2/) at 1 nM inhibit arginine-vasopressin (AVP)-induced water reabsorption, while 100 nM PGE/sub 1/ and PGE/sub 2/ alone stimulate water reabsorption. Reported here are studies designed to investigate the molecular basis for the biphasic physiological action of PGE/sub 1/ and PGE/sub 2/ in the collecting duct. In freshly isolated RCCT cells, PGE/sub 1/, PGE/sub 2/, and 16,16-dimethyl-PGE/sub 2/ (DM-PGE/sub 2/) stimulated cAMP synthesis at concentrations ranging from 0.1 to 10 M. Other prostaglandins including the synthetic PGE/sub 2/ analogue, sulprostone, failed to stimulate cAMP synthesis. Moreover, sulprostone did not antagonize PGE/sub 2/-stimulated cAMP formation. In contrast, PGE/sub 2/ and sulprostone at concentrations ranging from 1 to 100 nM, inhibited AVP-induced cAMP accumulation in freshly isolated RCCT cells. PGE/sub 2/, PGE/sub 1/, DM-PGE/sub 2/ and sulprostone at 100 nM were equally effective in inhibiting AVP-induced cAMP formation. Moreover sulprostone inhibited AVP-stimulated adenylate cyclase activity. These results suggest that PGE derivatives mediate either inhibition or activation of adenylate cyclase by stimulating different PGE receptors. To further test this concept, PGE/sub 2/ binding to freshly isolated RCCT cell membranes was characterized. Two different classes of PGE/sub 2/ binding were detected. //sup 3/H/PGE/sub 2/ binding to the high affinity class of sites was increased by the GTP-analogue, GTP S, while pertussis toxin pretreatment blocked the stimulatory action. In contrast, //sup 3/H/ PGE/sub 2/ binding to the low affinity class of sites was decreased by GTP S; this inhibitory effect was not blocked by pertussis toxin pretreatment.

  4. Radiation-induced changes in the profile of spinal cord serotonin, prostaglandin synthesis, and vascular permeability

    SciTech Connect

    Siegal, T.; Pfeffer, M.R.

    1995-01-01

    To investigate the profile of biochemical and physiological changes induced in the rat spinal cord by radiation, over a period of 8 months. The thoraco-lumbar spinal cords of Fisher rats were irradiated to a dose of 15 Gy. The rats were then followed and killed at various times afterward. Serotonin (5-HT) and its major metabolite 5-hydroxyindole-3-acetic acid (5-HIAA) were assayed as well as prostaglandin synthesis. Microvessel permeability was assessed by quantitative evaluation of Evans blue dye extravasation. None of the rats developed neurologic dysfunction, and histologic examination revealed only occasional gliosis in the ventral white matter at 240 days after irradiation. Serotonin levels were unchanged at 2, 14, and 56 days after radiation but increased at 120 and 240 days in the irradiated cord segments when compared to both the nonirradiated thoracic and cervical segments (p < 0.01) and age-matched controls (p < 0.03). The calculated utilization ratio of serotonin (5-HIAA/5-HT) remained unchanged. Immediately after radiation (at 3 and 24 h) an abrupt but brief increase in the synthesis of prostaglandin-E{sub 2} (PGE{sub 2}), thromboxane (TXB{sub 2}), and prostacyclin [6 keto-PGF1{alpha} (6KPGF)] was noted, which returned to normal at 3 days. This was followed after 7 and 14 days by a significant fall off in synthesis of all three prostaglandins. Thereafter, at 28, 56, 120, and 240 days, escalated production of thromboxane followed, white prostacyclin synthesis remained markedly reduced (-88% of control level at 240 days). Up to 7 days after radiation the calculated TXB{sub 2}/6KPGF ratio remained balanced, regardless of the observed abrupt early fluctuations in their rate of synthesis. Later, between 7 and 240 days after radiation, a significant imbalance was present which became more pronounced over time. In the first 24 h after radiation, a 104% increase in microvessel permeability was observed which returned to normal by 3 days. 57 refs., 3 figs.

  5. Role of prostaglandins in spinal transmission of the exercise pressor reflex in decerebrated rats.

    PubMed

    Stone, A J; Copp, S W; Kaufman, M P

    2014-09-26

    Previous studies found that prostaglandins in skeletal muscle play a role in evoking the exercise pressor reflex; however the role played by prostaglandins in the spinal transmission of the reflex is not known. We determined, therefore, whether or not spinal blockade of cyclooxygenase (COX) activity and/or spinal blockade of endoperoxide (EP) 2 or 4 receptors attenuated the exercise pressor reflex in decerebrated rats. We first established that intrathecal doses of a non-specific COX inhibitor Ketorolac (100 μg in 10 μl), a COX-2-specific inhibitor Celecoxib (100 μg in 10 μl), an EP2 antagonist PF-04418948 (10 μg in 10 μl), and an EP4 antagonist L-161,982 (4 μg in 10 μl) effectively attenuated the pressor responses to intrathecal injections of arachidonic acid (100 μg in 10 μl), EP2 agonist Butaprost (4 ng in 10 μl), and EP4 agonist TCS 2510 (6.25 μg in 2.5 μl), respectively. Once effective doses were established, we statically contracted the hind limb before and after intrathecal injections of Ketorolac, Celecoxib, the EP2 antagonist and the EP4 antagonist. We found that Ketorolac significantly attenuated the pressor response to static contraction (before Ketorolac: 23 ± 5 mmHg, after Ketorolac 14 ± 5 mmHg; p<0.05) whereas Celecoxib had no effect. We also found that 8 μg of L-161,982, but not 4 μg of L-161,982, significantly attenuated the pressor response to static contraction (before L-161,982: 21 ± 4 mmHg, after L-161,982 12 ± 3 mmHg; p<0.05), whereas PF-04418948 (10 μg) had no effect. We conclude that spinal COX-1, but not COX-2, plays a role in evoking the exercise pressor reflex, and that the spinal prostaglandins produced by this enzyme are most likely activating spinal EP4 receptors, but not EP2 receptors. PMID:25003710

  6. The role of prostaglandins in spinal transmission of the exercise pressor reflex in decerebrate rats

    PubMed Central

    Stone, Audrey J.; Copp, Steven W.; Kaufman, Marc P.

    2014-01-01

    Previous studies found that prostaglandins in skeletal muscle play a role in evoking the exercise pressor reflex; however the role played by prostaglandins in the spinal transmission of the reflex is not known. We determined, therefore, whether or not spinal blockade of cyclooxygenase (COX) activity and/or spinal blockade of endoperoxide receptor (EP) 2 or EP4 receptors attenuated the exercise pressor reflex in decerebrate rats. We first established that intrathecal doses of a non-specific COX inhibitor Ketorolac (100ug in 10ul), a COX-2 specific inhibitor Celecoxib (100μg in 10μl), an EP2 antagonist PF-04418948 (10μg in 10μl), and an EP4 antagonist L-161,982 (4μg in 10μl) effectively attenuated the pressor responses to intrathecal injections of Arachidonic Acid (100μg in 10μl), EP2 agonist Butaprost (4ng in 10 μl), and EP4 agonist TCS 2510 (6.25μg in 2.5 μl), respectively. Once effective doses were established, we statically contracted the hindlimb before and after intrathecal injections of Ketorolac, Celecoxib, the EP2 antagonist and the EP4 antagonist. We found that Ketorolac significantly attenuated the pressor response to static contraction (before Ketorolac: 23±5 mmHg, after Ketorolac 14±5 mmHg; p<0.05) whereas Celecoxib had no effect. We also found that 8μg of L-161,982, but not 4 μg of L-161,982, significantly attenuated the pressor response to static contraction (before L-161,982: 21±4 mmHg, after L-161,982 12±3 mmHg; p<0.05), whereas PF-04418948 (10μg) had no effect. We conclude that spinal COX-1, but not COX-2, plays a role in evoking the exercise pressor reflex, and that the spinal prostaglandins produced by this enzyme are most likely activating spinal EP4 receptors, but not EP2 receptors. PMID:25003710

  7. Neuroinflammation and J2 prostaglandins: linking impairment of the ubiquitin-proteasome pathway and mitochondria to neurodegeneration.

    PubMed

    Figueiredo-Pereira, Maria E; Rockwell, Patricia; Schmidt-Glenewinkel, Thomas; Serrano, Peter

    2014-01-01

    The immune response of the CNS is a defense mechanism activated upon injury to initiate repair mechanisms while chronic over-activation of the CNS immune system (termed neuroinflammation) may exacerbate injury. The latter is implicated in a variety of neurological and neurodegenerative disorders such as Alzheimer and Parkinson diseases, amyotrophic lateral sclerosis, multiple sclerosis, traumatic brain injury, HIV dementia, and prion diseases. Cyclooxygenases (COX-1 and COX-2), which are key enzymes in the conversion of arachidonic acid into bioactive prostanoids, play a central role in the inflammatory cascade. J2 prostaglandins are endogenous toxic products of cyclooxygenases, and because their levels are significantly increased upon brain injury, they are actively involved in neuronal dysfunction induced by pro-inflammatory stimuli. In this review, we highlight the mechanisms by which J2 prostaglandins (1) exert their actions, (2) potentially contribute to the transition from acute to chronic inflammation and to the spreading of neuropathology, (3) disturb the ubiquitin-proteasome pathway and mitochondrial function, and (4) contribute to neurodegenerative disorders such as Alzheimer and Parkinson diseases, and amyotrophic lateral sclerosis, as well as stroke, traumatic brain injury (TBI), and demyelination in Krabbe disease. We conclude by discussing the therapeutic potential of targeting the J2 prostaglandin pathway to prevent/delay neurodegeneration associated with neuroinflammation. In this context, we suggest a shift from the traditional view that cyclooxygenases are the most appropriate targets to treat neuroinflammation, to the notion that J2 prostaglandin pathways and other neurotoxic prostaglandins downstream from cyclooxygenases, would offer significant benefits as more effective therapeutic targets to treat chronic neurodegenerative diseases, while minimizing adverse side effects. PMID:25628533

  8. Involvement of prostaglandins F/sub 2. cap alpha. / and E/sub 1/ with rabbit endometrium

    SciTech Connect

    Orlicky, D.J.

    1985-01-01

    Several growth factors and hormones are thought to play a role in the growth control of endometrial cells. The authors have shown that prostaglandin F/sub 2..-->../ (PGF/sub 2..cap alpha../) is a growth factor for primary cultures of rabbit endometrium cultured in chemically-defined serum-free medium and that prostaglandin E/sub 1/ (PGE/sub 1/) antagonizes the PGF/sub 2..-->../ induction of growth. Both (/sup 3/H)PGF/sub 2..cap alpha../ and (/sup 3/H)PGE/sub 1/ bind in a time and temperature dependent, dissociable, saturable and specific manner. The binding of (/sup 3/H)PGF/sub 2..cap alpha../ and (/sup 3/H)PGE/sub 1/ can be both down and up regulated and is enzyme sensitive. PGE /sub 1/ stimulates intracellular cAMP synthesis and accumulation in a time and concentration dependent manner. PGF/sub 2..cap alpha../ probably exerts its effects through an amiloride-sensitive intermediate. Both PGF/sub 2..cap alpha../ and PGE/sub 1/ are constitutively synthesized by these primary cultures, and they have shown this synthesis to be both drug and hormone sensitive. They hypothesize that it is the ratio, rather than the absolute quantities, of PGF/sub 2..cap alpha../ and PGE/sub 1/ which is of more importance in the regulation of endometrial cell growth. Furthermore, they believe this regulation of endometrial growth plays a role in control of proliferation during the decidual response and that a derangement in the ratio of these prostaglandins may lead to either infertility or hyperplasia. The ability of these cultures to synthesize prostaglandins in a hormonally regulatable manner may be of importance in the study of dysmenorrhea and uterine cramping as caused by the myometrial contracting prostaglandin, PGF/sub 2..cap alpha../.

  9. Neuroinflammation and J2 prostaglandins: linking impairment of the ubiquitin-proteasome pathway and mitochondria to neurodegeneration

    PubMed Central

    Figueiredo-Pereira, Maria E.; Rockwell, Patricia; Schmidt-Glenewinkel, Thomas; Serrano, Peter

    2015-01-01

    The immune response of the CNS is a defense mechanism activated upon injury to initiate repair mechanisms while chronic over-activation of the CNS immune system (termed neuroinflammation) may exacerbate injury. The latter is implicated in a variety of neurological and neurodegenerative disorders such as Alzheimer and Parkinson diseases, amyotrophic lateral sclerosis, multiple sclerosis, traumatic brain injury, HIV dementia, and prion diseases. Cyclooxygenases (COX-1 and COX-2), which are key enzymes in the conversion of arachidonic acid into bioactive prostanoids, play a central role in the inflammatory cascade. J2 prostaglandins are endogenous toxic products of cyclooxygenases, and because their levels are significantly increased upon brain injury, they are actively involved in neuronal dysfunction induced by pro-inflammatory stimuli. In this review, we highlight the mechanisms by which J2 prostaglandins (1) exert their actions, (2) potentially contribute to the transition from acute to chronic inflammation and to the spreading of neuropathology, (3) disturb the ubiquitin-proteasome pathway and mitochondrial function, and (4) contribute to neurodegenerative disorders such as Alzheimer and Parkinson diseases, and amyotrophic lateral sclerosis, as well as stroke, traumatic brain injury (TBI), and demyelination in Krabbe disease. We conclude by discussing the therapeutic potential of targeting the J2 prostaglandin pathway to prevent/delay neurodegeneration associated with neuroinflammation. In this context, we suggest a shift from the traditional view that cyclooxygenases are the most appropriate targets to treat neuroinflammation, to the notion that J2 prostaglandin pathways and other neurotoxic prostaglandins downstream from cyclooxygenases, would offer significant benefits as more effective therapeutic targets to treat chronic neurodegenerative diseases, while minimizing adverse side effects. PMID:25628533

  10. Centrally administered CDP-choline induced cardiovascular responses are mediated by activation of the central phospholipase-prostaglandin signaling cascade.

    PubMed

    Topuz, Bora B; Altinbas, Burcin; Ilhan, Tuncay; Yilmaz, Mustafa S; Erdost, Hatice; Saha, Sikha; Savci, Vahide; Yalcin, Murat

    2014-05-14

    The present study was designed to determine the involvement of central prostaglandin synthesis on the pressor and bradycardic effect of cytidine 5'-diphosphocholine (CDP-choline). Intracerebroventricular (i.c.v.) administration of CDP-choline was made and blood pressure and heart rate were recorded in male Sprague Dawley rats throughout this study. Microdialysis and immunohistochemical studies were performed to measure extracellular total prostaglandin concentration and to show cyclooxygenase-1 and -2 (COX-1 and -2) immunoreactivities, respectively, in the posterior hypothalamic area. Moreover, rats were pretreated (i.c.v) with mepacrine [a phospholipase A2 (PLA2) inhibitor], ibuprofen [a nonselective COX inhibitor], neomycine [a phospholipase C (PLC) inhibitor] or furegrelate [a thromboxane A2 (TXA2) synthesis inhibitor] 5 min prior to the injection of CDP-choline to determine the effects of these inhibitors on cardiovascular responses to CDP-choline. Control rats were pretreated (i.c.v) with saline. CDP-choline caused a dose- and time-dependent increase in blood pressure and decrease in heart rate. Immunohistochemical studies showed that CDP-choline increased COX-1 and -2 immunoreactivities in the posterior hypothalamic area. CDP-choline also elevated hypothalamic extracellular total prostaglandin concentration by 62%, as shown in microdialysis studies. Mepacrine or ibuprofen pretreatments almost completely blocked the pressor and bradycardic responses to CDP-choline while neomycine or furegrelate partially attenuated the drug-induced cardiovascular effects. The results suggest that CDP-choline may stimulate prostaglandin synthesis through the activation of PLA2, cyclooxygenases (COX-1 and -2) and prostaglandins and at least TXA2, may mediate the drug׳s cardiovascular effects. PMID:24704528

  11. Secretory phospholipases A(2) isolated from Bothrops asper and from Crotalus durissus terrificus snake venoms induce distinct mechanisms for biosynthesis of prostaglandins E2 and D2 and expression of cyclooxygenases.

    PubMed

    Moreira, Vanessa; Gutiérrez, José Maria; Soares, Andreimar Martins; Zamunér, Stella Regina; Purgatto, Eduardo; Teixeira, Catarina de Fátima Pereira

    2008-09-01

    The effects of myotoxin III (MT-III), a phospholipase A(2) (sPLA2) from Bothrops asper snake venom, and crotoxin B (CB), a neurotoxic and myotoxic sPLA2 from the venom of Crotalus durissus terrificus, on cyclooxygenases (COXs) expression and biosynthesis of prostaglandins (PGs) were evaluated, together with the mechanisms involved in these effects. Upon intraperitoneal injection in mice, both sPLA(2)s promoted the synthesis of PGD2 and PGE2, with a different time-course. MT-III, but not CB, induced COX-2 expression by peritoneal leukocytes without modification on COX-1 constitutive expression, whereas CB increased the constitutive activity of COX-1. MT-III increased the enzymatic activity of COX-1 and COX-2. Similar effects were observed when these sPLA(2)s were incubated with isolated macrophages, evidencing a direct effect on these inflammatory cells. Moreover, both toxins elicited the release of arachidonic acid from macrophages in vitro. Inhibition of cPLA2 by AACOCF3, but not of iPLA2 by PACOCF3 or BEL, significantly reduced PGD2, PGE2 and arachidonic acid (AA) release promoted by MT-III. These inhibitors did not affect MT-III-induced COX-2 expression. In contrast, cPLA2 inhibition did not modify the effects of CB, whereas iPLA2 inhibition reduced PGD2 and AA production induced by CB. These findings imply that distinct regulatory mechanisms leading to PGs' synthesis are triggered by these snake venom sPLA(2)s. Such differences are likely to explain the dissimilar patterns of inflammatory reaction elicited by these sPLA(2)s in vivo. PMID:18619987

  12. Group V Secretory Phospholipase A2 Amplifies the Induction of Cyclooxygenase 2 and Delayed Prostaglandin D2 Generation in Mouse Bone Marrow Culture-Derived Mast Cells in a Strain-Dependent Manner.

    PubMed Central

    Diaz, Bruno L.; Satake, Yoshiyuki; Kikawada, Eriya; Balestrieri, Barbara; Arm, Jonathan P.

    2006-01-01

    Activation of bone marrow-derived mast cells (BMMC) with stem cell factor (SCF) or IgE and antigen elicits exocytosis and an immediate phase of prostaglandin (PG) D2 and leukotriene (LT) C4 generation. Activation of BMMC by SCF, IL-1β and IL-10 elicits a delayed phase of PGD2 generation dependent on cyclooxygenase (COX) 2 induction. Cytosolic phospholipase A2 α provides arachidonic acid in both phases and amplifies COX-2 induction. Pharmacological experiments implicate an amplifying role for secretory (s) PLA2. We used mice lacking the gene encoding group V sPLA2 (Pla2g5 −/−) to definitively test its role in eicosanoid generation by BMMC. Pla2g5 −/− BMMC on a C57BL/6 genetic background showed a modest reduction in exocytosis and immediate PGD2 generation after activation with SCF or with IgE and antigen, while LTC4 generation was not modified. Delayed-phase PGD2 generation and COX-2 induction were reduced ~35% in C57BL/6 Pla2g5 −/− BMMC and were restored by exogenous PGE2. There was no deficit in either phase of eicosanoid generation by Pla2g5 −/− BMMC on a BALB/c background. Thus, group V sPLA2 amplifies COX-2 expression and delayed phase PGD2 generation in a strain-dependent manner; it has at best a limited role in immediate eicosanoid generation by BMMC. PMID:17064958

  13. Distinct Roles of Central and Peripheral Prostaglandin E2 and EP Subtypes in Blood Pressure Regulation

    PubMed Central

    Yang, Tianxin; Du, Yaomin

    2012-01-01

    Prostaglandin E2 (PGE2) is a major prostanoid with a wide variety of biological activities. PGE2 can influence blood pressure (BP) both positively and negatively. In particular, centrally administered PGE2 induces hypertension whereas systemic administration of PGE2 produces a hypotensive effect. These physiologically opposing effects are generated by the existence of multiple EP receptors, namely EP1–4, which are G protein-coupled receptors with distinct signaling properties. This review highlights the distinct roles of PGE2 in BP regulation and the involvement of specific EP receptor subtypes. American Journal of Hypertension, advance online publication 14 June 2012; doi:10.1038/ajh.2012.67 PMID:22695507

  14. Radiation biology, immunologic, and hemorheologic effects of a prostaglandin-leukotriene inhibitor

    SciTech Connect

    Mahafzah, M.K.

    1986-01-01

    This work examined the effects of a prostaglandin-leukotriene inhibitor (Meclomen) on the radiation-induced proctitis and brain edema in primates, and on the total-body-irradiated Balb/c mice. This work also investigated the radioprotective effect on Meclomen on the radiation-induced mucositis in patients with malignancies. In preliminary animal toxicologic experiments we found that Meclomen at a dose of 20 mg/kg is safe when administered to monkeys and mice. We also found that the most frequent toxic signs, in mice receiving toxic doses, were hypoactivity, irritability, convulsions, and death. We observed that Meclomen minimized the death rate, prolonged the life expectancy, and prevented the microscopic liver changes of Balb/C mice that received total body irradiation. However, the drug had no effect on the LD50/15 of the irradiated mice. Meclomen proved to be a radioprotector against radiation-induced proctitis and brain edema in primates.

  15. Beneficial effects on the reproductive performance of sows of administering prostaglandin analogues after farrowing.

    PubMed

    Lopez, J V; Ptaszynska, M; Gonzalez, P; Jiménez, M; Martens, M R T M

    2009-06-27

    Twenty-four to 36 hours after farrowing, 192 sows were treated with a single intramuscular injection (2 ml per animal) of a prostaglandin analogue; 102 were treated with cloprostenol racemate and 97 with dinoprost tromethamine, and 90 were left untreated. There were no statistically significant differences between the groups in the percentages of sows that came into oestrus by eight days after weaning or conceived by eight days after weaning. Significantly more piglets were born per litter (10.71 and 11.00 piglets in the cloprostenol and dinoprost groups, respectively) and born alive (10.22 and 10.41, respectively) than in the controls (9.24 piglets born per litter and 8.66 piglets born alive). PMID:19561350

  16. A severe phenotype of Gitelman syndrome with increased prostaglandin excretion and favorable response to indomethacin

    PubMed Central

    Larkins, Nicholas; Wallis, Mathew; McGillivray, Barbara; Mammen, Cherry

    2014-01-01

    Our understanding of Gitelman syndrome (GS) and Bartter syndrome has continued to evolve with the use of genetic testing to more precisely define the tubular defects responsible. GS is caused by mutations in the SLC12A3 gene encoding the Na+–Cl− co-transporter of the distal convoluted tubule (NCCT) and tends to be associated with a milder salt-losing phenotype. We describe two female siblings presenting in infancy with a severe salt-losing tubulopathy and failure to thrive due to compound heterozygous mutations in the SLC12A3 gene encoding the NCCT. Both children were treated with indomethacin resulting in improved linear growth and polyuria. Some atypical biochemical findings in our cases are discussed including raised urinary prostaglandin (PGE2) excretion that normalized with intravenous fluid repletion. PMID:25852896

  17. Prostaglandin E₂ constrains systemic inflammation through an innate lymphoid cell-IL-22 axis.

    PubMed

    Duffin, Rodger; O'Connor, Richard A; Crittenden, Siobhan; Forster, Thorsten; Yu, Cunjing; Zheng, Xiaozhong; Smyth, Danielle; Robb, Calum T; Rossi, Fiona; Skouras, Christos; Tang, Shaohui; Richards, James; Pellicoro, Antonella; Weller, Richard B; Breyer, Richard M; Mole, Damian J; Iredale, John P; Anderton, Stephen M; Narumiya, Shuh; Maizels, Rick M; Ghazal, Peter; Howie, Sarah E; Rossi, Adriano G; Yao, Chengcan

    2016-03-18

    Systemic inflammation, which results from the massive release of proinflammatory molecules into the circulatory system, is a major risk factor for severe illness, but the precise mechanisms underlying its control are not fully understood. We observed that prostaglandin E2 (PGE2), through its receptor EP4, is down-regulated in human systemic inflammatory disease. Mice with reduced PGE2 synthesis develop systemic inflammation, associated with translocation of gut bacteria, which can be prevented by treatment with EP4 agonists. Mechanistically, we demonstrate that PGE2-EP4 signaling acts directly on type 3 innate lymphoid cells (ILCs), promoting their homeostasis and driving them to produce interleukin-22 (IL-22). Disruption of the ILC-IL-22 axis impairs PGE2-mediated inhibition of systemic inflammation. Hence, the ILC-IL-22 axis is essential in protecting against gut barrier dysfunction, enabling PGE2-EP4 signaling to impede systemic inflammation. PMID:26989254

  18. Up-regulation of cyclooxygenase-2 by product-prostaglandin E2

    NASA Technical Reports Server (NTRS)

    Tjandrawinata, R. R.; Hughes-Fulford, M.

    1997-01-01

    The development of prostate cancer has been linked to high level of dietary fat intake. Our laboratory investigates the connection between cancer cell growth and fatty acid products. Studying human prostatic carcinoma PC-3 cells, we found that prostaglandin E2 (PGE2) increased cell growth and up-regulated the gene expression of its own synthesizing enzyme, cyclooxygenase-2 (COX-2). PGE2 increased COX-2 mRNA expression dose-dependently with the highest levels of stimulation seen at the 3-hour period following PGE2 addition. The NSAID flurbiprofen (5 microM), in the presence of exogenous PGE2, inhibited the up-regulation of COX-2 mRNA and cell growth. These data suggest that the levels of local intracellular PGE2 play a major role in the growth of prostate cancer cells through an activation of COX-2 gene expression.

  19. Prostaglandin-secreting cells: a portable first aid kit for tissue repair

    PubMed Central

    Rakoff-Nahoum, Seth; Medzhitov, Ruslan

    2007-01-01

    After intestinal injury, both the number and type of intestinal epithelial cells must be restored. Intestinal stem cells, located at the base of the intestinal crypt, repopulate the depleted crypt in a process known as compensatory proliferation. In this issue of the JCI, Brown et al. describe a new mechanism by which this process is regulated (see the related article beginning on page 258). Surprisingly, they find that a subset of stromal cells present within the intestinal tissue and expressing the proliferative factor prostaglandin-endoperoxidase synthase 2 (Ptgs2) is repositioned next to the intestinal stem cell compartment where local production of PGE2 controls injury-induced epithelial cell proliferation. PMID:17200710

  20. Failure of prostaglandin induction labor in a Müllerian abnormality.

    PubMed

    Abreu, Rita; Barros, Sousa; Jardim, Ondina; Morais, Clara

    2010-08-01

    Rudimentary-horn pregnancy (RHP) is a rare condition which is usually presented as a rupture of the pregnant horn during the second or third trimester, resulting in life-threatening bleeding. The authors report two cases of RHP which were diagnosed at the time of labor induction following fetal death diagnosis. Although the failure of prostaglandin induction to initiate labor could suggest that an additional obstructive Müllerian uterine anomaly is present, a directed investigation of such anomaly is more acceptable in cases of antepartum fetal death or atypical mid-trimester abdominal pain. Therefore, a high index of suspicion combined with clinical and imagiological findings are important to establish a correct diagnosis of pre-rupture RHP. PMID:20182737

  1. Prostaglandin I2 and the nitric oxide donor molsidomine have synergistic effects on thromboresistance in man.

    PubMed Central

    Sinzinger, H; Rauscha, F; O'Grady, J; Fitscha, P

    1992-01-01

    1. In vitro synergistic effects of nitric oxide and prostaglandin I2 (PGI2) have been shown. Consequently we examined any potentiating effect of the nitric oxide donor molsidomine on the reduction in thrombogenicity produced by PGI2 in patients with peripheral vascular disease. 2. Thirty-six patients all with peripheral and also coronary artery disease were randomly allocated to receive PGI2 5 ng kg-1 min-1 for 6 h daily, 5 days a week for 5 weeks, alone (12 patients), with molsidomine 12 mg daily (12 patients) or molsidomine 12 mg daily alone (12 patients). 3. The effect of each treatment regimen was measured in terms of femoral artery platelet uptake and platelet survival after autologous 111Indium-oxine labelling. Molsidomine alone had no effect on platelet uptake or survival but in combination with PGI2 it significantly potentiated the decreased platelet uptake and prolonged platelet survival observed with PGI2 alone. PMID:1576049

  2. Effects of prostaglandin on experimental bone malignancy and on scintigrams of bone and marrow. [Rabbits

    SciTech Connect

    Otsuka, N.; Ito, Y.; Nagai, K.; Terashima, H.; Yanagimoto, S.; Muranaka, A.

    1981-05-01

    The correlation between prostaglandin E (PgE) and scintigrams of bone (Tc-99m MDP) and bone marrow (Tc-99m SC) was investigated in normal and VX-2-bearing rabbits. PgE in plasma of normal rabbits was 486.2. In rabbits with VX-2 transplanted into femoral muscles, PgE was in the normal range unless the tumor invaded bone. PgE was not increase significantly in rabbits when the tumor was transplanted into the marrow cavity. When tumor invaded bone, PgE increassed markedly (to 1335). Elevation of PgE did not necessarily coincide with the appearance of positive bone scans. PgE in an indomethacin-treated group did not necessarily coincide with the appearance of positive bone scans. PgE in an indomethacin-treated group did not higher than in the untreated group. Indomethacin may suppress the local acceleration of calcium metabolism.

  3. Effect of dietary vitamin E or selenium on prostaglandin dehydrogenase in hyperoxic rat lung

    NASA Technical Reports Server (NTRS)

    North, L. N.; Mathias, M. M.; Schatte, C. L.

    1984-01-01

    Weanling male rats were fed semipurified diets supplemented with 0, 60, or 600 IU/kg vitamin E or 0, 100, or 1000 ppb selenium. One group was injected daily with vitamin E at a rate equivalent to consumption of 60 IU/kg. Animals from all groups were sacrificed after exposure to normobaric oxygen or air for 48 h. Lung tissue was analyzed for the combined activity of prostaglandin dehydrogenase and reductase. Using the decline in enzyme activity as an indicator of susceptibility to oxygen poisoning, protection against hyperoxia was directly related to the level of vitamin E supplementation. Selenium supplemented at 100 ppb provided significant protection when compared to 0 ppb or 1000 ppb. The latter dose may have been marginally toxic. Thus dietary supplementation of vitamin E and selenium may influence the relative susceptibility of an animal to pulmonary oxygen poisoning.

  4. Prostaglandin E2 and the Suppression of Phagocyte Innate Immune Responses in Different Organs

    PubMed Central

    Medeiros, Alexandra; Peres-Buzalaf, Camila; Fortino Verdan, Felipe; Serezani, C. Henrique

    2012-01-01

    The local and systemic production of prostaglandin E2 (PGE2) and its actions in phagocytes lead to immunosuppressive conditions. PGE2 is produced at high levels during inflammation, and its suppressive effects are caused by the ligation of the E prostanoid receptors EP2 and EP4, which results in the production of cyclic AMP. However, PGE2 also exhibits immunostimulatory properties due to binding to EP3, which results in decreased cAMP levels. The various guanine nucleotide-binding proteins (G proteins) that are coupled to the different EP receptors account for the pleiotropic roles of PGE2 in different disease states. Here, we discuss the production of PGE2 and the actions of this prostanoid in phagocytes from different tissues, the relative contribution of PGE2 to the modulation of innate immune responses, and the novel therapeutic opportunities that can be used to control inflammatory responses. PMID:23024463

  5. Behavioural and autonomic induction of prostaglandin E-1 fever in squirrel monkeys.

    PubMed Central

    Crawshaw, L I; Stitt, J T

    1975-01-01

    1. Prostaglandins E1 (PGE1) was injected into the preoptic/anterior hypothalamic (PO/AH) area of the squirrel monkey. 2. Increases in rectal temperature (Tre) produced by PGE1 injections of 20 ng to 500 ng were dose-dependent. 3. When ambient temperature (Ta) was below the thermoneutral zone, increases in Tre were produced entirely by increases in metabolic rate. With Ta at the upper end of the thermoneutral zone, increases in Tre were produced by vasoconstriction in addition to lesser increases in metabolic rate. 4. During sessions of behavioural temperature regulation, PGE1 injections were followed by the selection of a higher Ta, increased skin temperature and subsequent increases in Tre. 5. PGE1 injections produce dose-dependent increases in Tre which are similar regardless of ambient temperature or whether behavioural or autonomic means are utilized to raise the heat content of the body. PMID:804544

  6. Hypothetical role of prostaglandins in the onset of preterm labor after fetal surgery.

    PubMed

    Pomini, Francesco; Noia, Giuseppe; Mancuso, Salvatore

    2007-01-01

    Preterm labor is one of the most important factors limiting the advancement of fetal surgery programs. While prostaglandins (PGs) have long been indicated as the key factor in the initiation of labor in humans, there is significant evidence showing that the chorionic membrane acts as a powerful barrier between the decidua/myometrium and amniotic PGs during normal pregnancy. After either open or endoscopic fetal surgery the imperfect, non-hermetical closure of the chorion permits leakage of PGs from the amnionic sac, allowing them to reach the decidua and myometrium. The surgical wound in the chorionic barrier could be the major factor involved in preterm labor and delivery after human fetal surgery. PMID:17135752

  7. Eicosanoids Derived From Arachidonic Acid and Their Family Prostaglandins and Cyclooxygenase in Psychiatric Disorders

    PubMed Central

    Yui, Kunio; Imataka, George; Nakamura, Hiroyuki; Ohara, Naoki; Naito, Yukiko

    2015-01-01

    Arachidonic acid (AA)-derived lipid mediators are called eicosanoids. Eicosanoids have emerged as key regulators of a wide variety of physiological responses and pathological processes, and control important cellular processes. AA can be converted into biologically active compounds by metabolism by cyclooxygenases (COX). Beneficial effect of COX-2 inhibitor celecoxib add-on therapy has been reported in early stage of schizophrenia. Moreover, add-on treatment of celecoxib attenuated refractory depression and bipolar depression. Further, the COX/prostaglandin E pathway play an important role in synaptic plasticity and may be included in pathophysiology in autism spectrum disorders (ASD). In this regard, plasma transferrin, which is an iron mediator related to eicosanoid signaling, may be related to social impairment of ASD. COX-2 is typically induced by inflammatory stimuli in the majority of tissues, and the only isoform responsible for propagating the inflammatory response. Thus, COX-2 inhibitors considered as the best target for Alzheimer’s disease. PMID:26521945

  8. Endocannabinoids, through opioids and prostaglandins, contribute to fever induced by key pyrogenic mediators.

    PubMed

    Fraga, Daniel; Zanoni, Cristiane I S; Zampronio, Aleksander R; Parada, Carlos A; Rae, Giles A; Souza, Glória E P

    2016-01-01

    This study aims to explore the contribution of endocannabinoids on the cascade of mediators involved in LPS-induced fever and to verify the participation of prostaglandins and endogenous opioids in fever induced by anandamide (AEA). Body temperature (Tc) of male Wistar rats was recorded over 6h, using a thermistor probe. Cerebrospinal fluid concentration of PGE2 and β-endorphin were measured by ELISA after the administration of AEA. Intracerebroventricular administration of the CB1 receptor antagonist AM251 (5μg, i.c.v.), reduced the fever induced by IL-1β (3ng, i.c.v.), TNF-α (250ng, i.c.v.), IL-6 (300ng, i.c.v.), corticotrophin release factor (CRH; 2.5μg, i.c.v.) and endothelin (ET)-1 (1pmol, i.c.v.), but not the fever induced by PGE2 (250ng, i.c.v.) or PGF2α (250ng, i.c.v.). Systemic administration of indomethacin (2mgkg(-1), i.p.) or celecoxib (5mgkg(-1), p.o.) reduced the fever induced by AEA (1μg, i.c.v.), while naloxone (1mgkg(-1), s.c.) abolished it. The increases of PGE2 and β-endorphin concentration in the CSF induced by AEA were abolished by the pretreatment of rats with AM251. These results suggest that endocannabinoids are intrinsically involved in the pyretic activity of cytokines (IL-1β, TNF-α, IL-6), CRH and ET-1 but not the PGE2 or PGF2α induced fevers. However, anandamide via CB1 receptor activation induces fever that is dependent on the synthesis of prostaglandin and opioids. PMID:26291402

  9. The Distribution of Prostaglandins in Afferent and Efferent Lymph From Inflammatory Sites

    PubMed Central

    Johnston, Miles G.; Hay, John B.; Movat, Henry

    1980-01-01

    Arachidonic acid labeled with 14C was injected directly into lymph nodes that had been stimulated at various times with Escherichia coli. The efferent lymph was collected, and labeled catabolites were extracted and analyzed chromatographically. The pimary conversion product recovered was Prostaglandin E2 (PGE2), with the lesser products thromboxane, prostacyclin and prostaglandin F2α (PGF2α) also detected. When the efferent lymph was analyzed by radioimmunoassay after subcutaneous injectino of E coli into the hock, PGE and PGF levels rapidly increased, reached the highest levels in the first 10 hours, and then returned to normal by 24 hours. When the afferent lymph plasma draining inflammatory sites was compared directly with efferent lymph, PGF levels were similar, but the PGE level was always several times higher in the afferent lymph. To examine the catabolism of PG, either 3,H-PGF2ά of 3H-PGE2 was injected into the node, and the efferent lymph plasma was analyzed. No conversion of PGF2α to other products was found. In contrast, catabolic products of PGE2 were detected. With the use of equilibrium dialysis techniques, the binding of PGE2 and PGF2α to proteins in lymph and to bovine serum albumin (BSA), human serum albumin (HSA), and BSA stripped of its fatty acids was established. The binding to lymph proteins correlated with the albumin concentrations in the lymph. This albumin binging probably facilitated the retention and transport of PG in the lymph. PG appears in the lymph at a time corresponding to the uptake and processing of antigen by the node and near the time when lymphokines are detected in lymph and could modulate several steps in the immune response. The PGE detectable in the lymph draining an inflammatory site may play a role in the modulation of blood flow. PMID:6992593

  10. Prostaglandin E2 decreases fetal breathing movements, but not pulmonary blood flow, in fetal sheep.

    PubMed

    Savich, R D; Guerra, F A; Lee, C C; Kitterman, J A

    1995-04-01

    Fetal breathing movements are vital for normal fetal lung growth. Inhibition of these fetal breathing movements is associated with pulmonary hypoplasia. Pulmonary hypoplasia also occurs subsequent to alterations in other factors, such as a significant decrease in pulmonary blood flow. The prostaglandin system is known to have profound effects on both fetal breathing movements and on the pulmonary vascular system. We studied six late-gestation chronically instrumented fetal sheep by using an electromagnetic flow transducer around the left pulmonary artery to determine whether a decrease in fetal breathing movements, subsequent to a continuous infusion of prostaglandin E2 (PGE2), is associated with a decrease in pulmonary blood flow. A continuous PGE2 infusion of 0.88 +/- 0.11 microgram.kg-1.min-1 over 120 min led to a significant decrease in fetal breathing movements (control 40.5 +/- 3.6%, infusion 3.3 +/- 1.6%; P < 0.001). In contrast, the PGE2 infusion had no effect on mean left pulmonary artery blood flow (control 27.7 +/- 9.3 ml.min-1.kg-1, infusion 23.8 +/- 7.0 ml.min-1.kg-1. The PGE2 infusion demonstrated central effects in the percentage of time the fetus was in high-voltage electrocortical activity (control 41.9 +/- 2.5%, infusion 56.5 +/- 5.4%; P < 0.05) and in the amount of time spent in low-voltage electrocortical activity without fetal breathing movements (control 17.5 +/- 2.7%, infusion 40.2 +/- 4.8%; P < 0.05). A significant decrease in the fetal heart rate during the infusion was seen with no effect on either the systemic or pulmonary blood pressure.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:7615458

  11. Effects of dimethyl prostaglandin A1 on herpes simplex virus and human immunodeficiency virus replication

    NASA Technical Reports Server (NTRS)

    Hughes-Fulford, M.; McGrath, M. S.; Hanks, D.; Erickson, S.; Pulliam, L.

    1992-01-01

    We have investigated the direct effect of dimethyl prostaglandin A1 (dmPGA1) on the replication of herpes simplex virus (HSV) and human immunodeficiency virus type 1 (HIV-1). dmPGA1 significantly inhibited viral replication in both HSV and HIV infection systems at concentrations of dmPGA1 that did not adversely alter cellular DNA synthesis. The 50% inhibitory concentration (ID50) for several HSV type 1 (HSV-1) strains ranged from 3.8 to 5.6 micrograms/ml for Vero cells and from 4.6 to 7.3 micrograms/ml for human foreskin fibroblasts. The ID50s for two HSV-2 strains varied from 3.8 to 4.5 micrograms/ml for Vero cells; the ID50 was 5.7 micrograms/ml for human foreskin fibroblasts. We found that closely related prostaglandins did not have the same effect on the replication of HSV; dmPGE2 and dmPGA2 caused up to a 60% increase in HSV replication compared with that in untreated virus-infected cells. HIV-1 replication in acutely infected T cells (VB line) and chronically infected macrophages was assessed by quantitative decreases in p24 concentration. The effective ID50s were 2.5 micrograms/ml for VB cells acutely infected with HIV-1 and 5.2 micrograms/m for chronically infected macrophages. dmPGA1 has an unusual broad-spectrum antiviral activity against both HSV and HIV-1 in vitro and offers a new class of potential therapeutic agents for in vivo use.

  12. Human brain prostaglandin D synthase has been evolutionarily differentiated from lipophilic-ligand carrier proteins.

    PubMed Central

    Nagata, A; Suzuki, Y; Igarashi, M; Eguchi, N; Toh, H; Urade, Y; Hayaishi, O

    1991-01-01

    cDNAs for glutathione-independent prostaglandin D synthase were isolated from cDNA libraries of human brain. The longest cDNA insert was 837 base pairs long and contained a coding region of 570 base pairs corresponding to 190 amino acid residues with a calculated Mr of 21,016. Between two cDNA inserts isolated from the two different libraries, nucleotide substitutions were observed at 16 positions, including conservative amino acid substitutions at 2 positions and nonconservative substitutions at 5 positions, indicating genetic heterogeneity of this enzyme in humans. The computer-assisted homology search revealed that the enzyme is a member of the lipocalin superfamily, comprising secretory hydrophobic molecule transporters, showing the greatest homology (28.8-29.4% identity; 51.3-53.1% similarity) to alpha 1-microglobulin among the members of this superfamily. In a phylogenetic tree of the superfamily, this enzyme, alpha 1-microglobulin, and the gamma chain of the complement component C8 form a cluster separate from the other 14 members. The two distinctive characteristics of glutathione-independent prostaglandin D synthase, as compared to the other members of this superfamily, are its enzymatic properties and its association with membranes that were probably acquired after evolutionary divergence of the two lipocalins. Based on the observed sequence homology, the tertiary structure of the enzyme was deduced to consist of an eight-stranded anti-parallel beta-barrel forming a hydrophobic pocket. Furthermore, the Cys-65 residue in the pocket, which is conserved only in the human and rat enzymes but not in other lipocalins, was considered to be a putative active site of the enzyme. Images PMID:1902577

  13. Impaired leukocyte influx in cervix of postterm women not responding to prostaglandin priming

    PubMed Central

    Sahlin, Lena; Stjernholm-Vladic, Ylva; Roos, Nathalie; Masironi, Britt; Ekman-Ordeberg, Gunvor

    2008-01-01

    Background Prolonged pregnancies are associated with increased rate of maternal and fetal complications. Post term women could be divided into at least two subgroups, one where parturition is possible to induce by prostaglandins and one where it is not. Our aim was to study parameters in cervical biopsies in women with spontaneous delivery at term (controls) and compare to those that are successfully induced post term (responders), and those that are not induced (non-responders), by local prostaglandin treatment. Methods Stromal parameters examined in this study were the accumulation of leukocytes (CD45, CD68), mRNAs and/or proteins for the extracellular matrix degrading enzymes (matrix metalloproteinase (MMP)-2, MMP-8 and MMP-9), their inhibitors (tissue inhibitor of MMP (TIMP)-1 and TIMP-2), interleukin-8 (IL-8), the platelet activating factor-receptor (PAF-R), syndecan-1 and estrogen binding receptors (estrogen receptor (ER)α, ERβ and G-coupled protein receptor (GPR) 30) as well as the proliferation marker Ki-67. Results The influx of leukocytes as assessed by CD45 was strongest in the responders, thereafter in the controls and significantly lower in the non-responders. IL-8, PAF-R and MMP-9, all predominantly expressed in leukocytes, showed significantly reduced immunostaining in the group of non-responders, while ERα and GPR30 were more abundant in the non-responders, as compared to the controls. Conclusion The impaired leukocyte influx, as reflected by the reduced number of CD45 positive cells as well as decreased immunostaining of IL-8, PAF-R and MMP-9 in the non-responders, could be one explanation of the failed ripening of the cervix in post term women. If the decreased leukocyte influx is a primary explanation to absent ripening or secondary, as a result of other factors, is yet to be established. PMID:18764934

  14. Estrogen Promotes Luteolysis by Redistributing Prostaglandin F2α Receptors Within Primate Luteal Cells*

    PubMed Central

    Kim, Soon Ok; Markosyan, Nune; Pepe, Gerald J.; Duffy, Diane M.

    2015-01-01

    Prostaglandin F2α (PGF2α) has been proposed as a functional luteolysin in primates. However, administration of PGF2α or prostaglandin synthesis inhibitors in vivo both initiate luteolysis. These contradictory findings may reflect changes in PGF2α receptors (PTGFR) or responsiveness to PGF2α at a critical point during the life span of the corpus luteum. The current study addressed this question using ovarian cells and tissues from female cynomolgus monkeys and luteinizing granulosa cells from healthy women undergoing follicle aspiration. PTGFRs were present in the cytoplasm of monkey granulosa cells, while PTGFRs were localized to the perinuclear region of large, granulosa-derived monkey luteal cells by mid-late luteal phase. A PTGFR agonist decreased progesterone production by luteal cells obtained at mid-late and late luteal phases but did not decrease progesterone production by granulosa or luteal cells from younger corpora lutea. These findings are consistent with a role for perinuclear PTGFRs in functional luteolysis. This concept was explored using human luteinizing granulosa cells maintained in vitro as a model for luteal cell differentiation. In these cells, PTGFRs relocated from the cytoplasm to the perinuclear area in an estrogen- and estrogen receptor-dependent manner. Similar to our findings with monkey luteal cells, human luteinizing granulosa cells with perinuclear PTGFRs responded to a PTGFR agonist with decreased progesterone production. These data support the concept that PTGFR stimulation promotes functional luteolysis only when PTGFRs are located in the perinuclear region. Estrogen receptor-mediated relocation of PTGFRs within luteal cells may be a necessary step in the initiation of luteolysis in primates. PMID:25687410

  15. A Neural Basis for Control of Cichlid Female Reproductive Behavior by Prostaglandin F2α.

    PubMed

    Juntti, Scott A; Hilliard, Austin T; Kent, Kai R; Kumar, Anusha; Nguyen, Andrew; Jimenez, Mariana A; Loveland, Jasmine L; Mourrain, Philippe; Fernald, Russell D

    2016-04-01

    In most species, females time reproduction to coincide with fertility. Thus, identifying factors that signal fertility to the brain can provide access to neural circuits that control sexual behaviors. In vertebrates, levels of key signaling molecules rise at the time of fertility to prime the brain for reproductive behavior [1-11], but how and where they regulate neural circuits is not known [12, 13]. Specifically, 17α,20β-dihydroxyprogesterone (DHP) and prostaglandin F2α (PGF2α) levels rise in teleost fish around the time of ovulation [10, 14, 15]. In an African cichlid fish, Astatotilapia burtoni, fertile females select a mate and perform a stereotyped spawning routine, offering quantifiable behavioral outputs of neural circuits. We show that, within minutes, PGF2α injection activates a naturalistic pattern of sexual behavior in female A. burtoni. We also identify cells in the brain that transduce the prostaglandin signal to mate and show that the gonadal steroid DHP modulates mRNA levels of the putative receptor for PGF2α (Ptgfr). We use CRISPR/Cas9 to generate the first targeted gene mutation in A. burtoni and show that Ptgfr is necessary for the initiation of sexual behavior, uncoupling sexual behavior from reproductive status. Our findings are consistent with a model in which PGF2α communicates fertility status via Ptgfr to circuits in the brain that drive female sexual behavior. Our targeted genome modification in a cichlid fish shows that dissection of gene function can reveal basic control mechanisms for behaviors in this large family of species with diverse and fascinating social systems [16, 17]. PMID:26996507

  16. Protein disulfide isomerase as a novel target for cyclopentenone prostaglandins: implications for hypoxic ischemic injury

    PubMed Central

    Liu, Hao; Chen, Jie; Li, Wenjin; Rose, Marie E.; Shinde, Sunita N.; Balasubramani, Manimalha; Uechi, Guy T.; Mutus, Bülent; Graham, Steven H.; Hickey, Robert W.

    2016-01-01

    Cyclooxygenase-2 (COX-2) is an important contributor to ischemic brain injury. Identification of the downstream mediators of COX-2 toxicity may allow the development of targeted therapies. Of particular interest is the cyclopentenone family of prostaglandin metabolites. Cyclopentenone prostaglandins (CyPGs) are highly reactive molecules that form covalent bonds with cellular thiols. Protein disulfide isomerase (PDI) is an important molecule for the restoration of denatured proteins following ischemia. Because PDI has several thiols, including thiols within the active thioredoxin-like domain, we hypothesized that PDI is a target of CyPGs and that CyPG binding of PDI is detrimental. CyPG–PDI binding was detected in vitro via immunoprecipitation and MS. CyPG–PDI binding decreased PDI enzymatic activity in recombinant PDI treated with CyPG, and PDI immunoprecipitated from neuronal culture treated with CyPG or anoxia. Toxic effects of binding were demonstrated in experiments showing that: (a) pharmacologic inhibition of PDI increased cell death in anoxic neurons, (b) PDI overexpression protected neurons exposed to anoxia and SH-SY5Y cells exposed to CyPG, and (c) PDI overexpression in SH-SY5Y cells attenuated ubiquitination of proteins and decreased activation of pro-apoptotic caspases. In conclusion, CyPG production and subsequent binding of PDI is a novel and potentially important mechanism of ischemic brain injury. We show that CyPGs bind to PDI, cyclopentenones inhibit PDI activity, and CyPG–PDI binding is associated with increased neuronal susceptibility to anoxia. Additional studies are necessary to determine the relative role of CyPG-dependent inhibition of PDI activity in ischemia and other neurodegenerative disorders. PMID:25754985

  17. [Hematopoietic prostaglandin D synthase inhibitors for the treatment of duchenne muscular dystrophy].

    PubMed

    Kamauchi, Shinya; Urade, Yoshihiro

    2011-11-01

    Duchenne muscular dystrophy (DMD) is a severe X-linked muscle disease, characterized by progressive skeletal muscle atrophy and weakness. DMD is caused by mutations in the dystrophin gene, which encodes for the cytoskeletal protein dystrophin. DMD is one of the most common types of muscular dystrophies, affecting approximately 1 in 3,500 boys. There is no complete cure for this disease. Clinical trials for gene transfer therapy as a treatment for DMD have been performed but mainly in animal models. Hematopoietic prostaglandin (PG) D synthase (H-PGDS) was found to be induced in grouped necrotic muscle fibers of DMD patients and animal models, mdx mice, and DMD dogs. We found an orally active H-PGDS inhibitor (HQL-79) and determined the 3D structure of the inhibitor-human H-PGDS complex by X-ray crystallography. Oral administration of HQL-79 markedly suppressed prostaglandin D2 (PGD2) production, reduced necrotic muscle volume, and improved muscle strength in mdx dystrophic mice. Based on the high-resolution 3D structures of the inhibitor-H-PGDS complex, we designed alternative H-PGDS inhibitors, which were 100- to 3000-times more potent than HQL-79, as assessed by in vitro and in vivo analyses. We used these novel inhibitors for the treatment of DMD dogs and confirmed that oral administration of these inhibitors prevented skeletal muscle atrophy and weakness by decreasing PGD2 production. These results indicate that PGD2, synthesized by H-PGDS, is involved in the expansion of muscle necrosis in DMD. Thus, inhibition of H-PGDS by using inhibitors is a novel therapy for DMD. PMID:22068479

  18. Activation of prostaglandin E2-EP4 signaling reduces chemokine production in adipose tissue.

    PubMed

    Tang, Eva H C; Cai, Yin; Wong, Chi Kin; Rocha, Viviane Z; Sukhova, Galina K; Shimizu, Koichi; Xuan, Ge; Vanhoutte, Paul M; Libby, Peter; Xu, Aimin

    2015-02-01

    Inflammation of adipose tissue induces metabolic derangements associated with obesity. Thus, determining ways to control or inhibit inflammation in adipose tissue is of clinical interest. The present study tested the hypothesis that in mouse adipose tissue, endogenous prostaglandin E2 (PGE2) negatively regulates inflammation via activation of prostaglandin E receptor 4 (EP4). PGE2 (5-500 nM) attenuated lipopolysaccharide-induced mRNA and protein expression of chemokines, including interferon-γ-inducible protein 10 and macrophage-inflammatory protein-1α in mouse adipose tissue. A selective EP4 antagonist (L161,982) reversed, and two structurally different selective EP4 agonists [CAY10580 and CAY10598] mimicked these actions of PGE2. Adipose tissue derived from EP4-deficient mice did not display this response. These findings establish the involvement of EP4 receptors in this anti-inflammatory response. Experiments performed on adipose tissue from high-fat-fed mice demonstrated EP4-dependent attenuation of chemokine production during diet-induced obesity. The anti-inflammatory actions of EP4 became more important on a high-fat diet, in that EP4 activation suppressed a greater variety of chemokines. Furthermore, adipose tissue and systemic inflammation was enhanced in high-fat-fed EP4-deficient mice compared with wild-type littermates, and in high-fat-fed untreated C57BL/6 mice compared with mice treated with EP4 agonist. These findings provide in vivo evidence that PGE2-EP4 signaling limits inflammation. In conclusion, PGE2, via activation of EP4 receptors, functions as an endogenous anti-inflammatory mediator in mouse adipose tissue, and targeting EP4 may mitigate adipose tissue inflammation. PMID:25510249

  19. Effect of ozone exposure on lung functions and plasma prostaglandin and thromboxane concentrations in guinea pigs

    SciTech Connect

    Miller, P.D.; Ainsworth, D.; Lam, H.F.; Amdur, M.O.

    1987-03-30

    Male Hartley guinea pigs were exposed either to filtered air or to 1 ppm ozone (O/sub 3/) for 1 hr. At 2, 8, 24, or 48 hr after exposure we measured ventilation, respiratory mechanics, lung volumes, diffusing capacity for carbon monoxide (DLCO), and alveolar volume (VA) in anesthetized, tracheotomized animals. Respiratory frequency and tidal volume were unchanged in all groups. Pulmonary resistance was increased 2 hr after O/sub 3/ but returned to control at 8 hr and thereafter. Prolonged reductions in lung volumes (total lung capacity, vital capacity, functional residual capacity, and residual volume) as well as in DLCO and VA occurred after O/sub 3/, with maximum decreases at 8 and 24 hr postexposure. Increased ratios of wet lung weight to body weight were seen at 2, 8, and 24 hr. In separate groups of animals, also exposed either to filtered air or to 1 ppm O/sub 3/, plasma eicosanoid (EC) concentrations were measured at 2, 8, 24, 48, or 72 hr after exposure. Significant increases in thromboxane B2 concentrations were seen at 2, 24, and 48 hr after exposure. Plasma concentrations of 6-keto prostaglandin F1 alpha (PGF1 alpha) and prostaglandin E1 (PGE1) were increased at 24 hr and at 24, 48, and 72 hr, respectively. The nature of this long-term pulmonary response to a short-term exposure to O/sub 3/ suggests alveolar involvement, including probable alveolar duct constriction and localized pulmonary edema. Although changes in plasma EC concentrations were observed concurrent with impaired lung functions, no simple causal relationship was apparent from these studies.

  20. Prostaglandin D2 pathway upregulation: Relation to asthma severity, control, and TH2 inflammation

    PubMed Central

    Fajt, Merritt L.; Gelhaus, Stacy L.; Freeman, Bruce; Uvalle, Crystal E.; Trudeau, John B.; Holguin, Fernando; Wenzel, Sally E.

    2013-01-01

    Background Bronchoalveolar lavage (BAL) fluid prostaglandin D2 (PGD2) levels are increased in patients with severe, poorly controlled asthma in association with epithelial mast cells (MCs). PGD2, which is generated by hematopoietic prostaglandin D synthase (HPGDS), acts on 3 G protein–coupled receptors, including chemoattractant receptor–homologous molecule expressed on TH2 lymphocytes (CRTH2) and PGD2 receptor 1 (DP1). However, much remains to be understood regarding the presence and activation of these pathway elements in asthmatic patients. Objective We sought to compare the expression and activation of PGD2 pathway elements in bronchoscopically obtained samples from healthy control subjects and asthmatic patients across a range of disease severity and control, as well as in relation to TH2 pathway elements. Methods Epithelial cells and BAL fluid were evaluated for HPGDS (quantitative real-time PCR/immunohistochemistry [IHC]) and PGD2 (ELISA/liquid chromatography mass spectrometry) in relation to levels of MC proteases. Expression of the 2 inflammatory cell receptors DP1 and CRTH2 was evaluated on luminal cells. These PGD2 pathway markers were then compared with asthma severity, level of control, and markers of TH2 inflammation (blood eosinophils and fraction of exhaled nitric oxide). Results Confirming previous results, BAL fluid PGD2 levels were highest in patients with severe asthma (overall P = .0001). Epithelial cell compartment HPGDS mRNA and IHC values differed among groups (P = .008 and P < .0001, respectively) and correlated with MC protease mRNA. CRTH2 mRNA and IHC values were highest in patients with severe asthma (P = .001 and P = .0001, respectively). Asthma exacerbations, poor asthma control, and TH2 inflammatory markers were associated with higher PGD2, HPGDS, and CRTH2 levels. Conclusion The current study identifies coordinated upregulation of the PGD2 pathway in patients with severe, poorly controlled, TH2-high asthma despite corticosteroid

  1. Studies on a novel series of acyl ester prodrugs of prostaglandin F2 alpha.

    PubMed Central

    Cheng-Bennett, A; Chan, M F; Chen, G; Gac, T; Garst, M E; Gluchowski, C; Kaplan, L J; Protzman, C E; Roof, M B; Sachs, G

    1994-01-01

    A novel series of prostaglandin F2 alpha (PGF2 alpha) prodrugs, with acyl ester groups at the 9, 11, and 15 positions, was prepared in order to design clinically acceptable prostaglandins for treating glaucoma. Studies involving isolated esterases and ocular tissue homogenates indicated that 9-acyl esters cannot provide a prodrug since PGF2 alpha would not be formed as a product. In contrast, 11-mono, 15-mono, and 11, 15-diesters were converted to PGF2 alpha in ocular tissues and could, therefore, be considered as prodrugs of PGF2 alpha. Carboxylesterase (CE) appeared critically important for the hydrolytic conversion of those PGF2 alpha prodrugs where the 11 or 15-OH group was esterified and such prodrugs were not substrates for acetylcholinesterase (ACHE) or butyrylcholinesterase (BuCHE). The enzymatic hydrolysis of PGF2 alpha-1-isopropyl ester was also investigated for comparative purposes. This PGF2 alpha prodrug was a good substrate for CE, but was also hydrolysed by BuCHE, albeit at a much slower rate. The most striking feature of the enzymatic hydrolysis of PGF2 alpha-1-isopropyl ester in ocular tissue homogenates was that it was much faster than for prodrugs esterified at the 11 and/or 15 positions. In terms of ocular hypotensive activity, all prodrugs which showed detectable conversion to nascent PGF2 alpha were potent ocular hypotensives. Although no separation of ocular hypotensive and ocular surface hyperaemic effects was apparent for PGF2 alpha-1-isopropyl ester, a temporal separation of these effects was apparent for the novel PGF2 alpha ester series. This difference may reflect an unfavourably rapid conversion of PGF2 alpha-1-isopropyl ester in ocular surface tissues compared with anterior segment tissues. PMID:7918269

  2. Inhibition of protein translation as a novel mechanism for prostaglandin E2 regulation of cell functions

    PubMed Central

    Okunishi, Katsuhide; DeGraaf, Angela J.; Zasłona, Zbigniew; Peters-Golden, Marc

    2014-01-01

    Prostaglandin E2 (PGE2) regulates numerous biological processes by modulating transcriptional activation, epigenetic control, proteolysis, and secretion of various proteins. Scar formation depends on fibroblast elaboration of matrix proteins such as collagen, and this process is strongly suppressed by PGE2 through activation of cAMP-dependent protein kinase A (PKA). However, the actual mechanism by which PGE2-PKA signaling inhibits collagen expression in fibroblasts has never been delineated, and that was the objective of this study. PGE2 unexpectedly induced a rapid reduction in procollagen I protein expression in adult lung fibroblasts, with a half-maximum effect at 1.5 h. This effect reflected its inhibition of translation rather than transcription. Global protein synthesis was also inhibited by PGE2. This action was mediated by PKA and involved both activation of ribosomal protein (rpS6) and suppression of mammalian target of rapamycin (mTOR). Similar effects of PGE2 were demonstrated in mouse peritoneal macrophages (PMs). These findings identify inhibition of translation as a new mechanism by which PGE2 regulates cellular function and a novel example of translational inhibition mediated by opposing actions on two distinct translational control pathways. Translational inhibition would be expected to contribute to dynamic alterations in cell function that accompany the changing PGE2 levels observed in disease states and with various pharmacotherapies.—Okunishi K., DeGraaf, A. J., Zasłona, Z., Peters-Golden, M. Inhibition of protein translation as a novel mechanism for prostaglandin E2 regulation of cell functions. PMID:24072780

  3. The role of prostaglandins for the coordination of myometrial forces during labour.

    PubMed

    Wiqvist, N; Bryman, I; Lindblom, B; Norström, A; Wikland, M

    1985-01-01

    Systematic studies using a superfusion technique for recording myometrial contractility in vitro have been conducted in our department to explore whether prostaglandins (PG) have a differential action on the different segments of the pregnant uterus and also whether the qualitative and quantitative response undergoes a change during spontaneous labour. Myometrial specimens were excised from the fundal area and from the lower uterine segment at elective caesarean section in the 39th week of pregnancy before commencement of labour and at acute caesarean section during ongoing labour. Before labour PGF2 alpha was without or had a very weak effect on upper segment preparations but was stimulatory on lower segment specimens. PGE2 and PGI2 generally induced a biphasic dose-dependent response (stimulation followed by inhibition). During spontaneous labour PGF2 alpha and PGE2 always stimulated upper segment preparations while the contractile activity of specimens from the lower segment was inhibited by PGE2, PGF2 alpha was generally without effect. PGI2 had the same biphasic action before as during labour. With all reservations for the validity of in vitro experiments, the results favour the hypothesis that initiation of labour in the human involves a qualitative shift in the myometrial reactivity to prostaglandins. These alterations may involve suppression of expulsive forces and perhaps some tightening of the lower uterine segment during pregnancy. Following initiation of labour there is a marked increase in the excitatory action of both PGE2 and PGF2 alpha in the fundal area while the lower uterine segment reacts in a way that favours dilatation. PMID:3893037

  4. Frondoside A inhibits breast cancer metastasis and antagonizes prostaglandin E receptors EP4 and EP2

    PubMed Central

    Ma, Xinrong; Kundu, Namita; Collin, Peter D; Goloubeva, Olga; Fulton, Amy

    2013-01-01

    Frondoside A, derived from the sea cucumber Cucumaria frondosa has demonstrable anticancer activity in several models, however, the ability of Frondoside A to affect tumor metastasis has not been reported. Using a syngeneic murine model of metastatic breast cancer, we now show that Frondoside A has potent antimetastatic activity. Frondoside A given i.p. to mice bearing mammary gland implanted mammary tumors, inhibits spontaneous tumor metastasis to the lungs. The elevated Cyclooxygenase -2 activity in many malignancies promotes tumor growth and metastasis by producing high levels of PGE2 which acts on the prostaglandin E receptors, chiefly EP4 and EP2. We examined the ability of Frondoside A to modulate the functions of these EP receptors. We now show that Frondoside A antagonizes the prostaglandin E receptors EP2 and EP4. 3H-PGE2 binding to recombinant EP2 or EP4-expressing cells was inhibited by Frondoside A at low μM concentrations. Likewise, EP4 or EP2-linked activation of intracellular cAMP as well as EP4-mediated ERK1/2 activation were also inhibited by Frondoside A. Consistent with the antimetastatic activity observed in vivo, migration of tumor cells in vitro in response to EP4 or EP2 agonists was also inhibited by Frondoside A. These studies identify a new function for an agent with known antitumor activity, and show that the antimetastatic activity may be due in part to a novel mechanism of action. These studies add to the growing body of evidence that Frondoside A may be a promising new agent with potential to treat cancer and may also represent a potential new modality to antagonize EP4. PMID:21761157

  5. Frondoside A inhibits breast cancer metastasis and antagonizes prostaglandin E receptors EP4 and EP2.

    PubMed

    Ma, Xinrong; Kundu, Namita; Collin, Peter D; Goloubeva, Olga; Fulton, Amy M

    2012-04-01

    Frondoside A, derived from the sea cucumber Cucumaria frondosa has demonstrable anticancer activity in several models, however, the ability of Frondoside A to affect tumor metastasis has not been reported. Using a syngeneic murine model of metastatic breast cancer, we now show that Frondoside A has potent antimetastatic activity. Frondoside A given i.p. to mice bearing mammary gland-implanted mammary tumors, inhibits spontaneous tumor metastasis to the lungs. The elevated Cyclooxygenase-2 activity in many malignancies promotes tumor growth and metastasis by producing high levels of PGE(2) which acts on the prostaglandin E receptors, chiefly EP4 and EP2. We examined the ability of Frondoside A to modulate the functions of these EP receptors. We now show that Frondoside A antagonizes the prostaglandin E receptors EP2 and EP4. (3)H-PGE(2) binding to recombinant EP2 or EP4-expressing cells was inhibited by Frondoside A at low μM concentrations. Likewise, EP4 or EP2-linked activation of intracellular cAMP as well as EP4-mediated ERK1/2 activation were also inhibited by Frondoside A. Consistent with the antimetastatic activity observed in vivo, migration of tumor cells in vitro in response to EP4 or EP2 agonists was also inhibited by Frondoside A. These studies identify a new function for an agent with known antitumor activity, and show that the antimetastatic activity may be due in part to a novel mechanism of action. These studies add to the growing body of evidence that Frondoside A may be a promising new agent with potential to treat cancer and may also represent a potential new modality to antagonize EP4. PMID:21761157

  6. Prostaglandin E{sub 2} regulates melanocyte dendrite formation through activation of PKC{zeta}

    SciTech Connect

    Scott, Glynis Fricke, Alex; Fender, Anne; McClelland, Lindy; Jacobs, Stacey

    2007-11-01

    Prostaglandins are lipid signaling intermediates released by keratinocytes in response to ultraviolet irradiation (UVR) in the skin. The main prostaglandin released following UVR is PGE{sub 2}, a ligand for 4 related G-protein-coupled receptors (EP{sub 1}, EP{sub 2}, EP{sub 3} and EP{sub 4}). Our previous work established that PGE{sub 2} stimulates melanocyte dendrite formation through activation of the EP{sub 1} and EP{sub 3} receptors. The purpose of the present report is to define the signaling intermediates involved in EP{sub 1}- and EP{sub 3}-dependent dendrite formation in human melanocytes. We recently showed that activation of the atypical PKC{zeta} isoform stimulates melanocyte dendricity in response to treatment with lysophosphatidylcholine. We therefore examined the potential contribution of PKC{zeta} activation on EP{sub 1}- and EP{sub 3}-dependent dendrite formation in melanocytes. Stimulation of the EP{sub 1} and EP{sub 3} receptors by selective agonists activated PKC{zeta}, and inhibition of PKC{zeta} activation abrogated EP{sub 1}- and EP{sub 3}-receptor-mediated melanocyte dendricity. Because of the importance of Rho-GTP binding proteins in the regulation of melanocyte dendricity, we also examined the effect of EP{sub 1} and EP{sub 3} receptor activation on Rac and Rho activity. Neither Rac nor Rho was activated upon treatment with EP{sub 1,3}-receptor agonists. We show that melanocytes express only the EP{sub 3A1} isoform, but not the EP{sub 3B} receptor isoform, previously associated with Rho activation, consistent with a lack of Rho stimulation by EP{sub 3} agonists. Our data suggest that PKC{zeta} activation plays a predominant role in regulation of PGE{sub 2}-dependent melanocyte dendricity.

  7. Calcium/calmodulin-dependent protein kinase II regulates cyclooxygenase-2 expression and prostaglandin E2 production by activating cAMP-response element-binding protein in rat peritoneal macrophages

    PubMed Central

    Zhou, Xueyuan; Li, Junying; Yang, Wenxiu

    2014-01-01

    Prostaglandin E2 (PGE2) is an important inducer of inflammation, which is also closely linked to the progress of tumours. In macrophages, PGE2 production is regulated by arachidonic acid release and cyclooxygenase-2 (COX-2) expression. In the present study, we found that COX-2 expression can be achieved by activating Ca2+/Calmodulin (CaM)-dependent protein kinase II (CaMKII) and cAMP-response element-binding protein (CREB) in rat peritoneal macrophages. Our results indicated that lipopolysaccharide and PMA could elicit the transient increase of the concentration of intracellular free calcium ions ([Ca2+]i), which induced activation of CaMKs with the presence of CaM. The subtype of CaMKs, CaMKII, then triggered the activation of CREB, which elevated COX-2 expression and PGE2 production in a chronological order. These results suggested that Ca2+/CaM-dependent CaMKII plays an important role in mediating COX-2 expression and PGE2 production by activating CREB in macrophages. The study also provides more useful information to clarify the mechanism of calcium regulation of PGE2 production, which plays an essential role in inflammation and cancers. PMID:24773364

  8. Potentially bioaccessible phenolics, antioxidant activity and nutritional quality of young buckwheat sprouts affected by elicitation and elicitation supported by phenylpropanoid pathway precursor feeding.

    PubMed

    Świeca, Michał

    2016-02-01

    This paper presents the study on impact of elicitation and the phenylpropanoid pathway feeding on the nutritional quality, the potentially bioaccessible phenolics and the antioxidant capacity of young buckwheat sprouts. Phenolics content was increased by elicitation and feeding with tyrosine and shikimic acid--an elevation of 30% and 17%, respectively. Antioxidant capacity was improved by feeding with tyrosine--an increase of 16.7% and 17.1% in both untreated and treated sprouts, respectively. The highest protein digestibility was determined for the control sprouts and those obtained after tyrosine feeding. The lowest starch digestibility was found for elicited sprouts obtained from seeds fed with tyrosine (a decrease by 52%). An increase of expected glycemic index by 38% was determined for elicited sprouts obtained after phenylalanine feeding. Starch and protein digestibility were negatively correlated with total phenolics (r = -0.55 and -0.58, respectively), however starch digestibility was also affected by resistant starch content. PMID:26304392

  9. Berberine, an isoquinoline alkaloid, inhibits melanoma cancer cell migration by reducing the expressions of cyclooxygenase-2, prostaglandin E2 and prostaglandin E2 receptors

    PubMed Central

    Singh, Tripti; Vaid, Mudit; Katiyar, Nandan; Sharma, Samriti; Katiyar, Santosh K.

    2011-01-01

    Melanoma is the leading cause of death from skin disease due, in large part, to its propensity to metastasize. We have examined the effect of berberine, an isoquinoline alkaloid, on human melanoma cancer cell migration and the molecular mechanisms underlying these effects using melanoma cell lines, A375 and Hs294. Using an in vitro cell migration assay, we show that over expression of cyclooxygenase (COX)-2, its metabolite prostaglandin E2 (PGE2) and PGE2 receptors promote the migration of cells. We found that treatment of A375 and Hs294 cells with berberine resulted in concentration-dependent inhibition of migration of these cells, which was associated with a reduction in the levels of COX-2, PGE2 and PGE2 receptors (EP2 and EP4). Treatment of cells with celecoxib, a COX-2 inhibitor, or transient transfection of cells with COX-2 small interfering RNA, also inhibited cell migration. Treatment of the cells with 12-O-tetradecanoylphorbol-13-acetate (TPA), an inducer of COX-2 or PGE2, enhanced cell migration, whereas berberine inhibited TPA- or PGE2-promoted cell migration. Berberine reduced the basal levels as well as PGE2-stimulated expression levels of EP2 and EP4. Treatment of the cells with the EP4 agonist stimulated cell migration and berberine blocked EP4 agonist-induced cell migration activity. Moreover, berberine inhibited the activation of nuclear factor-kappa B (NF-κB), an upstream regulator of COX-2, in A375 cells, and treatment of cells with caffeic acid phenethyl ester, an inhibitor of NF-κB, inhibited cell migration. Together, these results indicate for the first time that berberine inhibits melanoma cell migration, an essential step in invasion and metastasis, by inhibition of COX-2, PGE2 and PGE2 receptors. PMID:20974686

  10. Proanthocyanidins inhibit in vitro and in vivo growth of human non-small cell lung cancer cells by inhibiting the prostaglandin E(2) and prostaglandin E(2) receptors.

    PubMed

    Sharma, Som D; Meeran, Syed M; Katiyar, Santosh K

    2010-03-01

    Overexpression of cyclooxygenase-2 (COX-2) and prostaglandins (PG) is linked to a wide variety of human cancers. Here, we assessed whether the chemotherapeutic effect of grape seed proanthocyanidins (GSP) on non-small cell lung cancer (NSCLC) cells is mediated through the inhibition of COX-2 and PGE(2)/PGE(2) receptor expression. The effects of GSPs on human NSCLC cell lines in terms of proliferation, apoptosis, and expression of COX-2, PGE(2), and PGE(2) receptors were determined using Western blotting, fluorescence-activated cell sorting analysis, and reverse transcription-PCR. In vitro treatment of NSCLC cells (A549, H1299, H460, H226, and H157) with GSPs resulted in significant growth inhibition and induction of apoptosis, which were associated with the inhibitory effects of GSPs on the overexpression of COX-2, PGE(2), and PGE(2) receptors (EP1 and EP4) in these cells. Treatment of cells with indomethacin, a pan-COX inhibitor, or transient transfection of cells with COX-2 small interfering RNA, also inhibited cell growth and induced cell death. The effects of a GSP-supplemented AIN76A control diet fed to nude mice bearing tumor xenografts on the expression of COX-2, PGE(2), and PGE(2) receptors in the xenografts were also evaluated. The growth-inhibitory effect of dietary GSPs (0.5%, w/w) on the NSCLC xenograft tumors was associated with the inhibition of COX-2, PGE(2), and PGE(2) receptors (EP1, EP3, and EP4) in tumors. This preclinical study provides evidence that the chemotherapeutic effect of GSPs on lung cancer cells in vitro and in vivo is mediated, at least in part, through the inhibition of COX-2 expression and subsequently the inhibition of PGE(2) and PGE(2) receptors. PMID:20145019

  11. Possible involvement of brain prostaglandin E2 and prostanoid EP3 receptors in prostaglandin E2 glycerol ester-induced activation of central sympathetic outflow in the rat.

    PubMed

    Shimizu, Takahiro; Tanaka, Kenjiro; Nakamura, Kumiko; Taniuchi, Keisuke; Yawata, Toshio; Higashi, Youichirou; Ueba, Tetsuya; Dimitriadis, Fotios; Shimizu, Shogo; Yokotani, Kunihiko; Saito, Motoaki

    2014-07-01

    We recently reported that intracerebroventricularly administered 2-arachidonoylglycerol elevated plasma noradrenaline and adrenaline by brain monoacylglycerol lipase- (MGL) and cyclooxygenase-mediated mechanisms in the rat. These results suggest that 2-arachidonoylglycerol is hydrolyzed by MGL to free arachidonic acid, which is further metabolized to prostaglandins (PGs) by cyclooxygenase in the brain, thereby elevating plasma noradrenaline and adrenaline. On the other hand, 2-arachidonoylglycerol can be also metabolized by cyclooxygenase to PG glycerol esters (PG-Gs), which seems to be hydrolyzed by MGL to free PGs. Here, we examined the involvement of brain PG-Gs in the elevation of plasma noradrenaline and adrenaline regarding PGE2-G and prostanoid EP receptors using anesthetized male Wistar rats. Intracerebroventricularly administered PGE2-G (1.5 and 3 nmol/animal) dose-dependently elevated plasma noradrenaline but not adrenaline. PGE2-G also elevated systolic, mean and diastolic blood pressure and heart rate. The PGE2-G-induced elevation of plasma noradrenaline was attenuated by JZL184 (MGL inhibitor). Intracerebroventricularly administered PGE2 (0.3 and 1.5 nmol/animal) and sulprostone (0.1 and 0.3 nmol/animal) (EP1/EP3 agonist) also elevated plasma noradrenaline but not adrenaline in a dose-dependent manner. The sulprostone-induced elevation was attenuated by L-798,106 (EP3 antagonist), but not by SC-51322 (EP1 antagonist). L-798,106 also attenuated the PGE2-G- and PGE2-induced elevation of plasma noradrenaline, while PF-04418948 (EP2 antagonist) and L-161,982 (EP4 antagonist) had no effect on the PGE2-G-induced response. These results suggest a possibility that brain PGE2-G produced from 2-arachidonoylglycerol can be hydrolyzed to free PGE2, thereby activating central sympathetic outflow by brain prostanoid EP3 receptor-mediated mechanisms in the rat. PMID:24657150

  12. Effects of prostaglandin F2 alpha on bone formation and resorption in cultured neonatal mouse calvariae: Role of prostaglandin E2 production

    SciTech Connect

    Raisz, L.G.; Alander, C.B.; Fall, P.M.; Simmons, H.A. )

    1990-02-01

    Although most studies show that prostaglandin E2 (PGE2) is the most potent and effective of the prostanoids in bone, recent data in cell culture suggest that PGF2 alpha may have unique effects, particularly on cell replication. The present study was undertaken to compare the effects of PGF2 alpha and PGE2 in cultured neonatal mouse parietal bones by simultaneous measurement of bone resorption as release of previously incorporated 45Ca, bone formation as incorporation of (3H)proline into collagenase-digestible (CDP) and noncollagen protein, and DNA synthesis as incorporation of (3H)thymidine. PGF2 alpha was less effective than PGE2 as a stimulator of bone resorption, and its effects were partially inhibited by indomethacin and markedly inhibited by glucocorticoids. In contrast, the resorptive response to PGE2 was unaffected by indomethacin and only partially inhibited by cortisol. PGF2 alpha had little effect on bone formation, in contrast to the biphasic effect of PGE2, which inhibited labeling of CDP in the absence of cortisol and stimulated CDP labeling in the presence of cortisol. PGF2 alpha increased thymidine incorporation into DNA, but the effect was smaller than that of PGE2 and was inhibited by indomethacin. These observations suggested that PGF2 alpha might act in part by stimulating PGE2 production. By RIA, PGE2 concentrations were increased in the medium of bones treated with PGF2 alpha, and this increase was blocked by indomethacin. By HPLC, bones prelabeled with (3H)arachidonic acid showed an increase in labeled PGE2 release, and RIA showed an increase in PGE2 after PGF2 alpha treatment. These results indicate that PGF2 alpha is a relatively weak agonist in bone compared to PGE2 and that some of the effects of PGF2 alpha on bone resorption, formation, and cell replication may be mediated by an increase in endogenous PGE2 production.

  13. Augmentation of metastasis formation by thioglycollate-elicited macrophages.

    PubMed

    Gorelik, E; Wiltrout, R H; Brunda, M J; Holden, H T; Herberman, R B

    1982-05-15

    Inoculation of thioglycollate-elicited peritoneal exudate cells (PEC) into C57BL/6 mice reduced the rate of lung clearance of several intravenously (i.v.) injected murine tumor cells, and increased by up to 100-fold the number of artificially-induced metastatic lung nodules produced by the i.v. injection of B16 melanoma or Lewis lung carcinoma (3LL) tumor cells. Maximum effects were observed when PEC were injected either before, or shortly after, tumor cells. Modulation of lung clearance or metastasis formation was observed only with PEC and not with a variety of other cells, such as splenocytes, thymocytes P815 mastocytoma cells, or several macrophage-like cell lines (PU5-1.8 and IC-21). Lysates of PEC were as efficient in reducing lung clearance and augmenting metastasis formation as were intact viable PEC. Lysates of other cell types, including P815 and the macrophage-like cell lines, were unable to produce these effects. PEC populations, enriched for macrophages by adherence to plastic or by percoll density gradient sedimentation, also increased the number of B16-induced artificial metastasis, implicating the macrophage as the cell responsible for these observations. PMID:7095902

  14. Dreamed movement elicits activation in the sensorimotor cortex.

    PubMed

    Dresler, Martin; Koch, Stefan P; Wehrle, Renate; Spoormaker, Victor I; Holsboer, Florian; Steiger, Axel; Sämann, Philipp G; Obrig, Hellmuth; Czisch, Michael

    2011-11-01

    Since the discovery of the close association between rapid eye movement (REM) sleep and dreaming, much effort has been devoted to link physiological signatures of REM sleep to the contents of associated dreams [1-4]. Due to the impossibility of experimentally controlling spontaneous dream activity, however, a direct demonstration of dream contents by neuroimaging methods is lacking. By combining brain imaging with polysomnography and exploiting the state of "lucid dreaming," we show here that a predefined motor task performed during dreaming elicits neuronal activation in the sensorimotor cortex. In lucid dreams, the subject is aware of the dreaming state and capable of performing predefined actions while all standard polysomnographic criteria of REM sleep are fulfilled [5, 6]. Using eye signals as temporal markers, neural activity measured by functional magnetic resonance imaging (fMRI) and near-infrared spectroscopy (NIRS) was related to dreamed hand movements during lucid REM sleep. Though preliminary, we provide first evidence that specific contents of REM-associated dreaming can be visualized by neuroimaging. PMID:22036177

  15. Eliciting the most prominent perceived differences between microphones.

    PubMed

    Pearce, Andy; Brookes, Tim; Dewhirst, Martin; Mason, Russell

    2016-05-01

    The attributes contributing to the differences perceived between microphones (when auditioning recordings made with those microphones) are not clear from previous research. Consideration of technical specifications and expert opinions indicated that recording five programme items with eight studio and two microelectromechanical system microphones could allow determination of the attributes related to the most prominent inter-microphone differences. Pairwise listening comparisons between the resulting 50 recordings, followed by multi-dimensional scaling analysis, revealed up to 5 salient dimensions per programme item; 17 corresponding pairs of recordings were selected exemplifying the differences across those dimensions. Direct elicitation and panel discussions on the 17 pairs identified a hierarchy of 40 perceptual attributes. An attribute contribution experiment on the 31 lowest-level attributes in the hierarchy allowed them to be ordered by degree of contribution and showed brightness, harshness, and clarity to always contribute highly to perceived inter-microphone differences. This work enables the future development of objective models to predict these important attributes. PMID:27250188

  16. Naturalistic Enactment to Elicit and Recognize Caregiver State Anxiety.

    PubMed

    Miranda, Darien; Favela, Jesus; Ibarra, Catalina; Cruz, Netzahualcoyotl

    2016-09-01

    Caring for people with dementia imposes significant stress on family members and caregivers. Often, these informal caregivers have no coping strategy to deal with these behaviors. Anxiety and stress episodes are often triggered by problematic behaviors exhibited by the person who suffers from dementia. Detecting these behaviors could help them in dealing with them and reduce caregiver burden. However, work on anxiety detection using physiological signals has mostly been done under controlled conditions. In this paper we describe an experiment aimed at inducing anxiety among caregivers of people with dementia under naturalistic conditions. We report an experiment, using the naturalistic enactment technique, in which 10 subjects were asked to care for an older adult who acts as if she experiences dementia. We record physiological signals from the participants (GSR, HR, EEG) during the sessions that lasted for approximately 30 min. We explain how we obtained ground truth from self-report and observation data. We conducted two different tests using the Support Vector Machine technique. We obtained an average precision of 77.8 % and 38.1 % recall when classifying two different possible states: "Anxious" and "Not anxious". Analysis of the data provides evidence that the experiment elicits state anxiety and that it can be detected using wearable sensors. Furthermore, if episodes of problematic behaviors can also be detected, the recognition of anxiety in the caregiver can be improved, leading to the enactment of appropriate interventions to help caregivers cope with anxiety episodes. PMID:27443338

  17. Invisible visual stimuli elicit increases in alpha-band power.

    PubMed

    Bareither, Isabelle; Chaumon, Maximilien; Bernasconi, Fosco; Villringer, Arno; Busch, Niko A

    2014-09-01

    The cerebral cortex responds to stimuli of a wide range of intensities. Previous studies have demonstrated that undetectably weak somatosensory stimuli cause a functional deactivation or inhibition in somatosensory cortex. In the present study, we tested whether invisible visual stimuli lead to similar responses, indicated by an increase in EEG alpha-band power-an index of cortical excitability. We presented subliminal and supraliminal visual stimuli after estimating each participant's detection threshold. Stimuli consisted of peripherally presented small circular patches that differed in their contrast to a background consisting of a random white noise pattern. We demonstrate that subliminal and supraliminal stimuli each elicit specific neuronal response patterns. Supraliminal stimuli evoked an early, strongly phase-locked lower-frequency response representing the evoked potential and induced a decrease in alpha-band power from 400 ms on. By contrast, subliminal visual stimuli induced an increase of non-phase-locked power around 300 ms that was maximal within the alpha-band. This response might be due to an inhibitory mechanism, which reduces spurious visual activation that is unlikely to result from external stimuli. PMID:24872526

  18. Comparison of physiological responses to affect eliciting pictures and music.

    PubMed

    Kim, Jongwan; Wedell, Douglas H

    2016-03-01

    Recent investigations of the neural correlates of affect elicited from different modalities have found both modality-general and modality-specific representations (Chikazoe et al., 2014). The implications for how physiological responses to affect differ across stimulus modalities have not been fully investigated. This study examined similarities and differences between physiological signatures of affect derived from two different modes of presentation: visual pictures and auditory music sampled from an affective space defined by valence and arousal. Electromyography recordings for the zygomaticus major (EMGZ) and corrugator supercilii (EMGC) were measured along with heart rate and skin conductance level (SCL). Multidimensional scaling was used to visualize relationships from physiological and behavioral responses, and the observed relationships were statistically evaluated using multivariate and univariate analyses. Results for physiological measures demonstrated that valence was represented in the same general way across modalities, primarily reflected in EMGC responses. Arousal, however, was represented in a modality-specific manner, with SCL and EMGZ sensitive to music-based arousal but not picture-based arousal. Stimulus modality itself was predicted from EMGC. Thus, physiological responses to valence were similar across modalities but physiological responses to arousal differed across modalities. These results support the utility of testing for affective markers across modalities within the same experimental setting to reveal how physiological responses are linked to either affect, stimulus modality or both. PMID:26752207

  19. Point of view filming and the elicitation interview.

    PubMed

    Skinner, Jonathan; Gormley, Gerard J

    2016-08-01

    Face-to-face interviews are a fundamental research tool in qualitative research. Whilst this form of data collection can provide many valuable insights, it can often fall short of providing a complete picture of a research subject's experiences. Point of view (PoV) interviewing is an elicitation technique used in the social sciences as a means of enriching data obtained from research interviews. Recording research subjects' first person perspectives, for example by wearing digital video glasses, can afford deeper insights into their experiences. PoV interviewing can promote making visible the unverbalizable and does not rely as much on memory as the traditional interview. The use of such relatively inexpensive technology is gaining interest in health profession educational research and pedagogy, such as dynamic simulation-based learning and research activities. In this interview, Dr Gerry Gormley (a medical education researcher) talks to Dr Jonathan Skinner (an anthropologist with an interest in PoV interviewing), exploring some of the many crossover implications with PoV interviewing for medical education research and practice. PMID:27438056

  20. Chinese characters elicit face-like N170 inversion effects.

    PubMed

    Wang, Man-Ying; Kuo, Bo-Cheng; Cheng, Shih-Kuen

    2011-12-01

    Recognition of both faces and Chinese characters is commonly believed to rely on configural information. While faces typically exhibit behavioral and N170 inversion effects that differ from non-face stimuli (Rossion, Joyce, Cottrell, & Tarr, 2003), the current study examined whether a similar reliance on configural processing may result in similar inversion effects for faces and Chinese characters. Participants were engaged in an orientation judgment task (Experiment 1) and a one-back identity matching task (Experiment 2). Across two experiments, the N170 was delayed and enhanced in magnitude for upside-down faces and compound Chinese characters, compared to upright stimuli. The inversion effects for these two stimulus categories were bilateral for latency and right-lateralized for amplitudes. For simple Chinese characters, only the latency inversion effects were significant. Moreover, the size of the right-hemisphere inversion effects in N170 amplitude was larger for faces than Chinese characters. These findings show the N170 inversion effects from non-face stimuli closely parallel effects seen with faces. Face-like N170 inversion effects elicited by Chinese compound characters were attributed to the difficulty of part-whole integration as well as the disrupted regularity in relational information due to inversion. Hemispheric difference in Chinese character processing is also discussed. PMID:21944865

  1. Cancer-induced immunosuppression: IL-18-elicited immunoablative NK cells.

    PubMed

    Terme, Magali; Ullrich, Evelyn; Aymeric, Laetitia; Meinhardt, Kathrin; Coudert, Jérôme D; Desbois, Mélanie; Ghiringhelli, François; Viaud, Sophie; Ryffel, Bernard; Yagita, Hideo; Chen, Lieping; Mécheri, Salaheddine; Kaplanski, Gilles; Prévost-Blondel, Armelle; Kato, Masashi; Schultze, Joachim L; Tartour, Eric; Kroemer, Guido; Degli-Esposti, Mariapia; Chaput, Nathalie; Zitvogel, Laurence

    2012-06-01

    During cancer development, a number of regulatory cell subsets and immunosuppressive cytokines subvert adaptive immune responses. Although it has been shown that tumor-derived interleukin (IL)-18 participates in the PD-1-dependent tumor progression in NK cell-controlled cancers, the mechanistic cues underlying this immunosuppression remain unknown. Here, we show that IL-18 converts a subset of Kit(-) (CD11b(-)) into Kit(+) natural killer (NK) cells, which accumulate in all lymphoid organs of tumor bearers and mediate immunoablative functions. Kit(+) NK cells overexpressed B7-H1/PD-L1, a ligand for PD-1. The adoptive transfer of Kit(+) NK cells promoted tumor growth in two pulmonary metastases tumor models and significantly reduced the dendritic and NK cell pools residing in lymphoid organs in a B7-H1-dependent manner. Neutralization of IL-18 by RNA interference in tumors or systemically by IL-18-binding protein dramatically reduced the accumulation of Kit(+)CD11b(-) NK cells in tumor bearers. Together, our findings show that IL-18 produced by tumor cells elicits Kit(+)CD11b(-) NK cells endowed with B7-H1-dependent immunoablative functions in mice. PMID:22427351

  2. Optic nerve evoked potentials elicited by electrical stimulation.

    PubMed

    Kikuchi, Yasuhiro; Sasaki, Tatsuya; Matsumoto, Masato; Oikawa, Tomoyoshi; Itakura, Takeshi; Kodama, Namio

    2005-07-01

    This study investigated whether the optic nerve evoked potential (ONEP) elicited by electrical stimulation of the optic nerve can serve as a reliable intraoperative indicator of visual function. In the experimental study, two silver-ball stimulating electrodes were placed on the dog optic nerve adjacent to the apex of the orbit and one recording electrode was placed on the optic nerve near the chiasm. The nerve was stimulated with 0.1 to 10 mA rectangular pulses. Stable and reproducible ONEPs were obtained. The ONEPs were not influenced by electromyographic potentials and were recorded more clearly on the optic nerve than on the surrounding tissue. Stepwise incremental transection of the thickness of the nerve resulted in incremental amplitude reduction proportional to the transected area. No response was recorded after complete sectioning of the nerve. In the clinical study, recordings were obtained from 15 patients after craniotomy to treat parasellar tumors or cerebral aneurysms. Reproducible ONEPs were recorded intraoperatively from the electrode placed on the optic nerve near the chiasm in 14 of 15 patients. In the remaining patient, the ONEP, recorded only after tumor removal because the optic nerve was stretched and extremely thin, was remarkably small and the patient developed unilateral blindness postoperatively. These experimental and clinical results suggest the possibility of intraoperative monitoring of visual function in patients undergoing craniotomy for the treatment of lesions near the optic nerve. PMID:16041180

  3. Impact of discussion on preferences elicited in a group setting

    PubMed Central

    Stein, Ken; Ratcliffe, Julie; Round, Ali; Milne, Ruairidh; Brazier, John E

    2006-01-01

    Background The completeness of preferences is assumed as one of the axioms of expected utility theory but has been subject to little empirical study. Methods Fifteen non-health professionals was recruited and familiarised with the standard gamble technique. The group then met five times over six months and preferences were elicited independently on 41 scenarios. After individual valuation, the group discussed the scenarios, following which preferences could be changed. Changes made were described and summary measures (mean and median) before and after discussion compared using paired t test and Wilcoxon Signed Rank Test. Semi-structured telephone interviews were carried out to explore attitudes to discussing preferences. These were transcribed, read by two investigators and emergent themes described. Results Sixteen changes (3.6%) were made to preferences by seven (47%) of the fifteen members. The difference between individual preference values before and after discussion ranged from -0.025 to 0.45. The average effect on the group mean was 0.0053. No differences before and after discussion were statistically significant. The group valued discussion highly and suggested it brought four main benefits: reassurance; improved procedural performance; increased group cohesion; satisfying curiosity. Conclusion The hypothesis that preferences are incomplete cannot be rejected for a proportion of respondents. However, brief discussion did not result in substantial number of changes to preferences and these did not have significant impact on summary values for the group, suggesting that incompleteness, if present, may not have an important effect on cost-utility analyses. PMID:16571106

  4. Eliciting Parents' Individual Requirements for an Inclusive Digital School System.

    PubMed

    Eftring, Håkan; Rassmus-Gröhn, Kirsten; Hedvall, Per-Olof

    2016-01-01

    Parents often have a busy time sorting out their life puzzles, including getting information about their children's activities in school. More and more communication between teachers and parents take place via digital school systems. It can be hard for parents to find the information they are looking for and the teacher decides when information is sent and what communication method to use. All parents, but especially parents with disabilities, might have individual preferences on how to receive information and how to adapt meetings at school. In this paper we present a project where we involved parents and teachers in focus groups, an idea workshop and iterative user trials of a digital prototype. The goal was to elicit parents' individual requirements for an inclusive digital school system, where they can store their individual preferences about how and when to receive information from school and what requirements they have on meetings at school. Preliminary results show that we managed to create open and focused discussions among parents and teachers. The parents reacted very positively on an onboarding page with the possibility to quickly and easily enter preferences after their first log in, but more work needs to be done on how preferences are categorized on the onboarding page. Finally, parents need to get clear feedback from teachers and school when they have entered or updated preferences, so they can trust that their preferences will be met. PMID:27534306

  5. Mesencephalic stimulation elicits inhibition of phrenic nerve activity in cat.

    PubMed

    Gallman, E A; Lawing, W L; Millhorn, D E

    1991-05-01

    1. Previous work from this laboratory has indicated that the mesencephalon is the anatomical substrate for a mechanism capable of inhibiting central respiratory drive in glomectomized cats for periods of up to 1 h or more following brief exposure to systemic hypoxia; phrenic nerve activity was used as an index of central respiratory drive. 2. The present study was undertaken to further localize the region responsible for the observed post-hypoxic inhibition of respiratory drive. We studied the phrenic nerve response to stimulations of the mesencephalon in anaesthetized, paralysed peripherally chemo-denervated cats with end-expired PCO2 and body temperature servo-controlled. 3. Stimulations of two types were employed. Electrical stimulation allowed rapid determination of sites from which phrenic inhibition could be elicited. Microinjections of excitatory amino acids were used subsequently in order to confine excitation to neuronal cell bodies and not axons of passage. 4. Stimulation of discrete regions of the ventromedial aspect of the mesencephalon in the vicinity of the red nucleus produced substantial inhibition of phrenic activity which lasted up to 45 min. Stimulation of other areas of the mesencephalon either produced no phrenic inhibition or resulted in a slight stimulation of phrenic activity. 5. The results are discussed in the context of the central respiratory response to hypoxia. PMID:1676420

  6. The Scharff-technique: eliciting intelligence from human sources.

    PubMed

    Oleszkiewicz, Simon; Granhag, Pär Anders; Montecinos, Sebastian Cancino

    2014-10-01

    This study is on how to elicit intelligence from human sources. We compared the efficacy of two human intelligence gathering techniques: the Scharff-technique (conceptualized as four different tactics) and the Direct Approach (a combination of open and direct questions). Participants (N = 60) were asked to take on the role of "sources" and were given information about a planned terrorist attack. They were to reveal part of this information in an upcoming interview. Critically, the participants were instructed to strike a balance between not revealing too much or too little information. As predicted, the participants revealed significantly more, and more precise, new information when interviewed with the Scharff-technique (vs. the Direct Approach). Furthermore, and as predicted, the participants in the Scharff condition underestimated how much new information they revealed whereas the participants in the Direct Approach overestimated how much new information they revealed. The study provides rather strong support for the Scharff-technique as an effective human intelligence gathering technique. PMID:24707914

  7. Intracrine prostaglandin E(2) signalling regulates hypoxia-inducible factor-1α expression through retinoic acid receptor-β.

    PubMed

    Fernández-Martínez, Ana B; Jiménez, María I Arenas; Manzano, Victoria Moreno; Lucio-Cazaña, Francisco J

    2012-12-01

    We have previously found in human renal proximal tubular HK-2 cells that hypoxia- and all-trans retinoic acid-induced hypoxia-inducible factor-1α up-regulation is accompanied by retinoic acid receptor-β up-regulation. Here we first investigated whether hypoxia-inducible factor-1α expression is dependent on retinoic acid receptor-β and our results confirmed it since (i) hypoxia-inducible factor-1α-inducing agents hypoxia, hypoxia-mimetic agent desferrioxamine, all-trans retinoic acid and interleukin-1β increased retinoic acid receptor-β expression, (ii) hypoxia-inducible factor-1α up-regulation was prevented by retinoic acid receptor-β antagonist LE-135 or siRNA retinoic acid receptor-β and (iii) there was direct binding of retinoic acid receptor-β to the retinoic acid response element in hypoxia-inducible factor-1α promoter upon treatment with all-trans retinoic acid and 16,16-dimethyl-prostaglandin E(2). Since intracellular prostaglandin E(2) mediates hypoxia-inducible factor-1α up-regulation in normoxia in HK-2 cells, we next investigated and confirmed, its role in the up-regulation of retinoic acid receptor-β in normoxia by hypoxia-inducible factor-1α-inducing agents all-trans retinoic acid, interleukin-1β and 16,16-dimethyl-prostaglandin E(2) by inhibiting cyclooxygenases, prostaglandin influx transporter or EP receptors. Interestingly, the hypoxia-induced increase in retinoic acid receptor-β expression and accumulation of hypoxia-inducible factor-1α was also blocked by the inhibitors tested. This is the first time, to our knowledge, that retinoic acid receptor-β signalling is involved in the control of the expression of transcription factor hypoxia-inducible factor-1α in both normoxia and hypoxia and that retinoic acid receptor-β expression is found to be strictly regulated by intracellular prostaglandin E(2). Given the relevance of hypoxia-inducible factor-1α in the kidney in terms of tumorigenesis, progressive renal failure, production

  8. Treatment of obesity and pulmonary arterial hypertension with inhibitors of the prostaglandin transporter: evaluation of patent WO2014/204895A1.

    PubMed

    Dingemanse, Jasper; Bolli, Martin; Iglarz, Marc

    2015-01-01

    Prostaglandins display a wide array of pharmacological effects and prostaglandin analogs are already used in the treatment of pulmonary arterial hypertension (PAH). After synthesis and release from cells, prostaglandins undergo reuptake by the prostaglandin transporter (PGT). WO2014/204895 claims the use of a series of trisubstituted triazine derivatives for the treatment of obesity and PAH. Composition of matter of these triazines has been claimed in WO2011/037610 and the compounds are described as potent inhibitors of the PGT. One compound (nr 146) was shown to improve high fat diet-induced glucose tolerance in a mouse model. In addition, this compound has been explored in the rat monocrotaline model of PAH and reduced characteristic features of the pathology. This class of compounds presents a potential new treatment paradigm in the treatment of obesity-related disorders and PAH. PMID:26099857

  9. Screening of plants used by Southern African traditional healers in the treatment of dysmenorrhoea for prostaglandin-synthesis inhibitors and uterine relaxing activity.

    PubMed

    Lindsey, K; Jäger, A K; Raidoo, D M; van Staden, J

    1999-01-01

    Plants used by Southern African traditional healers for the treatment of menstrual pains were screened for prostaglandin-synthesis inhibitors and the ability to reduce isolated uterine muscle contraction using the cyclooxygenase and in vitro uterine bioassays respectively. Prostaglandins are synthesized from arachidonic acid and the enzyme that drives this reaction is cyclooxygenase. The excessive production of prostaglandins by the myometrium and endometrium induces uterine contractions. Inhibition of cyclooxygenase and hence of the prostaglandin biosynthetic pathway may lead to relief of menstrual pain. Ten plants used by traditional healers for menstrual pains were assayed for cyclooxygenase inhibitory activity. Several plant extracts exhibited high inhibitory activity in the assay. The highest activities were obtained with ethanolic extracts of Siphonochilus aethiopicus, Cenchrus ciliaris and Solanum mauritianum. Generally ethanolic extracts gave higher activity than the aqueous extracts. None of the ethanolic plant extracts were able to relax or reduce the contractions of the precontracted guinea pig uterus. PMID:10075117

  10. Photo-Elicitation and Visual Semiotics: A Unique Methodology for Studying Inclusion for Children with Disabilities

    ERIC Educational Resources Information Center

    Stockall, Nancy

    2013-01-01

    The methodology in this paper discusses the use of photographs as an elicitation strategy that can reveal the thinking processes of participants in a qualitatively rich manner. Photo-elicitation techniques combined with a Piercian semiotic perspective offer a unique method for creating a frame of action for later participant analysis. Illustrative…

  11. Concurrent Data Elicitation Procedures, Processes, and the Early Stages of L2 Learning: A Critical Overview

    ERIC Educational Resources Information Center

    Leow, Ronald P.; Grey, Sarah; Marijuan, Silvia; Moorman, Colleen

    2014-01-01

    Given the current methodological interest in eliciting direct data on the cognitive processes L2 learners employ as they interact with L2 data during the early stages of the learning process, this article takes a critical and comparative look at three concurrent data elicitation procedures currently employed in the SLA literature: Think aloud (TA)…

  12. Elicitation of the "Passe Compose" in French Preschoolers with and without Specific Language Impairment

    ERIC Educational Resources Information Center

    Royle, Phaedra; Thordardottir, Elin T.

    2008-01-01

    This study examines inflectional abilities in French-speaking children with specific language impairment (SLI) using a verb elicitation task. Eleven children with SLI and age-matched controls (37-52 months) participated in the experiment. We elicited the "passe compose" using eight regular and eight irregular high frequency verbs matched for age…

  13. Systematic review of expert elicitation methods as a tool for source attribution of enteric illness.

    PubMed

    Butler, Ainslie J; Thomas, M Kate; Pintar, Katarina D M

    2015-05-01

    Expert elicitation is a useful tool to explore sources of uncertainty and to answer questions where data are expensive or difficult to collect. It has been used across a variety of disciplines and represents an important method for estimating source attribution for enteric illness. A systematic review was undertaken to explore published expert elicitation studies, identify key considerations, and to make recommendations for designing an expert elicitation in the context of enteric illness source attribution. Fifty-nine studies were reviewed. Five key themes were identified: the expert panel including composition and recruitment; the pre-elicitation material, which clarifies the research question and provides training in uncertainty and probability; the choice of elicitation tool and method (e.g., questionnaires, surveys, and interviews); research design; and analysis of elicited data. Careful consideration of these themes is critical in designing and implementing an expert elicitation in order to reduce bias and produce the best possible results. While there are various epidemiological and microbiological methods available to explore source attribution of enteric illness, expert elicitation provides an opportunity to identify gaps in our understanding and where such studies are not feasible or available, represents the only possible method for synthesizing knowledge about transmission. PMID:25826450

  14. Identifying and Responding to Personal Stressors: Utilizing Photo Elicitation in Health Education Courses

    ERIC Educational Resources Information Center

    Hunter, Theresa

    2014-01-01

    The "Photo Elicitation Project" teaching idea applies the techniques of photo elicitation to stress prevention and management. This activity is designed to help students identify their personal stressors and to determine which stress prevention strategies are most useful for them. Objectives: students will be able to (a) identify current…

  15. Uncovering Pre-Service Teacher Beliefs about Young Children: A Photographic Elicitation Methodology

    ERIC Educational Resources Information Center

    Stockall, Nancy; Davis, Sara

    2011-01-01

    This illustrative paper provides an introduction to using mixed qualitative methods of photo-elicitation, face to face interviews and semiotic analysis to uncover pre-service students' beliefs about young children. The researchers share their experience on conducting a study using photo-elicitation and engaging pre-service teachers in a discussion…

  16. Stone Soup: Photo-Elicitation as a Learning Tool in the Food Geography Classroom

    ERIC Educational Resources Information Center

    Kurtz, Hilda E.; Wood, Jason

    2014-01-01

    This paper showcases self-reflective and inclusive pedagogy using photo-elicitation in a food geography course assignment. The Stone Soup project positions students as both researchers and participant-subjects in a participant-driven photo-elicitation (PDPE) study of students' foodways. Student papers for this assignment demonstrate rich…

  17. Naturalistic Observations of Elicited Expressive Communication of Children with Autism: An Analysis of Teacher Instructions

    ERIC Educational Resources Information Center

    Chiang, Hsu-Min

    2009-01-01

    This study observed expressive communication of 17 Australian and 15 Taiwanese children with autism who were mute or had limited spoken language during 2 hour regular school routines and analyzed teacher instructions associated with elicited expressive communication. Results indicated: (a) the frequency of occurrence of elicited expressive…

  18. From Drawings to Diagrams: Maintaining Researcher Control during Graphic Elicitation in Qualitative Interviews

    ERIC Educational Resources Information Center

    Varga-Atkins, Tunde; O'Brien, Mark

    2009-01-01

    Graphic elicitation, i.e. asking participants to draw, is an interview technique used to focus the interviewee on the given topic or gain extra meaning not covered verbally as part of the interview. This study analyses two interview contexts which included visual elicitation. It describes a successful example in which the researcher maintained…

  19. Designedly Incomplete Utterances: A Pedagogical Practice for Eliciting Knowledge Displays in Error Correction Sequences.

    ERIC Educational Resources Information Center

    Koshik, Irene

    2002-01-01

    Uses a conversation analytic framework to analyze a practice used by teachers in 1-0-1, second language writing conferences when eliciting self-correction of students' written language errors. This type of turn used to elicit a knowledge display from the student is labeled designedly incomplete utterance (DIU). Teachers use DIUs made up of…

  20. Dynamic Assessment of Elicited Imitation: A Case Analysis of an Advanced L2 English Speaker

    ERIC Educational Resources Information Center

    van Compernolle, Rémi A.; Zhang, Haomin

    2014-01-01

    The focus of this paper is on the design, administration, and scoring of a dynamically administered elicited imitation test of L2 English morphology. Drawing on Vygotskian sociocultural psychology, particularly the concepts of zone of proximal development and dynamic assessment, we argue that support provided during the elicited imitation test…

  1. Cell cycle arrest by prostaglandin A1 at the G1/S phase interface with up-regulation of oncogenes in S-49 cyc- cells

    NASA Technical Reports Server (NTRS)

    Hughes-Fulford, M.

    1994-01-01

    Our previous studies have implied that prostaglandins inhibit cell growth independent of cAMP. Recent reports, however, have suggested that prostaglandin arrest of the cell cycle may be mediated through protein kinase A. In this report, in order to eliminate the role of c-AMP in prostaglandin mediated cell cycle arrest, we use the -49 lymphoma variant (cyc-) cells that lack adenylate cyclase activity. We demonstrate that dimethyl prostaglandin A1 (dmPGA1) inhibits DNA synthesis and cell growth in cyc- cells. DNA synthesis is inhibited 42% by dmPGA1 (50 microM) despite the fact that this cell line lacks cellular components needed for cAMP generation. The ability to decrease DNA synthesis depends upon the specific prostaglandin structure with the most effective form possessing the alpha, beta unsaturated ketone ring. Dimethyl PGA1 is most effective in inhibiting DNA synthesis in cyc- cells, with prostaglandins PGE1 and PGB1 being less potent inhibitors of DNA synthesis. DmPGE2 caused a significant stimulation of DNA synthesis. S-49 cyc- variant cells exposed to (30-50 microns) dmPGA1, arrested in the G1 phase of the cell cycle within 24 h. This growth arrest was reversed when the prostaglandin was removed from the cultured cells; growth resumed within hours showing that this treatment is not toxic. The S-49 cyc- cells were chosen not only for their lack of adenylate cyclase activity, but also because their cell cycle has been extensively studied and time requirements for G1, S, G2, and M phases are known. Within hours after prostaglandin removal the cells resume active DNA synthesis, and cell number doubles within 15 h suggesting rapid entry into S-phase DNA synthesis from the G1 cell cycle block.(ABSTRACT TRUNCATED AT 250 WORDS).

  2. Stable analogs of prostaglandins E1 and F2 alpha ameliorate the proteinuria of aminonucleoside-of-puromycin nephrosis in Lewis rats.

    PubMed Central

    Ulich, T. R.; Meline, J. A.; Ni, R. X.; Keys, M.; Wu, C. H.

    1987-01-01

    Prostaglandins have been implicated by previous investigators in the pathogenesis of the nephrotic syndrome. A single subcutaneous injection of 1 mg/kg of stable analogs of prostaglandins E1 or F2 alpha (15[S]-15-methyl -PGE1 [M-PGE1] and -PGF2 alpha [M-PGF2 alpha]) was found in the present study to dramatically decrease proteinuria on Day 10 of puromycin aminonucleoside (PAN) nephrosis in Lewis rats. The decrease in proteinuria was mediated at least in part by a decrease in glomerular filtration rate (GFR), as quantitated by inulin clearances in nephrotic control and prostaglandin-treated rats. M-PGE1, moderately, and M-PGF2 alpha, to a lesser degree, also decreased the GFR in normal rats. Interestingly, the GFR was dramatically decreased in nephrotic as compared with nonnephrotic control rats, which suggests that PAN nephrosis may not be an ideal experimental model for human minimal change nephrosis in which the GFR is usually not severely compromised. The prostaglandin-induced decrease in GFR in both nephrotic and normal rats was coincident with a drop in systemic blood pressure. Nephrotic rats, however, had a slightly higher baseline blood pressure than normals, and the hypotensive effects of both prostaglandins were much less in nephrotic than in normal rats. The decrease in proteinuria was not related to a cytoprotective effect, as indicated by the failure of daily doses of 5 micrograms/kg M-PGE1 to reduce proteinuria 6, 8, or 10 days after injection of puromycin aminonucleoside. The similar antiproteinuric effects of prostaglandin synthesis inhibitors and of pharmacologic doses of prostaglandins are somewhat paradoxical but are reminiscent of the similarly paradoxical mutual antiinflammatory effects of these agents. The high doses of prostaglandins required to reduce proteinuria as well as their reduction of blood pressure and GFR will limit their clinical usefulness in the nephrotic syndrome. PMID:3499082

  3. Metaphors of Distress: Photo-Elicitation Enhances a Discourse Analysis of Parents' Accounts.

    PubMed

    Kantrowitz-Gordon, Ira; Vandermause, Roxanne

    2016-07-01

    In research on sensitive topics, photo-elicitation can be a profound aid to data collection and interpretation processes. Photo-elicitation methods were used in this manner in a discourse analysis of parents' distress at least 6 months after preterm birth. After an initial interview, participants were asked to take digital photographs representing their distress and to return for a second interview to discuss the photographs. The elicited photo representations supported participants' engagement with their current or past distress and generated new meanings from the reappraisal of old photographs. Photo-elicitation demonstrated the embodiment of parents' distress in the child and the placement of distress in specific locations. Photographs of documents showed the power of the written word in generating and maintaining distress. Participants used existing photographs from their child's photo history to generate rich metaphors for their distress as parents. These findings have implications for enhancing interpretive health research by incorporating photo-elicitation methods. PMID:25792488

  4. Comparison of elicitation methods for moral and affective beliefs in the theory of planned behaviour.

    PubMed

    Dean, M; Arvola, A; Vassallo, M; Lähteenmäki, L; Raats, M M; Saba, A; Shepherd, R

    2006-09-01

    Although the theory of planned behaviour (TPB) has been applied successfully in the area of food choice, it has been criticized for its pure utilitarian approach to the factors determining behaviour. Despite the increase in predictive power of the model with added components such as affective attitude and moral and ethical concerns, in most studies the elicitation process still only addresses people's utilitarian beliefs about the behaviour with little attention paid to other aspects. This study compares the traditional method of elicitation of advantages and disadvantages with two other methods (word association and open-ended) in the elicitations of beliefs, attitudes and moral concerns in relation to the consumption of organic foods. Results show the traditional method to be best for eliciting cognitive beliefs, open-ended emotion task for eliciting emotional beliefs and open-ended beliefs task best for moral concerns. The advantages and disadvantages of each method are discussed. PMID:16782230

  5. Feeding-elicited cataplexy in orexin knockout mice

    PubMed Central

    Clark, Erika L.; Baumann, Christian R.; Cano, Georgina; Scammell, Thomas E.; Mochizuki, Takatoshi

    2009-01-01

    Mice lacking orexin/hypocretin signaling have sudden episodes of atonia and paralysis during active wakefulness. These events strongly resemble cataplexy, episodes of sudden muscle weakness triggered by strong positive emotions in people with narcolepsy, but it remains unknown whether murine cataplexy is triggered by positive emotions. To determine whether positive emotions elicit murine cataplexy, we placed orexin knockout (KO) mice on a scheduled feeding protocol with regular or highly palatable food. Baseline sleep/wake behavior was recorded with ad lib regular chow. Mice were then placed on a scheduled feeding protocol in which they received 60% of their normal amount of chow 3 hr after dark onset for the next 10 days. Wild-type and KO mice rapidly entrained to scheduled feeding with regular chow, with more wake and locomotor activity prior to the feeding time. On day 10 of scheduled feeding, orexin KO mice had slightly more cataplexy during the food-anticipation period and more cataplexy in the second half of the dark period, when they may have been foraging for residual food. To test whether more palatable food increases cataplexy, mice were then switched to scheduled feeding with an isocaloric amount of Froot Loops, a food often used as a reward in behavioral studies. With this highly palatable food, orexin KO mice had much more cataplexy during the food-anticipation period and throughout the dark period. The increase in cataplexy with scheduled feeding, especially with highly palatable food, suggests that positive emotions may trigger cataplexy in mice, just as in people with narcolepsy. Establishing this connection helps validate orexin KO mice as an excellent model of human narcolepsy and provides an opportunity to better understand the mechanisms that trigger cataplexy. PMID:19362119

  6. Muscular dysfunction elicited by creep of lumbar viscoelastic tissue.

    PubMed

    Solomonow, M; Baratta, R V; Zhou, B-H; Burger, E; Zieske, A; Gedalia, A

    2003-08-01

    The biomechanics, histology and electromyography of the lumbar viscoelastic tissues and multifidus muscles of the in vivo feline were investigated during 20 min of static as well as cyclic flexion under load control and during 7 h of rest following the flexion. It was shown that the creep developed in the viscoelastic tissues during the 20 min of static or cyclic flexion did not fully recover over the 7 h of following rest. It was further seen that a neuromuscular disorder with five distinct components developed during and after the static and cyclic flexion. The neuromuscular disorder consisted of a decreasing magnitude of reflexive EMG from the multifidus upon flexion as well as of superimposed spasms. The recovery period was characterized by an initial muscle hyperexcitability, a slowly increasing reflexive EMG and a delayed hyperexcitability. Histological data from the supraspinous ligament demonstrate significant increase (x 10) in neutrophil density in the ligament 2 h into the recovery and even larger increase (x 100) 6 h into the recovery from the 20 min flexion, indicating an acute soft tissue inflammation. It was concluded that sustained static or cyclic loading of lumbar viscoelastic tissues may cause micro-damage in the collagen structure, which in turn reflexively elicit spasms in the multifidus as well as hyperexcitability early in the recovery when the majority of the creep recovers. The micro-damage, however, results in the time dependent development of inflammation. In all cases, the spasms, initial and delayed hyperexcitabilities represent increased muscular forces applied across the intervertebral joints in an attempt to limit the range of motion and unload the viscoelastic tissues in order to prevent further damage and to promote healing. It is suggested that a significant insight is gained as to the development and implications of a common idiopathic low back disorder as well as to the development of cumulative trauma disorders. PMID:12832168

  7. Functional Changes in the Snail Statocyst System Elicited by Microgravity

    PubMed Central

    Balaban, Pavel M.; Malyshev, Aleksey Y.; Ierusalimsky, Victor N.; Aseyev, Nikolay; Korshunova, Tania A.; Bravarenko, Natasha I.; Lemak, M. S.; Roshchin, Matvey; Zakharov, Igor S.; Popova, Yekaterina; Boyle, Richard

    2011-01-01

    Background The mollusk statocyst is a mechanosensing organ detecting the animal's orientation with respect to gravity. This system has clear similarities to its vertebrate counterparts: a weight-lending mass, an epithelial layer containing small supporting cells and the large sensory hair cells, and an output eliciting compensatory body reflexes to perturbations. Methodology/Principal Findings In terrestrial gastropod snail we studied the impact of 16- (Foton M-2) and 12-day (Foton M-3) exposure to microgravity in unmanned orbital missions on: (i) the whole animal behavior (Helix lucorum L.), (ii) the statoreceptor responses to tilt in an isolated neural preparation (Helix lucorum L.), and (iii) the differential expression of the Helix pedal peptide (HPep) and the tetrapeptide FMRFamide genes in neural structures (Helix aspersa L.). Experiments were performed 13–42 hours after return to Earth. Latency of body re-orientation to sudden 90° head-down pitch was significantly reduced in postflight snails indicating an enhanced negative gravitaxis response. Statoreceptor responses to tilt in postflight snails were independent of motion direction, in contrast to a directional preference observed in control animals. Positive relation between tilt velocity and firing rate was observed in both control and postflight snails, but the response magnitude was significantly larger in postflight snails indicating an enhanced sensitivity to acceleration. A significant increase in mRNA expression of the gene encoding HPep, a peptide linked to ciliary beating, in statoreceptors was observed in postflight snails; no differential expression of the gene encoding FMRFamide, a possible neurotransmission modulator, was observed. Conclusions/Significance Upregulation of statocyst function in snails following microgravity exposure parallels that observed in vertebrates suggesting fundamental principles underlie gravi-sensing and the organism's ability to adapt to gravity changes. This

  8. Xylaria hypoxylon Lectin as Adjuvant Elicited Tfh Cell Responses.

    PubMed

    Kang, J; Zuo, Y; Guo, Q; Wang, H; Liu, Q; Liu, Q; Xia, G; Kang, Y

    2015-11-01

    Foot-and-mouth disease (FMD) caused by FMD virus (FMDV) is a major health and economic problem in the farming industry. Vaccination of livestock against this highly infectious viral disease is crucial, and inactivated FMD vaccine has been effective at controlling infection. However, accumulated data show that the inactivated vaccine generates weak immune responses and that the oil formulation results in undesirable side effects. Mushroom lectins have recently been shown to display adjuvant effects when incorporated into DNA vaccines. In this study, to enhance the cellular immune response of FMDV antigen (146S), C57BL/6 mice were immunized with 146S combined with Xylaria hypoxylon lectin (XHL). The oil formulation (146S/Oil) was served as control group. Strong humoral immune responses were elicited in mice immunized with 146S/XHL as shown by high 146S antigen-specific IgG levels, and also in 146S/Oil group. Interestingly, XHL in conjunction with inactivated FMD vaccine activated strong Th1 and Tc1 cell responses, especially Tfh cell responses, in immunized mice. XHL stimulated dendritic cell maturation by upregulating expression of major histocompatibility complex II (MHCII) molecules and co-stimulatory molecules CD40 and CD86 in immunized mice. No XHL-specific IgG or inflammatory factors were detected indicating the safety of XHL as an adjuvant. Taken together, these results suggest the effectiveness of XHL at inducing cellular immune responses and therefore confirm its suitability as an adjuvant for inactivated FMD vaccine. PMID:26289530

  9. What monitor can replace the cathode-ray tube for visual stimulation to elicit multifocal electroretinograms?

    PubMed

    Matsumoto, Celso Soiti; Shinoda, Kei; Matsumoto, Harue; Seki, Keisuke; Nagasaka, Eiichiro; Iwata, Takeshi; Mizota, Atsushi

    2014-01-01

    To compare a conventional cathode-ray tube (CRT) screen to organic light-emitting diode (OLED) and liquid crystal display (LCD) screens as visual stimulators to elicit multifocal electroretinograms (mfERGs), mfERGs were recorded from seven eyes of seven healthy volunteers (21 ± 2 years). The mfERGs elicited by a conventional CRT screen (S710, Compaq Computer Co.) were compared to those elicited by a studio-grade master OLED monitor (PVM-1741, Sony, Japan) and a conventional LCD (S1721, Flexscan, Eizo Nanao Corp., Japan). The luminance changes of each monitor were measured with a photodiode. CRT, OLED, and LCD screens with a frame frequency of 60 Hz were studied. A hexagonal stimulus array with 61 stimulus elements was created on each monitor. The serial white stimuli of the OLED screen at 60 Hz did not fuse, and that of the LCD screens fused. The amplitudes of P1 and P2 of the first-order kernels of the mfERGs were not significantly different from those elicited by the CRT and OLED screens, and the P1 amplitude of the first-order kernel elicited by the LCD stimuli was significantly smaller than that elicited by the CRT in all the groups of the averaged hexagonal elements. The implicit times were approximately 10 ms longer in almost all components elicited by the LCD screen compared to those elicited by the CRT screen. The mfERGs elicited by monitors other than the CRT should be carefully interpreted, especially those elicited by LCD screens. The OLED had good performance, and we conclude that it can replace the CRT as a stimulator for mfERGs; however, a collection of normative data is recommended. PMID:25096155

  10. Non-oscillatory discharges of an F-prostaglandin responsive neuron population in the olfactory bulb-telencephalon transition area in lake whitefish.

    PubMed

    Laberge, F; Hara, T J

    2003-01-01

    Our previous studies on olfactory bulbar responses in salmonid fishes suggest that pheromone signals might be processed by a mechanism distinct from that of other odorants. Using in vivo single-unit and electroencephalographic recordings, we investigated response characteristics of olfactory neurons in lake whitefish, Coregonus clupeaformis, a species characterized by high electrophysiological and behavioral sensitivities to the reproductive pheromone candidates F-prostaglandins. We found a neuron population responsive to F-prostaglandins in the ventromedial brain tissue strip connecting the olfactory bulb to the telencephalon. Of the 64 neurons examined in this area, 33% showed excitatory and 11% inhibitory responses to F-prostaglandins, while 52% were non-responsive to all the stimuli tested. Both phasic and tonic F-prostaglandin neuron response patterns were observed during the 10-s stimulus period; some responses were delayed from the onset of stimulation, and some persisted for a long time following stimulus cessation. This neuron population did not induce synchronized oscillatory waves upon stimulation with F-prostaglandins, despite massive discharges. We demonstrate for the first time that the olfactory bulb-telencephalon area of the brain is a distinct neural structure through which putative reproductive pheromone signals are integrated. Amino acid and F-prostaglandin neuron population discharges have different temporal characteristics, suggesting different processing mechanisms exist for odorant and pheromone signals. The observed sustained neuron discharges may play a role in amplifying pheromone signals required for triggering stereotyped neuroendocrine and/or behavior changes. PMID:12617950

  11. Protective effect of (±)α-tocopherol on brominated diphenyl ether-47-stimulated prostaglandin pathways in human extravillous trophoblasts in vitro.

    PubMed

    Park, Hae-Ryung; Loch-Caruso, Rita

    2015-10-01

    Brominated diphenyl ether (BDE)-47 is a prevalent flame retardant chemical found in human tissues and is linked to adverse pregnancy outcomes in humans. Because dysregulation of the prostaglandin pathway is implicated in adverse pregnancy outcomes, the present study investigates BDE-47 induction of prostaglandin synthesis in a human extravillous trophoblast cell line, HTR-8/SVneo, examining the hypothesis that BDE-47 increases generation of reactive oxygen species (ROS) to stimulate the prostaglandin response. Treatment with 20 μM BDE-47 significantly increased mRNA expression of prostaglandin-endoperoxide synthase 2 (PTGS2) at 4, 12 and 24 h, and 24-h treatment significantly increased cyclooxygenase (COX)-2 cellular protein expression and prostaglandin E2 (PGE2) concentration in culture medium. The BDE-47-stimulated PGE2 release was inhibited by the COX inhibitors indomethacin and NS398, implicating COX activity. Exposure to 20 μM BDE-47 significantly increased ROS generation as measured by carboxydichlorofluorescein fluorescence, and this response was blocked by cotreatment with the peroxyl radical scavenger (±)-α-tocopherol. (±)-α-Tocopherol cotreatment suppressed BDE-47-stimulated increases of PGE2 release without significant effects on COX-2 mRNA and protein expression, implicating a role for ROS in post-translational regulation of COX activity. Because prostaglandins regulate trophoblast functions necessary for placentation and pregnancy, further investigation is warranted of BDE-47 impacts on trophoblast responses. PMID:26026498

  12. Cyclooxygenases and prostaglandin E2 receptors in growth plate chondrocytes in vitro and in situ--prostaglandin E2 dependent proliferation of growth plate chondrocytes.

    PubMed

    Brochhausen, Christoph; Neuland, Pia; Kirkpatrick, C James; Nüsing, Rolf M; Klaus, Günter

    2006-01-01

    Prostaglandin E2 (PGE2) plays an important role in bone development and metabolism. To interfere therapeutically in the PGE2 pathway, however, knowledge about the involved enzymes (cyclooxygenases) and receptors (PGE2 receptors) is essential. We therefore examined the production of PGE2 in cultured growth plate chondrocytes in vitro and the effects of exogenously added PGE2 on cell proliferation. Furthermore, we analysed the expression and spatial distribution of cyclooxygenase (COX)-1 and COX-2 and PGE2 receptor types EP1, EP2, EP3 and EP4 in the growth plate in situ and in vitro. PGE2 synthesis was determined by mass spectrometry, cell proliferation by DNA [3H]-thymidine incorporation, mRNA expression of cyclooxygenases and EP receptors by RT-PCR on cultured cells and in homogenized growth plates. To determine cellular expression, frozen sections of rat tibial growth plate and primary chondrocyte cultures were stained using immunohistochemistry with polyclonal antibodies directed towards COX-1, COX-2, EP1, EP2, EP3, and EP4. Cultured growth plate chondrocytes transiently secreted PGE2 into the culture medium. Although both enzymes were expressed in chondrocytes in vitro and in vivo, it appears that mainly COX-2 contributed to PGE2-dependent proliferation. Exogenously added PGE2 stimulated DNA synthesis in a dose-dependent fashion and gave a bell-shaped curve with a maximum at 10-8 M. The EP1/EP3 specific agonist sulprostone and the EP1-selective agonist ONO-D1-004 increased DNA synthesis. The effect of PGE2 was suppressed by ONO-8711. The expression of EP1, EP2, EP3, and EP4 receptors in situ and in vitro was observed; EP2 was homogenously expressed in all zones of the growth plate in situ, whereas EP1 expression was inhomogenous, with spared cells in the reserve zone. In cultured cells these four receptors were expressed in a subset of cells only. The most intense staining for the EP1 receptor was found in polygonal cells surrounded by matrix. Expression of

  13. Efficacy and tolerability of brinzolamide/brimonidine suspension and prostaglandin analogs in patients previously treated with dorzolamide/timolol solution and prostaglandin analogs

    PubMed Central

    Lo, Jonathan S; Pang, Pierre M; Lo, Samuel C

    2016-01-01

    Objective Fixed combination glaucoma medication is increasingly used in glaucoma treatment. There is a lack of comparative study in the literature of non-beta blocker combination agents used adjunctively with a glaucoma agent in a different class. The objective of this study is to evaluate the effect of intraocular pressure (IOP) control and tolerability of non-beta blocker combination suspension with prostaglandin analogs (PGA) in patients with open angle glaucoma who were previously treated with beta blocker combination solution with PGA. Design Open-label retrospective review of patient records. Patients and methods This study looked at patients with open angle glaucoma taking dorzolamide/timolol solution with PGA that were switched to brinzolamide/brimonidine combination suspension with PGA. This study reviewed the charts of all patients who were at least 21 years old with a clinical diagnosis of open-angle glaucoma or ocular hypertension in at least one eye. Patients needed to have been treated with concomitant use of PGA and dorzolamide/timolol solution for at least one month. Patients using dorzolamide/timolol solution plus PGA with medication related ocular irritation were switched to brinzolamide/brimonidine suspension with the same PGA. Best-corrected visual acuity, ocular hyperemia grading, slit lamp biomicroscopy and Goldmann applanation tonometry measurements, and patient medication preferences were assessed at baseline, 1 month and 3 months. Results Forty eyes with open angle glaucoma. The mean age of the patients was 68 and 60% were females. The IOP before the switch was 17.2 and 16.5 (P=0.70) following the switch at 3 months. We found a decreasing trend of ocular hyperemia (P=0.064) and strong preference (P=0.011) for non-beta blocker combination suspension but no difference of visual acuity and slit lamp findings. Conclusion Brinzolamide/brimonidine combination suspension when used adjunctively with PGA is equally effective. Patients in this study

  14. Prostaglandins in the brain of rats given, acutely, and chronically, a hyperthermic dose of met-enkephalin.

    PubMed

    Scoto, G M; Spadaro, C; Spampinato, S; Arrigo-Reina, R; Ferri, S

    1979-01-31

    An enhanced prostaglandinlike activity is shown in homogenates of brain from rats treated intracerebroventricularly with 100 microgram of metenkephalin. The increase is significantly reduced by naloxone pretreatment. A relationship is proposed between generation of prostaglandins in the brain following met-enkephalin administration and hyperthermic effect of the opiatelike factor in the rat. Normalization of prostaglandinlike activity following chronic administration of met-enkephalin in the rat may also account for the development of tolerance to its thermic effect. PMID:106433

  15. Identification of prostaglandin E2 and leukotriene B4 in the synovial fluid of painful, dysfunctional temporomandibular joints.

    PubMed

    Quinn, J H; Bazan, N G

    1990-09-01

    It has been hypothesized that prostaglandin E2 (PGE2) and leukotriene B4 (LTB4) should be present in the synovial fluid of inflamed, dysfunctional temporomandibular joints. An assay to identify PGE2 and LTB4 and platelet-activating factor (PAF) was used, and a strong correlation between the levels of these lipid mediators of pain and inflammation and an index of clinical joint pathology was found. PMID:2168477

  16. Topography of prostaglandin H synthase. Antiinflammatory agents and the protease-sensitive arginine 253 region.

    PubMed

    Kulmacz, R J

    1989-08-25

    Prostaglandin H synthase catalyzes two reactions: the bis-dioxygenation of arachidonic acid to form prostaglandin G2 (cyclooxygenase activity), and the reduction of hydroperoxides to the corresponding alcohols (peroxidase activity). The cyclooxygenase activity can be selectively inhibited by many nonsteroidal antiinflammatory agents including indomethacin. In the native synthase, there is a single prominent protease-sensitive region, located near Arg253; binding of the heme prosthetic group makes the synthase resistant to proteases. To investigate the spatial relationship between the area of the synthase which interacts with indomethacin and the protease-sensitive region, the effects of indomethacin and similar agents on the protease sensitivity of the two enzymatic activities and of the synthase polypeptide were examined. Incubation of the synthase apoenzyme with trypsin (3.6% w/w) resulted in the time-dependent coordinate loss (75% at 1 h) of both enzymatic activities and the cleavage (85% at 1 h) of the 70-kDa subunit into 38- and 33-kDa fragments, indicating that proteolytic cleavage of the polypeptide at Arg253, destroyed both activities of the synthase simultaneously. Indomethacin, (S)-flurbiprofen, or meclofenamate (each at 20 microM) rendered both activities and the synthase polypeptide (at 5 microM subunit) resistant to attack by trypsin or proteinase K; these agents also inhibited the cyclooxygenase activity of the intact synthase. Two reversible cyclooxygenase inhibitors, ibuprofen and flufenamate, also made both of the activities and the synthase polypeptide more resistant to trypsin. Titration of the apoenzyme with indomethacin (0-3 mol/mol of synthase dimer) resulted in proportional increases in the inhibition of the cyclooxygenase and in the resistance to attack by trypsin. (R)-Flurbiprofen did not increase the resistance to protease or appreciably inhibit the cyclooxygenase. These results suggest that the same stereospecific interaction of these

  17. Activation of prostaglandin EP receptors by lubiprostone in rat and human stomach and colon

    PubMed Central

    Bassil, A K; Borman, R A; Jarvie, E M; McArthur-Wilson, R J; Thangiah, R; Sung, E Z H; Lee, K; Sanger, G J

    2008-01-01

    Background and purpose: Lubiprostone (Amitiza), a possible ClC-2 channel opener derived from prostaglandin E1 and indicated for the treatment of constipation, increases chloride ion transport and fluid secretion into the intestinal lumen. As lubiprostone may also directly modulate gastrointestinal motility, we investigated its actions and the possible involvement of prostaglandin EP receptor activation on rat and human isolated gastrointestinal preparations. Experimental approach: Rat and human isolated preparations were mounted in tissue baths for isometric recording. The effects of lubiprostone on muscle tension and on electrically stimulated, neuronal contractions were investigated in the absence and presence of EP receptor antagonists. Key results: In rat and human stomach longitudinal muscle, lubiprostone induced a contraction (pEC50 of 7.0±0.0, n=4 and 6.4±0.2, n=3, respectively), which was inhibited by pretreatment with the EP1 receptor antagonist, EP1A 300 nM (pEC50 reduced to 6.2±0.2, n=6), but not by the EP3 or EP4 receptor antagonists (L-798106 and GW627368X, respectively, 1 μM, P>0.05). Lubiprostone also reduced electrically stimulated, neuronal contractions in rat and human colon circular muscle preparations (pIC50 of 8.9±0.4, n=7 and 8.7±0.9, n=6, respectively), an effect mediated pre-junctionally. This effect was reduced by the EP4 receptor antagonist (pIC50 of 6.7±1.1, n=7 and 7.7±0.4, n=6, respectively) but not by EP1 or EP3 receptor antagonists. Conclusions and implications: In rats and humans, lubiprostone contracts stomach longitudinal muscle and inhibits neuronally mediated contractions of colon circular muscle. Experiments are now needed to determine if this additional activity of lubiprostone contributes to its clinical efficacy and/or side-effect profile. PMID:18332851

  18. Defective secretion of Prostaglandin F2α during development of idiopathic persistent corpus luteum in mares.

    PubMed

    Ginther, O J; Castro, T; Baldrighi, J M; Wolf, C A; Santos, V G

    2016-04-01

    Five mares that developed idiopathic persistent corpus luteum (PCL) were compared with 5 mares with apparently normal interovulatory intervals (IOIs). Progesterone (P4) and a metabolite of prostaglandin F2α (PGFM) were assayed daily beginning on the day of ovulation (Day 0). Transition between the end of an initial progressive P4 increase and the beginning of a gradual decrease in P4 occurred on mean Day 6. The gradual decrease in P4 between Days 6 and 12 was less (approached significance, P < 0.06) in the PCL group than in the IOI group. The P4 concentration on Day 12 (before luteolysis in IOI group) was greater (P < 0.05) in the PCL group than in the IOI group. In a post hoc comparison, an interaction (P < 0.04) of group by day for Days 4 to 7 indicated that the end of the progressive increase in P4 was temporally associated with a transient increase in concentration of PGFM in IOI mares but not in PCL mares. Complete luteolysis (P4 < 1 ng/mL) occurred in the IOI mares on Days 13 to 15. Partial luteolysis (mean P4 decrease, 62%) occurred in 3 of the 5 PCL mares. Normalization to the day at the end of the most pronounced P4 decrease in the IOI mares and in the 3 PCL mares with partial luteolysis resulted in a day-by-group interaction (P < 0.05) for PGFM concentration. The interaction was partly from lower PGFM concentration on the day at the end of the pronounced P4 decrease in the 3 PCL mares than in the IOI mares. The peak of a transient PGFM increase and the day at the end of the most pronounced decrease in P4 were synchronized in each IOI mare but not in any of the 3 PCL mares. In the other 2 PCL mares, partial luteolysis did not occur, and a transient increase in PGFM was not apparent. Results tentatively indicated that the relationship between P4 and PGFM may be altered as early as Day 6 in PCL mares and supported the hypothesis that prostaglandin F2α secretion is defective in mares with idiopathic PCL. PMID:26773369

  19. Prostaglandins can modify gamma-radiation and chemical induced cytotoxicity and genetic damage in vitro and in vivo.

    PubMed

    Das, U N; Ramadevi, G; Rao, K P; Rao, M S

    1989-12-01

    The effect of prostaglandin E1, E2, and F2 alpha on gamma-radiation, benzo(a)pyrene and diphenylhydantoin-induced cytotoxicity in vivo and genotoxicity in vitro was investigated. Prostaglandin E1 prevented both cytotoxic and genotoxic actions of all the three agents, where as both PGE2 and PGF2 alpha were ineffective. In fact, it was seen that both PGE2 and PGF2 alpha are genotoxic by themselves. Gamma-linolenic acid and dihomogamma-linolenic acid, the precursor of PGE1 were also as protective as that of PGE1, where as arachidonic acid, the precursor of 2 series PGs, has genotoxic actions to human lymphocytes in vitro. These results suggest that prostaglandins and their precursors can determine the susceptibility of cells to cytotoxic and genotoxic actions of chemicals and radiation. This study is particularly interesting since, it is known that some tumor cells contain excess of PGE2 and PGF2 alpha and many carcinogens can augment the synthesis of 2 series of PGs. PMID:2633211

  20. The Prostaglandin Transporter: Eicosanoid Reuptake, Control of Signaling, and Development of High-Affinity Inhibitors as Drug Candidates

    PubMed Central

    Schuster, Victor L.; Chi, Yuling; Lu, Run

    2015-01-01

    We discovered the prostaglandin transporter (PGT) and cloned the human cDNA and gene. PGT transports extracellular prostaglandins (PGs) into the cytoplasm for enzymatic inactivation. PGT knockout mice have elevated prostaglandin E2 (PGE2) and neonatal patent ductus arteriosus, which reflects PGT's control over PGE2 signaling at EP1/EP4 cell-surface receptors. Interestingly, rescued PGT knockout pups have a nearly normal phenotype, as do human PGT nulls. Given the benign phenotype of PGT genetic nulls, and because PGs are useful medicines, we have approached PGT as a drug target. Triazine library screening yielded a lead compound of inhibitory constant 50% (IC50) = 3.7 μM, which we developed into a better inhibitor of IC50 378 nM. Further structural improvements have yielded 26 rationally designed derivatives with IC50 < 100 nM. The therapeutic approach of increasing endogenous PGs by inhibiting PGT offers promise in diseases such as pulmonary hypertension and obesity. PMID:26330684