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Sample records for enhances prostaglandin e2

  1. Nasopharyngeal prostaglandin E(2) in infant bronchiolitis.

    Science.gov (United States)

    Griggs, Kim M; Forsyth, Kevin D; Dixon, Dani-Louise

    2011-12-01

    The mechanism by which severe bronchiolitis can result in the development of recurrent childhood wheeze is unclear. However, mucosal inflammation and immune activation may play a major role. Prostaglandin (PG) E(2) has been highlighted as a possible therapeutic target for both the treatment of bronchiolitis and the prevention of subsequent airway hyperresponsiveness. The aim of this pilot study was to examine PGE(2) in the airways of infants hospitalised with bronchiolitis. Nasopharyngeal aspirates (NPA) were collected from 18 infants within 12 hours of admission and assayed by enzyme immunoassays for PGE(2), interleukin (IL)-10, and IL-12, as well as cyclooxygenase (COX) 1 and 2 activity. NPA PGE(2) concentration correlated with length of illness preadmission, but was not related to disease severity, causal virus, or IL-10. NPA COX 1 and 2 activity and IL-12 were all below the level of detection. Neither NPA PGE(2) nor disease severity was related to development of recurrent wheeze over 3 years following bronchiolitis. These data suggest that nasopharygeal PGE(2) at hospital admission may be neither directly causal or diagnostic of severity of infant bronchiolitis, or prognostic of development of recurrent wheeze. However, large-cohort temporal examinations are required to adequately define this mediator as a therapeutic target for bronchiolitis.

  2. Inhibition of Nitric Oxide and Prostaglandin E 2 Expression by ...

    African Journals Online (AJOL)

    Inhibition of Nitric Oxide and Prostaglandin E 2 Expression by Methanol Extract of Polyopes affinis in Lipopolysaccharide-stimulated BV2 Microglial Cells through Suppression of Akt-dependent NF-kB Activity and MAPK Pathway.

  3. The bronchodilators 8-iso-prostaglandin E2 and prostaglandin E2 induce K+ current suppression via thromboxane A2 receptors in porcine tracheal smooth muscle.

    Science.gov (United States)

    Helli, Peter B; Catalli, Adriana; Janssen, Luke J

    2004-10-06

    We examined relaxations and changes in K(+) current evoked by 8-iso-prostaglandin E(2) and prostaglandin E(2) in porcine tracheal smooth muscle. Both autacoids completely reversed cholinergic tone; blockade of thromboxane A(2) receptors had no effect on relaxations to either compound. 8-iso-prostaglandin E(2) and prostaglandin E(2) suppressed outward K(+) currents while the thromboxane A(2) receptor agonist U46619 (9, 11-dideoxy-9a,11a-methanoepoxy prostaglandin F(2alpha)) had no significant effect. During thromboxane A(2) receptor antagonism, however, 8-iso-prostaglandin E(2) markedly augmented K(+) currents while prostaglandin E(2) no longer suppressed K(+) currents, indicating that the inhibition of K(+) currents by both compounds was thromboxane A(2) receptor-mediated. Furthermore, the observation that K(+) currents were augmented by 8-iso-prostaglandin E(2) but not by prostaglandin E(2) suggests that the salutory effect is not exerted through a prostaglandin E receptor. Additionally, our observations argue against any causal role for K(+) current activation in mediating relaxations evoked by isoprostanes or by prostaglandin E(2). We conclude that 8-iso-prostaglandin E(2) relaxes porcine tracheal smooth muscle independent of K(+) current activity, and that 8-iso-prostaglandin E(2) may also act at a non-thromboxane A(2)/non-prostaglandin E receptor to augment K(+) currents.

  4. Prostaglandin E2 Receptor Expression by Osteoblasts is Modulated by Implant Surface Roughness and Prostaglandin E2

    Science.gov (United States)

    2006-05-01

    CAPT CAMPBELL CASEY M 7. PERFORMING ORGANIZATION NAME(S) AND ADDRESS(ES) 8. PERFORMING ORGANIZATION UNIVERSITY OF TEXAS HSC AT SAN ANTONIO REPORT...Analysis, 4. Verlag Chemica , Weinheim, 65-92. Breyer RM, Bagdassarian CK, Myers SA, Breyer MD (2001): Prostanoid receptors: subtypes and signaling...prostaglandin E2 in organ culture. Prostaglandins 8:377-385. Sabbieti MG, Marchetti L, Abreu C, Montero A, Hand AR, Raisz LG, Hurley MM (1999

  5. MiR-31-5p-ACOX1 Axis Enhances Tumorigenic Fitness in Oral Squamous Cell Carcinoma Via the Promigratory Prostaglandin E2.

    Science.gov (United States)

    Lai, Yi-Hsuan; Liu, Hsuan; Chiang, Wei-Fan; Chen, Ting-Wen; Chu, Lichieh Julie; Yu, Jau-Song; Chen, Shu-Jen; Chen, Hua-Chien; Tan, Bertrand Chin-Ming

    2018-01-01

    During neoplastic development, a multitude of changes in genome-encoded information are progressively selected to confer growth and survival advantages to tumor cells. microRNAs-mRNAs regulatory networks, given their role as a critical layer of robust gene expression control, are frequently altered in neoplasm. However, whether and how these gene perturbations impact metabolic homeostasis remains largely unresolved. Methods: Through targeted miRNA expression screening, we uncovered an oral squamous cell carcinoma (OSCC)-associated miRNAome, among which miR-31-5p was identified based on extent of up-regulation, functional impact on OSCC cell migration and invasion, and direct regulation of the rate-limiting enzyme in peroxisomal β-oxidation, ACOX1. Results: We further found that both miR-31-5p and ACOX1 underpin, in an antagonistic manner, the overall cellular lipidome profiles as well as the migratory and invasive abilities of OSCC cells. Interestingly, the extracellular levels of prostaglandin E2 (PGE2), a key substrate of ACOX1, were controlled by the miR-31-5p-ACOX1 axis, and were shown to positively influence the extent of cell motility in correlation with metastatic status. The promigratory effect of this metabolite was mediated by an elevation in EP1-ERK-MMP9 signaling. Of note, functional significance of this regulatory pathway was further corroborated by its clinicopathologically-correlated expression in OSCC patient specimens. Conclusions: Collectively, our findings outlined a model whereby misregulated miR-31-5p-ACOX1 axis in tumor alters lipid metabolomes, consequently eliciting an intracellular signaling change to enhance cell motility. Our clinical analysis also unveiled PGE2 as a viable salivary biomarker for prognosticating oral cancer progression, further underscoring the importance of lipid metabolism in tumorigenesis.

  6. Prostaglandin E2(PGE2) induces headache in healthy subjects

    DEFF Research Database (Denmark)

    Wienecke, T; Olesen, Jes; Oturai, P S

    2009-01-01

    The role of prostanoids in nociception is well established. The headache-eliciting effects of prostaglandin E(2) (PGE(2)) and its possible mechanisms have previously not been systematically studied in man. We hypothesized that infusion of PGE(2) might induce headache and vasodilation of cranial...

  7. Inhibition of Nitric Oxide and Prostaglandin E2 Expression by ...

    African Journals Online (AJOL)

    HP

    Purpose: To determine whether the methanol extract of Polyopes affinis (MEPA) down-regulates the expression of pro-inflammatory mediators in lipopolysaccharide (LPS)-stimulated BV2 microglial cells. Methods: The production of nitric oxide (NO) and prostaglandin E2 (PGE2) was measured by the Griess reagents and ...

  8. Prenatal exposure to the organophosphate insecticide chlorpyrifos enhances brain oxidative stress and prostaglandin E2 synthesis in a mouse model of idiopathic autism.

    Science.gov (United States)

    De Felice, Alessia; Greco, Anita; Calamandrei, Gemma; Minghetti, Luisa

    2016-06-14

    Autism spectrum disorders (ASD) are emerging as polygenic and multifactorial disorders in which complex interactions between defective genes and early exposure to environmental stressors impact on the correct neurodevelopment and brain processes. Organophosphate insecticides, among which chlorpyrifos (CPF), are widely diffused environmental toxicants associated with neurobehavioral deficits and increased risk of ASD occurrence in children. Oxidative stress and dysregulated immune responses are implicated in both organophosphate neurodevelopmental effects and ASD etiopathogenesis. BTBR T+tf/J mice, a well-studied model of idiopathic autism, show several behavioral and immunological alterations found in ASD children, and we recently showed that CPF gestational exposure strengthened some of these autistic-like traits. In the present study, we aimed at investigating whether the behavioral effects of gestational CPF administration are associated with brain increased oxidative stress and altered lipid mediator profile. Brain levels of F2-isoprostanes (15-F2t-IsoP), as index of in vivo oxidative stress, and prostaglandin E2 (PGE2), a major arachidonic acid metabolite released by immune cells and by specific glutamatergic neuron populations mainly in cortex and hippocampus, were assessed by specific enzyme-immuno assays in brain homogenates from BTBR T+tf/J and C57Bl6/J mice, exposed during gestation to either vehicle or CPF. Measures were performed in mice of both sexes, at different postnatal stages (PNDs 1, 21, and 70). At birth, BTBR T+tf/J mice exhibited higher baseline 15-F2t-IsoP levels as compared to C57Bl6/J mice, suggestive of greater oxidative stress processes. Gestational treatment with CPF-enhanced 15-F2t-IsoP and PGE2 levels in strain- and age-dependent manner, with 15-F2t-IsoP increased in BTBR T+tf/J mice at PNDs 1 and 21, and PGE2 elevated in BTBR T+tf/J mice at PNDs 21 and 70. At PND 21, CPF effects were sex-dependent being the increase of the two

  9. Prostaglandin E2 Regulation of Chondrocyte Proliferation and Differentiation

    Science.gov (United States)

    1994-05-01

    the period of bone remodeling (18 . A different limb immobilization study in dogs utilized aspirin, 75 mg/kg/day for four weeks and found that aspirin...for alveolar bone augmentation in dogs (123,124). In these studies, significant increases in new bone formation was seen in a dose-dependent manner...Levine, P. Goldhaber. 1972. Evidence that the bone resorption stimulating factor produced by mouse fibrosarcoma cells is prostaglandin E2. J. Exp. Med

  10. Bone formation induced in an infant by systemic prostaglandin-E2 administration

    DEFF Research Database (Denmark)

    Jørgensen, H R; Svanholm, H; Høst, A

    1988-01-01

    We report a case of long-term systemic administration of prostaglandin E2 (PGE2) to a newborn infant with ductus-dependent congenital heart disease. After 46 days of treatment, radiography showed cortical hyperostosis of the long bones. The child died 62 days after discontinuation of prostaglandi...

  11. Estradiol-17β, prostaglandin E2 (PGE2) and the prostaglandin E2 receptor are involved in PGE2 positive feedback loop in the porcine endometrium

    OpenAIRE

    Waclawik, Agnieszka; Jabbour, Henry N.; Blitek, Agnieszka; Ziecik, Adam J.

    2009-01-01

    Before implantation, the porcine endometrium and trophoblast synthesize elevated amounts of luteoprotective prostaglandin E2 (PGE2). We hypothesized that embryo signal, estradiol-17β (E2) and PGE2 modulate expression of key enzymes in PG synthesis: prostaglandin-endoperoxide synthase-2 (PTGS2), PGE synthase (mPGES-1), PGF synthase (PGFS), and prostaglandin 9-ketoreductase (CBR1); as well as PGE2 receptor (PTGER2 and 4) expression and signaling within the endometrium. We determinated the site ...

  12. Estradiol-17β, prostaglandin E2 (PGE2) and the prostaglandin E2 receptor are involved in PGE2 positive feedback loop in the porcine endometrium

    Science.gov (United States)

    Waclawik, Agnieszka; Jabbour, Henry N.; Blitek, Agnieszka; Ziecik, Adam J.

    2009-01-01

    Before implantation, the porcine endometrium and trophoblast synthesize elevated amounts of luteoprotective prostaglandin E2 (PGE2). We hypothesized that embryo signal, estradiol-17β (E2) and PGE2 modulate expression of key enzymes in PG synthesis: prostaglandin-endoperoxide synthase-2 (PTGS2), PGE synthase (mPGES-1), PGF synthase (PGFS), and prostaglandin 9-ketoreductase (CBR1); as well as PGE2 receptor (PTGER2 and 4) expression and signaling within the endometrium. We determinated the site of action of PGE2 in endometrium during the estrous cycle and pregnancy. Endometrial tissue explants obtained from gilts (n=6) on days 11-12 of the estrous cycle were treated with vehicle (control), PGE2 (100 nM), E2 (1-100 nM) or phorbol 12-myristate 13-acetate (100 nM, positive control). E2 increased PGE2 secretion through elevating expression of mPGES-1 mRNA and PTGS2 and mPGES-1 protein in endometrial explants. By contrast, E2 decreased PGFS and CBR1 protein expression. E2 also stimulated PTGER2 but not PTGER4 protein content. PGE2 enhanced mPGES-1 and PTGER2 mRNA as well as PTGS2, mPGES-1 and PTGER2 protein expression. PGE2 had no effect on PGFS, CBR1 and PTGER4 expression and PGF2α release. Treatment of endometrial tissue with PGE2 increased cAMP production. Co-treatment with PTGER2 antagonist (AH6809) but not PTGER4 antagonist (GW 627368X) inhibited significantly PGE2-mediated cAMP production. PTGER2 protein was localized in luminal and glandular epithelium and blood vessels of endometrium, and was significantly up-regulated on days 11-12 of pregnancy. Our results suggest that E2, prevents luteolysis through enzymatic modification of PG synthesis and that E2, PGE2 and endometrial PTGER2 are involved in PGE2 positive feedback loop in porcine endometrium. PMID:19359378

  13. Prostaglandin-E2: a point of divergence in estradiol-mediated sexual differentiation.

    Science.gov (United States)

    Todd, Brigitte J; Schwarz, Jaclyn M; McCarthy, Margaret M

    2005-12-01

    The preoptic area of the mammalian forebrain is a critical substrate for the development and maintenance of many sexually dimorphic behaviors relevant to reproduction. Normal development of the male rodent brain requires completion of two processes: (1) masculinization-induction of the male phenotype, and (2) defeminization-removal of the female phenotype. Both processes, although distinct, are largely directed by the same steroid, estradiol. Whether estradiol achieves both ends via the same or separate mechanisms has been unknown. Here, we report that prostaglandin-E(2) (PGE(2)) acting downstream of estradiol, is necessary and sufficient to masculinize sexual behavior but does not affect defeminization of sexual behavior or maternal behavior. Moreover, the volume of the sexually dimorphic nucleus of the preoptic area predicts defeminization of sexual behavior, but not masculinization of sexual behavior. Another sexually dimorphic cellular endpoint regulated by estradiol, spinophilin protein expression in the mediobasal hypothalamus, was not affected by PGE(2). Thus, PGE(2) is a key divergence point in the downstream actions of estradiol to simultaneously masculinize and defeminize sexual behavior.

  14. Immune challenge by intraperitoneal administration of lipopolysaccharide directs gene expression in distinct blood-brain barrier cells toward enhanced prostaglandin E(2) signaling.

    Science.gov (United States)

    Vasilache, Ana Maria; Qian, Hong; Blomqvist, Anders

    2015-08-01

    The cells constituting the blood-brain barrier are critical for the transduction of peripheral immune signals to the brain, but hitherto no comprehensive analysis of the signaling events that occur in these cells in response to a peripheral inflammatory stimulus has been performed. Here, we examined the inflammatory transcriptome in blood-brain barrier cells, including endothelial cells, pericytes, and perivascular macrophages, which were isolated by fluorescent-activated cell sorting, from non-immune-challenged mice and from mice stimulated by bacterial wall lipopolysaccharide. We show that endothelial cells and perivascular macrophages display distinct transcription profiles for inflammatory signaling and respond in distinct and often opposing ways to the immune stimulus. Thus, endothelial cells show induced PGE2 synthesis and transport with attenuation of PGE2 catabolism, increased expression of cytokine receptors and down-stream signaling molecules, and downregulation of adhesion molecules. In contrast, perivascular macrophages show downregulation of the synthesis of prostanoids other than PGE2 and of prostaglandin catabolism, but upregulation of interleukin-6 synthesis. Pericytes were largely unresponsive to the immune stimulation, with the exception of downregulation of proteins involved in pericyte-endothelial cell communication. While the endothelial cells account for most of the immune-induced gene expression changes in the blood-brain barrier, the response of the endothelial cells occurs in a concerted manner with that of the perivascular cells to elevate intracerebral levels of PGE2, hence emphasizing the critical role of PGE2 in immune-induced signal transduction across the blood-brain barrier. Copyright © 2015 Elsevier Inc. All rights reserved.

  15. Prostaglandin I2 and Prostaglandin E2 Modulate Human Intrarenal Artery Contractility Through Prostaglandin E2-EP4, Prostacyclin-IP, and Thromboxane A2-TP Receptors

    DEFF Research Database (Denmark)

    Eskildsen, Morten P; Hansen, Pernille B L; Stubbe, Jane

    2014-01-01

    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......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...... 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...

  16. Helicobacter pylori VacA enhances prostaglandin E2 production through induction of cyclooxygenase 2 expression via a p38 mitogen-activated protein kinase/activating transcription factor 2 cascade in AZ-521 cells

    DEFF Research Database (Denmark)

    Hisatsune, Junzo; Yamasaki, Eiki; Nakayama, Masaaki

    2007-01-01

    Treatment of AZ-521 cells with Helicobacter pylori VacA increased cyclooxygenase 2 (COX-2) mRNA in a time- and dose-dependent manner. A p38 mitogen-activated protein kinase (MAPK) inhibitor, SB203580, blocked elevation of COX-2 mRNA levels, whereas PD98059, which blocks the Erk1/2 cascade......A-induced COX-2 expression. In parallel with COX-2 expression, VacA increased prostaglandin E(2) (PGE(2)) production, which was inhibited by SB203580 and NS-398, a COX-2 inhibitor. VacA-induced PGE(2) production was markedly attenuated in AZ-521 cells stably expressing DN-p38. VacA increased transcription...... promoter activation. The reduction of ATF-2 expression in AZ-521 cells transformed with ATF-2-small interfering RNA duplexes resulted in suppression of COX-2 expression. Thus, VacA enhances PGE(2) production by AZ-521 cells through induction of COX-2 expression via the p38 MAPK/ATF-2 cascade, leading...

  17. Decreased levels of salivary prostaglandin E2 and epidermal growth factor in recurrent aphthous stomatitis.

    Science.gov (United States)

    Wu-Wang, C Y; Patel, M; Feng, J; Milles, M; Wang, S L

    1995-12-01

    Prostaglandin E2 and epidermal growth factor are two important cytoprotective compounds in saliva. This study investigated their salivary levels in controls and individuals with minor recurrent aphthous stomatitis. The development of recurrent aphthous stomatitis was divided into three stages: (1) early active stage (mucosal redness); (2) active stage (mucosal ulceration); (3) convalescent stage. Unstimulated mixed saliva was collected from each volunteer. Salivary prostaglandin E2 and epidermal growth factor concentrations were determined by radioimmunoassay. Their levels (mean +/- SEM) were significantly lower during the active stage of ulceration as compared to the control: (a) for prostaglandin E2, 200 +/- 55 versus 73 +/- 11 pg/mg salivary protein (p stomatitis. The prostaglandin E2 concentration decreased significantly during the active stage of ulceration, and then increased significantly during the convalescent stage. However, the recovery of salivary epidermal growth factor after the ulceration was slower than that of the prostaglandin E2. It is suggested that the diminution of prostaglandin E2 and epidermal growth factor in the saliva may be associated with the ulcer development.

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

    Directory of Open Access Journals (Sweden)

    Halima Rakhila

    2015-01-01

    Full Text Available 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.

  19. Induction of Labour by Simultaneous Intravenous Administration of Prostaglandin E2 and Oxytocin

    Science.gov (United States)

    Naismith, William C. M. K.; Barr, Wallace; MacVicar, J.

    1972-01-01

    In a group of 20 matched primigravid patients labour was induced by forewater amniotomy followed by intravenous oxytocin (Syntocinon) administered in escalating doses. Ten of these patients, in a double-blind trial, also received prostaglandin E2 infused simultaneously with the oxytocin. In the combined prostaglandin-oxytocin group there was a noticeable reduction in the dosage of oxytocin required to produce effective uterine action, and the duration of labour was also reduced. No side effects were observed. PMID:4569549

  20. Oxidative stress, nitric oxide and prostaglandin E2 levels in the gastrointestinal tract of aging rats.

    Science.gov (United States)

    Mármol, Frederic; Sánchez, Juan; López, Diego; Martínez, Nuria; Mitjavila, Maria Teresa; Puig-Parellada, Pere

    2009-02-01

    To evaluate the presence of oxidative stress and alterations in the levels of two cytoprotective agents, prostaglandin E2 and nitric oxide, in the gastrointestinal tract of aging rats. The production of superoxide anion, lipid peroxides, levels of superoxide dismutase and catalase, and production of prostaglandin E2 and nitric oxide in the stomach and duodenum of rats were determined at 1.5, 3, 12, 18 and 24 months of age. Oxidative stress was present in the stomach of the old rats (24 months), whereas prostaglandin E2 and nitric oxide production remained stable at 18 and 24 months. In the duodenum, no oxidative stress was observed at 24 months, but at 18 months, an increase in superoxide anion levels was detected. Prostaglandin E2 remained constant in the aged rats but nitric oxide decreased significantly at 24 months. The absence of macroscopic gastric injury throughout the gastrointestinal tract indicates that the oxidative stress in the stomach and the significant decrease of nitric oxide in the duodenum in the old rats are not sufficient to disrupt the mucosal defence network. The results support the notion that the disruption of the mucosal network is essentially regulated by the cytoprotective agents prostaglandin E2 and nitric oxide, and that injury appears only when both substances are concurrently reduced.

  1. Prostaglandin E2 induces expression of MAPK phosphatase 1 (MKP-1) in airway smooth muscle cells.

    Science.gov (United States)

    Rumzhum, Nowshin N; Ammit, Alaina J

    2016-07-05

    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. Copyright © 2016 Elsevier B.V. All rights reserved.

  2. Uterine action after induction of labour with oral prostaglandin E2 tablets compared with intravenous oxytocin.

    Science.gov (United States)

    Elder, M G

    1975-08-01

    Uterine action throughout the whole of labour induced by low amniotomy and either oral prostaglandin E2 tablets or intravenous ocytocin was studied in 10 randomly matched pairs of patients. Oral prostaglandin E2 tablets induced fewer contractions per hour, and these contractions were longer and more variable in length than those induced by intravenous oxytocin. There was no difference in basal uterine tone or in the amplitude of contractions. A comparison was made between the outcome of labour induced by low amniotomy and either oral prostaglandin E2 tablets 0-5 mg. hourly in 65 patients, or intravenous ocytocin in 41 patients. This dose of prostaglandin E2 tablets was an inadequate adjunct to low amniotomy in nulliparous patients. Despite this, the induction-delivery interval for the whole prostaglandin group was not significantly greater than that for the oxytocin group. There were no significant differences in fetal heart rate pattern, or in the incidence of gastro-intestinal side-effects between the two groups.

  3. Prostaglandin E2 tablets compared with intravenous oxytocin in induction of labour.

    Science.gov (United States)

    Miller, J F; Welply, G A; Elstein, M

    1975-01-01

    Stimulation of uterine activity after amniotomy has been carried out with prostaglandin E2 (PGE2) tablets in two dosage regimens and with intravenous oxytocin. Oxytocin stimulation was the most successful. The difference in success rate was most marked in nulliparous patients and those with low Bishop score. PMID:1120220

  4. Phenylbutazone induces equine glandular gastric disease without decreasing prostaglandin E2 concentrations.

    Science.gov (United States)

    Pedersen, S K; Cribb, A E; Read, E K; French, D; Banse, H E

    2017-11-16

    In equids, phenylbutazone at high doses induces gastric disease, primarily in the glandular portion of the stomach. However, the mechanism of nonsteroidal anti-inflammatory drug (NSAID)-induced gastric disease in horses has yet to be determined. While phenylbutazone-associated ulceration is often attributed to a decrease in basal gastric prostaglandins, this has not been demonstrated in the horse. Twelve horses were randomly assigned to treatment (n = 6; 4.4 mg/kg phenylbutazone PO in 20 ml molasses q 12 hr for 7 days) or placebo (n = 6; 20 ml molasses PO q 12 hr for 7 days) groups. Before treatment and 3 and 7 days after initiation of treatment, gastroscopy was performed and glandular gastric biopsies were collected and frozen at -80°C. Glandular disease was assessed on a scale of 0-4. Prostaglandin E2 concentrations in biopsies were measured using a commercially available enzyme-linked immunosorbent assay. All phenylbutazone-treated horses developed grade ≥2 glandular disease. Prostaglandin concentrations increased over time (p = .0017), but there was no effect of treatment (p = .49). These findings indicate that despite induction of glandular disease grade ≥2, phenylbutazone did not decrease basal glandular gastric prostaglandin E2 concentration. © 2017 John Wiley & Sons Ltd.

  5. Transforming Growth Factor β2 Promotes Transcription of COX2 and EP4, Leading to a Prostaglandin E2-Driven Autostimulatory Loop That Enhances Virulence of Theileria annulata-Transformed Macrophages

    Science.gov (United States)

    Echebli, Nadia; Ding, Ying; Kamau, Everlyn

    2015-01-01

    Transforming growth factor beta (TGF-β) is a pleiotropic cytokine known to regulate cell growth, differentiation, and motility and is a potent modulator of immune function. TGF-β consequently plays a central role in carcinogenesis, and a dampened TGF-β2 response by Theileria annulata-infected monocytes/macrophages underpins disease resistance to tropical theileriosis. Here, we show that concomitant with the loss of TGF-β2 production, there is ablated expression of COX2 and EP4, which leads to a drop in cyclic AMP (cAMP) levels and, consequently, reduced activation of protein kinase A (PKA) and EPAC. This ablated phenotype can be rescued in attenuated macrophages by the addition of exogenous TGF-β2, which reactivates the expression of COX2 and EP4 while repressing that of protein kinase inhibitor gamma (PKIG) to the levels in virulent macrophages. TGF-β2 therefore promotes the adhesion and invasiveness of virulent macrophages by modulating COX2, EP4, and PKIG transcription to initiate a prostaglandin E2 (PGE2)-driven autostimulatory loop that augments PKA and EPAC activities. A virulence phenotype stemming from the double activation of PKA and EPAC is the induction of a CREB-mediated transcriptional program and the upregulation of JAM-L- and integrin 4αβ1-mediated adhesion of Theileria-infected macrophages. PMID:25690101

  6. Effect of Aspirin and Indomethacin on Prostaglandin E2 Synthesis in C6 Glioma Cells

    OpenAIRE

    Hwang, Shiuh-Lin; Lee, Kung-Shing; Lin, Chih-Lung; Lieu, Ann-Shung; Cheng, Chi-Yun; Loh, Joon-Khim; Hwang, Yan-Fen; Su, Yu-Feng; Howng, Shen-Long

    2004-01-01

    Prostaglandin E2 (PGE2) plays an important role in immunosuppression and tumor growth. PGE2 inhibitors such as aspirin and indomethacin suppress experimental tumor growth. Little is known of the relationship between PGE2 synthesis in brain tumors and the dose of aspirin or indomethacin. The present study was undertaken to evaluate the effect of different doses of aspirin and indomethacin on PGE2 synthesis in C6 glioma cells. C6 glioma cells were incubated with different concentrations (2, 4, ...

  7. Prostaglandin E2 increases hematopoietic stem cell survival and accelerates hematopoietic recovery after radiation injury

    Science.gov (United States)

    Porter, Rebecca L.; Georger, Mary; Bromberg, Olga; McGrath, Kathleen E.; Frisch, Benjamin J.; Becker, Michael W.; Calvi, Laura M.

    2013-01-01

    Hematopoietic stem and progenitor cells (HSPCs), which continuously maintain all mature blood cells, are regulated within the marrow microenvironment. We previously reported that pharmacologic treatment of naïve mice with prostaglandin E2 (PGE2) expands HSPCs. However, the cellular mechanisms mediating this expansion remain unknown. Here we demonstrate that PGE2 treatment in naïve mice inhibits apoptosis of HSPCs without changing their proliferation rate. In a murine model of sub-lethal total body irradiation (TBI), in which HSPCs are rapidly lost, treatment with a long-acting PGE2 analogue (dmPGE2) reversed the apoptotic program initiated by TBI. dmPGE2 treatment in vivo decreased the loss of functional HSPCs following radiation injury, as demonstrated both phenotypically and by their increased reconstitution capacity. The antiapoptotic effect of dmPGE2 on HSPCs did not impair their ability to differentiate in vivo, resulting instead in improved hematopoietic recovery after TBI. dmPGE2 also increased microenvironmental cyclooxygenase-2 expression and expanded the α-SMA+ subset of marrow macrophages, thus enhancing the bone marrow microenvironmental response to TBI. Therefore, in vivo treatment with PGE2 analogues may be particularly beneficial to HSPCs in the setting of injury by targeting them both directly and also through their niche. The current data provide rationale for in vivo manipulation of the HSPC pool as a strategy to improve recovery after myelosuppression. PMID:23169593

  8. Doxycycline Attenuates Endotoxin-Induced Uveitis by Prostaglandin E2-EP4 Signaling.

    Science.gov (United States)

    Huang, Jingwen; Su, Wenru; Chen, Xiaoqing; Cheng, Xiaokang; Dai, Ye; Han, Longhui; Liang, Dan

    2015-10-01

    We explored the anti-inflammatory effects of doxycycline in experimental uveitis and the underlying mechanisms. Rats with endotoxin-induced uveitis (EIU) received doxycycline (1.5 mg/kg) or the control vehicle via intraperitoneal injection. Clinical scores were graded under a slit lamp. Rat peritoneal macrophages were used in vitro to further explore the anti-inflammatory mechanisms of doxycycline. The levels of nitric oxide (NO), TNF-α, IL-1β, prostaglandin E2 (PGE2), cyclooxygenase (COX)-2, I kappa B-α (IκB-α), inducible nitric oxide synthase (iNOS), Akt, caspase-3, and nuclear factor-kappa B (NF-κB) were analyzed. Treatment with doxycycline dramatically reduced the clinical scores of EIU (P doxycycline significantly inhibited the production of NO, IL-1β, and TNF-α in peritoneal macrophages by modulating the PI3K/Akt/IκB-α/NF-κB pathway. Importantly, we found that doxycycline significantly enhanced COX2 expression and PGE2 production both in vivo and in vitro. More importantly, blockade of the EP4 receptor of PGE2 significantly reversed the doxycycline-mediated inhibition of macrophages and the PI3K/Akt pathway in vitro. Furthermore, simultaneous injection of an EP4 antagonist and doxycycline significantly blocked the doxycycline-mediated attenuation of EIU. Doxycycline can ameliorate EIU, and PGE2-EP4 signaling is essential for the anti-inflammatory effects of doxycycline in vitro and in vivo.

  9. (-)-Epigallocatechin gallate synergistically potentiates prostaglandin E2-stimulated osteoprotegerin synthesis in osteoblasts.

    Science.gov (United States)

    Kuroyanagi, Gen; Tokuda, Haruhiko; Yamamoto, Naohiro; Kainuma, Shingo; Fujita, Kazuhiko; Ohguchi, Reou; Kawabata, Tetsu; Sakai, Go; Matsushima-Nishiwaki, Rie; Harada, Atsushi; Kozawa, Osamu; Otsuka, Takanobu

    2017-01-01

    (-)-Epigallocatechin gallate (EGCG), the most abundant flavonoid in green tea, and chlorogenic acid, the main polyphenol found in coffee, attract significant attention owing to health benefits. We have previously demonstrated that prostaglandin E 2 (PGE 2 ) stimulates osteoprotegerin synthesis through the activation of p38 mitogen-activated protein (MAP) kinase and stress-activated protein kinase/c-Jun N-terminal kinase (SAPK/JNK) in osteoblast-like MC3T3-E1 cells. In the present study, we investigated the effects of EGCG or chlorogenic acid on the PGE 2 -stimulated osteoprotegerin synthesis in MC3T3-E1 cells. EGCG significantly amplified the PGE 2 -induced release. EGCG markedly enhanced the expression levels of osteoprotegerin mRNA induced by PGE 2 . On the contrary, chlorogenic acid had no effect on the PGE 2 -stimulated release of osteoprotegerin. EGCG significantly strengthened the PGE 2 -induced phosphorylation of p38 MAP kinase and SAPK/JNK, whereas chlorogenic acid failed to affect them. BIRB0796 and SP600125, a p38 MAP kinase inhibitor and a SAPK/JNK inhibitor, respectively, markedly reduced the amplification by EGCG of the PGE 2 -stimulated osteoprotegerin release. These results strongly suggest that EGCG synergistically enhances the PGE 2 -stimulated osteoprotegerin synthesis via potentiation of p38 MAP kinase and SAPK/JNK in osteoblasts. Our present findings could present a new significant aspect in the favorable effect of EGCG on the prevention of osteoporotic bone loss and fracture especially in elderly people since osteoprotegerin secreted from osteoblasts is well-recognized to act as a suppressor of osteoclastic bone resorption. Copyright © 2017 Elsevier Inc. All rights reserved.

  10. Prostaglandin E2 promotes features of replicative senescence in chronically activated human CD8+ T cells.

    Directory of Open Access Journals (Sweden)

    Jennifer P Chou

    Full Text Available Prostaglandin E2 (PGE2, a pleiotropic immunomodulatory molecule, and its free radical catalyzed isoform, iso-PGE2, are frequently elevated in the context of cancer and chronic infection. Previous studies have documented the effects of PGE2 on the various CD4+ T cell functions, but little is known about its impact on cytotoxic CD8+ T lymphocytes, the immune cells responsible for eliminating virally infected and tumor cells. Here we provide the first demonstration of the dramatic effects of PGE2 on the progression of human CD8+ T cells toward replicative senescence, a terminal dysfunctional state associated multiple pathologies during aging and chronic HIV-1 infection. Our data show that exposure of chronically activated CD8+ T cells to physiological levels of PGE2 and iso-PGE2 promotes accelerated acquisition of markers of senescence, including loss of CD28 expression, increased expression of p16 cell cycle inhibitor, reduced telomerase activity, telomere shortening and diminished production of key cytotoxic and survival cytokines. Moreover, the CD8+ T cells also produced higher levels of reactive oxygen species, suggesting that the resultant oxidative stress may have further enhanced telomere loss. Interestingly, we observed that even chronic activation per se resulted in increased CD8+ T cell production of PGE2, mediated by higher COX-2 activity, thus inducing a negative feedback loop that further inhibits effector function. Collectively, our data suggest that the elevated levels of PGE2 and iso-PGE2, seen in various cancers and HIV-1 infection, may accelerate progression of CD8+ T cells towards replicative senescence in vivo. Inhibition of COX-2 activity may, therefore, provide a strategy to counteract this effect.

  11. Prostaglandin E2 produced following infection with Theiler's virus promotes the pathogenesis of demyelinating disease.

    Science.gov (United States)

    Kim, Seung Jae; Jin, Young-Hee; Kim, Byung S

    2017-01-01

    Infection of various cells with Theiler's murine encephalomyelitis virus (TMEV) activates the TLR- and melanoma differentiation-associated gene 5 (MDA5)-dependent pathways, resulting in the production of IL-1β via the activation of caspase-1 upon assembly of the node-like receptor protein 3 (NLRP3) inflammasome. The role of IL-1β in the pathogenesis of TMEV-induced demyelinating disease was previously investigated. However, the signaling effects of prostaglandin E2 (PGE2) downstream of the NLRP3 inflammasome on the immune responses to viral determinants and the pathogenesis of demyelinating disease are unknown. In this study, we investigated the levels of intermediate molecules leading to PGE2 signaling and the effects of blocking PGE2 signaling on the immune response to TMEV infection, viral persistence and the development of demyelinating disease. We demonstrate here that TMEV infection activates the NLRP3 inflammasome and PGE2 signaling much more vigorously in dendritic cells (DCs) and CD11b+ cells from susceptible SJL mice than in cells from resistant B6 mice. Inhibition of virus-induced PGE2 signaling using AH23848 resulted in decreased pathogenesis of demyelinating disease and viral loads in the central nervous system (CNS). In addition, AH23848 treatment caused the elevation of protective early IFN-γ-producing CD4+ and CD8+ T cell responses. Because the levels of IFN-β were lower in AH23848-treated mice but the level of IL-6 was similar, over-production of pathogenic IFN-β was modulated and the generation of IFN-γ-producing T cell responses was enhanced by the inhibition of PGE2 signaling. These results strongly suggest that excessive activation of the NLRP3 inflammasome and downstream PGE2 signaling contribute to the pathogenesis of TMEV-induced demyelinating disease.

  12. Prostaglandin E2 levels in cerebrospinal fluid of normal and narcoleptic dogs.

    Science.gov (United States)

    Nishino, S; Mignot, E; Kilduff, T S; Sakai, T; Hayaishi, O; Dement, W C

    1990-11-15

    It has been shown that endogenous prostaglandin D2 and prostaglandin E2 (PGE2) are involved in sleep-wake regulation. Our recent experimental result that exogenously administered PGE2 significantly reduces canine cataplexy (a pathological equivalent of rapid-eye-movement sleep atonia and a symptom of narcolepsy) suggests that PGE2 is involved in the pathophysiology of canine narcolepsy. In order to further investigate the role of prostaglandins (PGs) in this disorder, PG levels in cerebrospinal fluid (CSF) of genetically homozygous narcoleptic, heterozygous (unaffected), and control Doberman pinschers were studied. PGE2 levels were measured by direct radioimmunoassay (RIA) and after high-grade purification using PG affinity columns and high-performance liquid chromatography. PGD2 and PGF2 alpha levels were measured by RIA after high-grade purification. There was no significant difference in PGE2 levels between homozygous narcoleptic and heterozygous or controls dogs, and PGD2 and PGF2 alpha levels were undetectable in most cases. Our results do not favor the hypothesis that central PGE2 levels are modified in canine narcolepsy, assuming that PGE2 levels in cisternal CSF properly reflect PGE2 production in the brain.

  13. Prostaglandin E2 stimulates Fas ligand expression via the EP1 receptor in colon cancer cells.

    LENUS (Irish Health Repository)

    O'Callaghan, G

    2012-02-03

    Fas ligand (FasL\\/CD95L) is a member of the tumour necrosis factor superfamily that triggers apoptosis following crosslinking of the Fas receptor. Despite studies strongly implicating tumour-expressed FasL as a major inhibitor of the anti-tumour immune response, little is known about the mechanisms that regulate FasL expression in tumours. In this study, we show that the cyclooxygenase (COX) signalling pathway, and in particular prostaglandin E(2) (PGE(2)), plays a role in the upregulation of FasL expression in colon cancer. Suppression of either COX-2 or COX-1 by RNA interference in HCA-7 and HT29 colon tumour cells reduced FasL expression at both the mRNA and protein level. Conversely, stimulation with PGE(2) increased FasL expression and these cells showed increased cytotoxicity against Fas-sensitive Jurkat T cells. Prostaglandin E(2)-induced FasL expression was mediated by signalling via the EP1 receptor. Moreover, immunohistochemical analysis using serial sections of human colon adenocarcinomas revealed a strong positive correlation between COX-2 and FasL (r=0.722; P<0.0001) expression, and between EP1 receptor and FasL (r=0.740; P<0.0001) expression, in the tumour cells. Thus, these findings indicate that PGE(2) positively regulates FasL expression in colon tumour cells, adding another pro-neoplastic activity to PGE(2).

  14. Anti-inflammatory and bronchoprotective roles of endogenous prostaglandin E2

    Directory of Open Access Journals (Sweden)

    Hiroki Sakakibara

    1999-01-01

    Full Text Available Prostaglandin E2 (PGE2 is produced by resident cells in the airway, such as airway epithelial cells, airway smooth muscle cells and alveolar macrophages, and is always present in the airway. Various exogenous and endogenous stimuli cause immediate increases in PGE2 from several-fold to multiples of 10-fold. Prostaglandin E2 controls the function of cells that contribute to immune and inflammatory responses, such as lymphocytes, eosinophils, mast cells, macrophages and polymorphonuclear cells, and exhibits suppressor activity in the initial and advanced stages of allergic airway inflammation (establishment of sensitization, induction of early asthmatic response, chemotaxis of inflammatory cells and continuation of the late asthmatic response. Therefore, if the endogenous protective effects of PGE2 are weakened or absent, inflammation and hypersensitive responses readily occur in the airway. Although the effects of PGE2 remain to be clarified, the possibility of the involvement of decreased PGE2 activity in the pathogenesis of asthma exists. However, in aspirin-induced asthma the role of PGE2 as a protective factor, through an as yet undetermined mechanism, is marked. It is thought that, in this type of asthma, symptoms may be induced by the elimination of the protective action of PGE2 by non-steroidal anti-inflammatory drugs (NSAID. It is possible that PGE2 agonists that produce little airway irritation and drugs that raise the endogenous PGE2 level have potential as new types of anti-inflammatory or anti-asthma drugs.

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

    Directory of Open Access Journals (Sweden)

    Manoocher Soleimani

    Full Text Available 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

  16. The Prostaglandin E2 Receptor EP4 Regulates Obesity-Related Inflammation and Insulin Sensitivity.

    Directory of Open Access Journals (Sweden)

    Mika Yasui

    Full Text Available With increasing body weight, macrophages accumulate in adipose tissue. There, activated macrophages secrete numerous proinflammatory cytokines and chemokines, giving rise to chronic inflammation and insulin resistance. Prostaglandin E2 suppresses macrophage activation via EP4; however, the role of EP4 signaling in insulin resistance and type 2 diabetes mellitus remains unknown. In this study, we treated db/db mice with an EP4-selective agonist, ONO-AE1-329, for 4 weeks to explore the role of EP4 signaling in obesity-related inflammation in vivo. Administration of the EP4 agonist did not affect body weight gain or food intake; however, in the EP4 agonist-treated group, glucose tolerance and insulin resistance were significantly improved over that of the vehicle-treated group. Additionally, administration of the EP4 agonist inhibited the accumulation of F4/80-positive macrophages and the formation of crown-like structures in white adipose tissue, and the adipocytes were significantly smaller. The treatment of the EP4 agonist increased the number of anti-inflammatory M2 macrophages, and in the stromal vascular fraction of white adipose tissue, which includes macrophages, it markedly decreased the levels of proinflammatory cytokines and chemokines. Further, EP4 activation increased the expression of adiponectin and peroxidase proliferator-activated receptors in white adipose tissue. Next, we examined in vitro M1/M2 polarization assay to investigate the impact of EP4 signaling on determining the functional phenotypes of macrophages. Treatment with EP4 agonist enhanced M2 polarization in wild-type peritoneal macrophages, whereas EP4-deficient macrophages were less susceptible to M2 polarization. Notably, antagonizing peroxidase proliferator-activated receptor δ activity suppressed EP4 signaling-mediated shift toward M2 macrophage polarization. Thus, our results demonstrate that EP4 signaling plays a critical role in obesity-related adipose tissue

  17. Heritability of thromboxane A2 and prostaglandin E2 biosynthetic machinery in a Spanish population.

    Science.gov (United States)

    Vila, Luis; Martinez-Perez, Angel; Camacho, Mercedes; Buil, Alfonso; Alcolea, Sonia; Pujol-Moix, Nuria; Soler, Marta; Antón, Rosa; Souto, Juan-Carlos; Fontcuberta, Jordi; Soria, José-Manuel

    2010-01-01

    Prostanoids play a critical role in clinical areas such as inflammation, thrombosis, immune response, and cancer. Although some studies suggest that there are genes that determine variability of some prostanoid-related phenotypes, the genetic influence on these traits has not been evaluated. The relative contributions of genetic and environmental influences to the prostanoid biosynthetic pathway-related phenotypes, cyclooxygenase isoenzymes, microsomal-PGE-synthase-1 and TxA-synthase expression, and thromboxane-A(2) and prostaglandin-E(2) production by stimulated whole blood, were assessed in a sample of 308 individuals in 15 extended families. The effects of measured covariates (such as sex, age, and smoking), genes, and environmental variables shared by members of a household were quantified. Heritabilities ranging from 0.406 to 0.634 for enzyme expression and from 0.283 to 0. 751 for prostanoid production were found. These results demonstrate clearly the importance of genetic factors in determining variation in phenotypes that are components of the prostanoid biosynthetic pathways. The presence of such strong genetic effects suggest that it will be possible to localize previously unknown genes that influence quantitative variation in these phenotypes, some of which affect multiple aspects of cell biology, with important clinical implications.

  18. Prostaglandin E2 signals through PTGER2 to regulate sclerostin expression.

    Directory of Open Access Journals (Sweden)

    Damian C Genetos

    2011-03-01

    Full Text Available The Wnt signaling pathway is a robust regulator of skeletal homeostasis. Gain-of-function mutations promote high bone mass, whereas loss of Lrp5 or Lrp6 co-receptors decrease bone mass. Similarly, mutations in antagonists of Wnt signaling influence skeletal integrity, in an inverse relation to Lrp receptor mutations. Loss of the Wnt antagonist Sclerostin (Sost produces the generalized skeletal hyperostotic condition of sclerosteosis, which is characterized by increased bone mass and density due to hyperactive osteoblast function. Here we demonstrate that prostaglandin E(2 (PGE(2, a paracrine factor with pleiotropic effects on osteoblasts and osteoclasts, decreases Sclerostin expression in osteoblastic UMR106.01 cells. Decreased Sost expression correlates with increased expression of Wnt/TCF target genes Axin2 and Tcf3. We also show that the suppressive effect of PGE(2 is mediated through a cyclic AMP/PKA pathway. Furthermore, selective agonists for the PGE(2 receptor EP2 mimic the effect of PGE(2 upon Sost, and siRNA reduction in Ptger2 prevents PGE(2-induced Sost repression. These results indicate a functional relationship between prostaglandins and the Wnt/β-catenin signaling pathway in bone.

  19. Comparison of prostaglandin E2 vaginal tablet with amniotomy and intravenous oxytocin for induction of labour.

    Science.gov (United States)

    Lo, L; Ho, M W; Leung, P

    1994-05-01

    Prostaglandins have been increasingly used in obstetrical practice for cervical ripening and induction of labour. We set out to investigate the effectiveness of prostaglandin E2 (PGE2) vaginal pessaries in inducing labour in the Chinese population in Hong Kong. In the period August, 1991 to August, 1992, we recruited 206 pregnant Chinese women who required induction of labour for various obstetrical indications into the trial. The study group had induction of labour by PGE2 vaginal pessaries and the control group underwent amniotomy plus oxytocin infusion. These patients were alternately assigned either method of induction. They were further divided into primiparous and multiparous (parity 1 and 2 only) groups. Only 101 primiparas and 99 multiparas were available in the final analysis of the trial. Various aspects of labour, delivery, maternal and fetal outcome were compared. For primiparas, the traditional combined induction was the preferred method. For multiparas, both induction methods were quite satisfactory and there was a trend toward lesser blood loss and pethidine requirement in the PGE2 users.

  20. Role of prostaglandin E2 on amoebic liver abscess formation in hamsters.

    Science.gov (United States)

    Sánchez-Ramírez, B; Escalante, B; Rosales-Encina, J L; Talamás-Rohana, P

    1997-06-01

    Entamoeba histolytica can modulate macrophage functions and cytokine production by a prostaglandin E2 (PGE2) mechanism. To study the participation of PGE2 on amoebic liver abscess formation, we tested the effect of the PG synthesis inhibitor indomethacin (INDO) on abscess development in hamsters infected intrahepatically with E. histolytica trophozoites. Male infected animals had higher levels of plasma PGE2 (5.7 +/- 0.7 pg/ml pre-infection; 26.0 +/- 2.0 pg/ml 7 days postinfection; p abscess weight by 18% and 30% respectively (p abscesses through generation and support of the inflammation. The partial effect of INDO treatment suggests that additional factors are involved.

  1. Localization of prostaglandin E(2) EP2 and EP4 receptors in the rat kidney

    DEFF Research Database (Denmark)

    Jensen, B L; Stubbe, J; Hansen, P B

    2001-01-01

    segments showed EP2 expression in descending thin limb of Henle's loop (DTL) and in vasa recta of the outer medulla. The EP4 receptor was expressed in distal convoluted tubule (DCT) and cortical collecting duct (CCD) in preglomerular vessels, and in outer medullary vasa recta. Butaprost, an EP2 receptor......We investigated the localization of cAMP-coupled prostaglandin E(2) EP2 and EP4 receptor expression in the rat kidney. EP2 mRNA was restricted to the outer and inner medulla in rat kidney, as determined by RNase protection assay. RT-PCR analysis of microdissected resistance vessels and nephron......-selective agonist, dose dependently raised cAMP levels in microdissected DTL and outer medullary vasa recta specimens but had no effect in EP2-negative outer medullary collecting duct segments. Dietary salt intake did not alter EP2 expression in the kidney medulla. These results suggest that PGE(2) may act...

  2. Magaldrate stimulates endogenous prostaglandin E2 synthesis in human gastric mucosa in vitro and in vivo.

    Science.gov (United States)

    Schmidt, C; Baumeister, B; Kipnowski, J; Miederer, S E; Vetter, H

    1998-01-01

    Prostaglandin E2 (PGE2) plays an important role in the inhibition of gastric acid production and exerts cytoprotective action. The in vitro and in vivo effect of magaldrate, an aluminum containing antacid, on PGE2 synthesis in the gastric mucosa was investigated. In the first part of the study, magaldrate was added to a suspension of isolated gastric mucosal cells. In the second part, the antacid gel was applied to the gastric mucosa during gastroscopy and biopsies were taken from the same site 5 and 10 min later. The antacid significantly stimulated PGE2 release from the suspension of isolated gastric cells in vitro. The biopsies obtained after the application of magaldrate showed an increased PGE2 production compared to specimens obtained before. The data suggest that in addition to its neutralizing capacity as an antacid, magaldrate contributes to the cytoprotective activity of the mucosa by stimulating endogenous PGE2 synthesis.

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

    DEFF Research Database (Denmark)

    Kaltoft, Nicolai; Tilotta, Maria C; Witte, Anne-Barbara

    2010-01-01

    EP1, EP2, EP3, and EP4 is not significantly different between neoplasia diseased patients and controls. This indicates that increased indomethacin-sensitive mechanisms in colonic mucosa from neoplasia diseased patients are not related to differences in functional expression of EP receptor subtypes....... 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...... 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...

  4. Prostaglandin E2 role in inhibition of joint cartilage collagen destruction in patients with osteoarthritis

    Directory of Open Access Journals (Sweden)

    E V Chetina

    2009-01-01

    Full Text Available Prostaglandin E2 role in inhibition of articular cartilage collagen degradation in patients with osteoarthritis. Objective. To assess prostaglandin E2 (PGE2 role in inhibition of type II collagen digestion in explants of articular cartilage of pts with osteoarthritis (OA. Material and methods. Explants of articular cartilage of pts with OA were cultured with PGE2 1pg to 10 ng/ml. Type II collagen digestion was assessed with immuno-enzyme assay. Gene expression was evaluated with PCR in real time. Results. PGE2 10 pg/ml as well as transforming growth factor β2 (TGFβ2 suppressed type II collagen digestion in explants of articular cartilage of pts with OA. This concentration of PGE2 did not suppress proteoglycan (aggrecan degradation. Gene expression analysis in 5 OA pts showed that PGE2 10 pg/ml suppressed metallomonooxigenase (MMP-13, MMP-1 and marker of chondrocyte hypertrophy type X collagen (COL10A1 as well as proinflammatory cytokines interleukine (IL-1β and tumor necrosis factor (TNFα. Naproxen, nonselective cyclooxygenase(COX-2 and 1 inhibitor concentration from 5 to 30 mcg/ml blocked TGFβ2 induced collagen digestion inhibition proving that PGE2 mediate influence of this growth factor. Naproxen concentration 5 mcg/ml increased collagen degradation. Conclusion. The study showed that PGE2 is a chondroprotector because it is able to suppress selectively OA pts cartilage collagen degradation. Beside that cartilage chondrocyte hypertrophy in OA connected functionally with increased collagen digestion is also regulated by low concentrations of PGE2

  5. Prostaglandin E2 release from dermis regulates sodium permeability of frog skin epithelium

    DEFF Research Database (Denmark)

    Rytved, Klaus A.; Brodin, Birger; Nielsen, Robert

    1995-01-01

    Arachidonic acid, cAMP, epithelium, frog skin, intracellular calcium, prostaglandin E*U2, sodium transport, tight epithelium.......Arachidonic acid, cAMP, epithelium, frog skin, intracellular calcium, prostaglandin E*U2, sodium transport, tight epithelium....

  6. The Effect of Thyroid Hormone, Prostaglandin E2, and Calcium Gluconate on Orthodontic Tooth Movement and Root Resorption in Rats.

    Science.gov (United States)

    Seifi, Massoud; Hamedi, Roya; Khavandegar, Zohre

    2015-03-01

    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). 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. 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. 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 mm(2)) and the other groups. 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.

  7. Prostaglandin E2 metabolism in rat brain: Role of the blood-brain interfaces

    Directory of Open Access Journals (Sweden)

    Strazielle Nathalie

    2008-03-01

    Full Text Available Abstract Background Prostaglandin E2 (PGE2 is involved in the regulation of synaptic activity and plasticity, and in brain maturation. It is also an important mediator of the central response to inflammatory challenges. The aim of this study was to evaluate the ability of the tissues forming the blood-brain interfaces to act as signal termination sites for PGE2 by metabolic inactivation. Methods The specific activity of 15-hydroxyprostaglandin dehydrogenase was measured in homogenates of microvessels, choroid plexuses and cerebral cortex isolated from postnatal and adult rat brain, and compared to the activity measured in peripheral organs which are established signal termination sites for prostaglandins. PGE2 metabolites produced ex vivo by choroid plexuses were identified and quantified by HPLC coupled to radiochemical detection. Results The data confirmed the absence of metabolic activity in brain parenchyma, and showed that no detectable activity was associated with brain microvessels forming the blood-brain barrier. By contrast, 15-hydroxyprostaglandin dehydrogenase activity was measured in both fourth and lateral ventricle choroid plexuses from 2-day-old rats, albeit at a lower level than in lung or kidney. The activity was barely detectable in adult choroidal tissue. Metabolic profiles indicated that isolated choroid plexus has the ability to metabolize PGE2, mainly into 13,14-dihydro-15-keto-PGE2. In short-term incubations, this metabolite distributed in the tissue rather than in the external medium, suggesting its release in the choroidal stroma. Conclusion The rat choroidal tissue has a significant ability to metabolize PGE2 during early postnatal life. This metabolic activity may participate in signal termination of centrally released PGE2 in the brain, or function as an enzymatic barrier acting to maintain PGE2 homeostasis in CSF during the critical early postnatal period of brain development.

  8. A biphasic response of urinary prostaglandin E2 excretion to water deprivation in conscious diabetes insipidus Brattleboro rats

    DEFF Research Database (Denmark)

    Kanters, J K; Holstein-Rathlou, N H; Christensen, P

    1989-01-01

    The effects of water deprivation on the urinary excretion rate of prostaglandin E2 (PGE2) were examined in conscious Brattleboro rats. In order to study the time course of the changes in the PGE2 excretory rate, urine was collected in 6 periods, Control: 0-1 hour (h.). 1: 3-4.5 h., 8-10 h., III: ...

  9. Functional and molecular characterization of prostaglandin E2 dilatory receptors in the rat craniovascular system in relevance to migraine

    DEFF Research Database (Denmark)

    Myren, Maja; Baun, Michael; Ploug, Kenneth Beri

    2010-01-01

    Migraine pain is thought to involve an increase in trigeminal nerve terminal activity around large cerebral and meningeal arteries, leading to vasodilatation. Because prostaglandin E(2) (PGE(2)) is elevated in cephalic venous blood during migraine attacks, and is also capable of inducing headache...... in healthy volunteers, we hypothesize that PGE(2) dilatory receptors, EP(2) and EP(4), mediate the response....

  10. Prostaglandin E2 stimulates the expression of cumulus expansion-related genes in pigs: the role of protein kinase B

    Czech Academy of Sciences Publication Activity Database

    Blaha, Milan; Procházka, Radek; Adámková, K.; Nevoral, J.; Němcová, Lucie

    2017-01-01

    Roč. 130, č. 2 (2017), s. 38-46 ISSN 1098-8823 R&D Projects: GA MZe(CZ) QJ1510138; GA MŠk EF15_003/0000460 Institutional support: RVO:67985904 Keywords : cumulus * oocyte * prostaglandin E2 * protein kinase B Subject RIV: EG - Zoology Impact factor: 2.640, year: 2016

  11. Diarylheptanoid from Pleuranthodium racemigerum with in vitro prostaglandin E(2) inhibitory and cytotoxic activity.

    Science.gov (United States)

    Wohlmuth, Hans; Deseo, Myrna A; Brushett, Don J; Thompson, Dion R; Macfarlane, Graham; Stevenson, Lesley M; Leach, David N

    2010-04-23

    Bioactivity-guided fractionation of an ethanolic extract of the rhizome of Pleuranthodium racemigerum, a tropical Zingiberaceae species from Northeastern Australia, resulted in the isolation and structural elucidation of 1-(4''-methoxyphenyl)-7-(4'-hydroxyphenyl)-(E)-hept-2-ene (1), a new diarylheptanoid related to curcumin. Compound 1 was a fairly potent inhibitor of prostaglandin E(2) production in 3T3 murine fibroblasts (IC(50) approximately 34 microM) and also displayed moderate cytotoxicity against this cell line (IC(50) = 52.8 microM). The compound also demonstrated cytotoxic activity against the P388D1 murine lymphoblast cell line (IC(50) = 117.0 microM) and four human cell lines: Caco-2 colonic adenocarcinoma (IC(50) = 44.8 microM), PC3 prostate adenocarcinoma (IC(50) = 23.6 microM), HepG2 hepatocyte carcinoma (IC(50) = 40.6 microM), and MCF7 mammary adenocarcinoma (IC(50) = 56.9 microM). The cytotoxicity of compound 1 closely resembled that of curcumin, in terms of both IC(50) values and dose-response curves.

  12. Levels of CSF prostaglandin E2, cognitive decline, and survival in Alzheimer's disease

    Science.gov (United States)

    Combrinck, M; Williams, J; De Berardinis, M A; Warden, D; Puopolo, M; Smith, A D; Minghetti, L

    2006-01-01

    Background Although epidemiological, clinical, and experimental evidence indicates that the inducible isoform of cyclo‐oxygenase (COX‐2) may be involved in the pathogenesis of several neurodegenerative disorders, the mechanisms whereby COX‐2 contributes to Alzheimer's disease are largely unknown. Objective To undertake a longitudinal study of CSF levels of a major product of COX activity, prostaglandin E2 (PGE2), in relation to cognitive decline and survival in patients with Alzheimer's disease. Methods CSF PGE2 was measured on at least three annual visits in 35 controls and 33 Alzheimer patients (26 necropsy confirmed) who completed the Cambridge cognitive assessment (CAMCOG). Results Compared with controls, CSF PGE2 was higher in patients with mild memory impairment, but lower in those with more advanced Alzheimer's disease. The median survival time of patients with higher initial PGE2 levels was five years longer than those with lower levels. Conclusions COX activity in Alzheimer's disease varies with stage of the disease. PGE2 levels correlate positively with patient survival. These findings suggest that inhibition of COX activity does not represent a major target for the pharmacological treatment of Alzheimer's disease. PMID:15944180

  13. Effect of Aspirin and Indomethacin on Prostaglandin E2 Synthesis in C6 Glioma Cells

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    Shiuh-Lin Hwang

    2004-01-01

    Full Text Available Prostaglandin E2 (PGE2 plays an important role in immunosuppression and tumor growth. PGE2 inhibitors such as aspirin and indomethacin suppress experimental tumor growth. Little is known of the relationship between PGE2 synthesis in brain tumors and the dose of aspirin or indomethacin. The present study was undertaken to evaluate the effect of different doses of aspirin and indomethacin on PGE2 synthesis in C6 glioma cells. C6 glioma cells were incubated with different concentrations (2, 4, and 8 μM of aspirin and indomethacin for 1, 2, 4, 6, 8, 12, and 24 hours. Intracellular PGE2 concentration was measured by enzyme immunoassay. Each concentration of aspirin and indomethacin effectively inhibited PGE2 synthesis. Concentrations of 2, 4, and 8 μM of aspirin significantly inhibited PGE2 production at 6, 4, and 1 hours, respectively, and the inhibition persisted for more than 24 hours (p 0.05. Indomethacin 8 μM was effective at 1 hour and the inhibition persisted beyond 24 hours (p < 0.05. Our study demonstrates that aspirin and indomethacin inhibit PGE2 synthesis in C6 glioma cells and that low-dose aspirin is as effective as high-dose aspirin. This study may encourage future clinical use of low-dose aspirin in the prevention or treatment of brain tumors.

  14. Prostaglandin E2 receptor EP4 contributes to inflammatory pain hypersensitivity.

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    Lin, Chung-Ren; Amaya, Fumimasa; Barrett, Lee; Wang, Haibin; Takada, Junji; Samad, Tarek A; Woolf, Clifford J

    2006-12-01

    Prostaglandin E(2) (PGE(2)) is both an inflammatory mediator released at the site of tissue inflammation and a neuromodulator that alters neuronal excitability and synaptic processing. The effects of PGE(2) are mediated by four G-protein-coupled EP receptors (EP1-EP4). Here we show that the EP4 receptor subtype is expressed by a subset of primary sensory dorsal root ganglion (DRG) neurons, and that its levels, but not that of the other EP1-3 subtypes, increase in the DRG after complete Freund' adjuvant-induced peripheral inflammation. Administration of both an EP4 antagonist [AH23848, (4Z)-7-[(rel-1S,2S,5R)-5-((1,1'-biphenyl-4-yl)methoxy)-2-(4-morpholinyl)-3-oxocyclopentyl]-4-heptenoic acid] and EP4 knockdown with intrathecally delivered short hairpin RNA attenuates inflammation-induced thermal and mechanical behavioral hypersensitivity, without changing basal pain sensitivity. AH23848 also reduces the PGE(2)-mediated sensitization of capsaicin-evoked currents in DRG neurons in vitro. These data suggest that EP4 is a potential target for the pharmacological treatment of inflammatory pain.

  15. Can we predict successful cervical ripening with prostaglandin E2 vaginal inserts?

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    Hiersch, Liran; Borovich, Adi; Gabbay-Benziv, Rinat; Maimon-Cohen, Moria; Aviram, Amir; Yogev, Yariv; Ashwal, Eran

    2017-02-01

    Previous studies have suggested that a variety of maternal and obstetrical characteristics may predict successful prostaglandin E2 (PGE2) cervical ripening. However, in most studies women were administered vaginal tablets or gel so scarce is known regarding potential predictors in women administrated slow-release vaginal inserts. We aimed to characterize the response of cervical ripening for labor induction using slow-release PGE2 vaginal insert and to identify predictors for success. A retrospective cohort study in a single center (2013-2015). The association between maternal characteristics at admission and cervical ripening success/failure were explored. Cervical ripening failure was defined as a Bishop's score women met inclusion criteria, of them, 774 (78.56%) succeeded and 212 (21.5%) failed cervical ripening. Cervical ripening success was associated with (OR, 95% CI): nulliparity (0.42, 0.22-0.81, p = 0.009, i.e., nulliparity was negatively associated with successful ripening), gestational age (GA) at delivery (1.29, 1.02-1.61, p success. A prediction model which included the abovementioned characteristics had an AUC of 0.792 (95% CI 0.743-0.840). Overall, basic parameters, such as parity, cervical dilatation at admission and gestational age can predict successful cervical ripening PGE2 vaginal inserts.

  16. Effect of probenecid on breathing movements and cerebral clearance of prostaglandin E2 in fetal sheep

    Science.gov (United States)

    Walker, David W; Pratt, Naomi

    1998-01-01

    Intravenous infusion of probencid (79-160 mg kg−1) into unanaesthetized fetal sheep (127-143 days gestation) in utero significantly decreased the incidence and amplitude of spontaneous breathing movements, but did not change the incidence of low voltage electrocortical (ECoG) activity, plasma prostaglandin E2 (PGE2) concentrations, blood gases or pH. In fetuses pretreated with paracetamol (350 mg kg−1) to inhibit PG synthase activity, infusion of probenecid did not change the mean incidence or amplitude of breathing movements, indicating that the inhibitory effect of probenecid on breathing movements required the presence of active PG synthesis. Probenecid infusion in four unanaesthetized fetuses significantly increased the PGE2 concentrations in cisternal cerebrospinal fluid (CSF) by 6.6 ± 1.5-fold (P probenecid infusion decreased the clearance of [3H]PGE2 from CSF during ventriculo-cisternal perfusion of artificial CSF containing [3H]PGE2. These results suggest that there is active transport of PGs from CSF to blood in fetal sheep from at least 127 days gestation. Inhibition of this transport results in the accumulation of PGs within interstitial fluid of the brain, one effect of which is to suppress the spontaneous activity of the respiratory centres. PMID:9481686

  17. Prostaglandin E2 level in gingival crevicular fluid from patients with Down syndrome.

    Science.gov (United States)

    Barr-Agholme, M; Krekmanova, L; Yucel-Lindberg, T; Shinoda, K; Modéer, T

    1997-04-01

    The levels of prostaglandin E2 (PGE2) and interleukin-1 beta (IL-1 beta) were determined in gingival crevicular fluid (GCF) collected from patients with gingivitis: 15 Down syndrome children and 15 controls. The mean level of PGE2 in GCF was significantly higher (P syndrome group (10.0 pg/microliters GCF) than in the control group (4.6 pg/microliters GCF). In GCF samples collected from sites characterized as noninflamed, the mean level of PGE2 was significantly higher (P syndrome group than in the controls. The mean level of PGE2 in samples from inflamed sites, on the other hand, did not differ between the two groups. The mean level of IL-1 beta was not significantly higher in the Down syndrome group than in the controls. This study shows that the level of PGE2 detected in GCF from Down syndrome patients is increased, a fact that may be of importance in the pathogenesis of the periodontal disease frequently seen in these patients.

  18. Prostaglandin E2 gel In ripening of cervix in induction of labour.

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    Warke H

    1999-10-01

    Full Text Available A study was done in 75 patients who underwent induction of labour with Prostaglandin E2 gel. All these patients had an unripe cervix. The commonest indications were post-datism, intrauterine growth retardation and pregnancy-induced hypertension. All patients were primigravidas with singleton pregnancy and beyond 35 weeks of pregnancy. The mean Bishop score at the time of instillation was less than three. The improvement of another 2-3 points within six hours and by 7-8 points within 12 hours was found after instillation of the gel. 92% of the patients went into spontaneous labour and 8% required reinstillation. The incidence of failed induction was 1.33%. The mean duration of latent phase was 10.34 hours. Induction delivery time was 16.43 hours. 68.1% patients required augmentation of labour and 31.9% did not require augmentation of labour with oxytocin drip. The incidence of vaginal delivery was 81.33% and that of caesarean section was 17.33%. The commonest indication of caesarean section was foetal distress.

  19. Prostaglandin E2 Regulates Liver versus Pancreas Cell Fate Decisions and Endodermal Outgrowth

    Science.gov (United States)

    Nissim, Sahar; Sherwood, Richard I.; Wucherpfennig, Julia; Saunders, Diane; Harris, James M.; Esain, Virginie; Carroll, Kelli J.; Frechette, Gregory M.; Kim, Andrew J.; Hwang, Katie L.; Cutting, Claire C.; Elledge, Susanna; North, Trista E.; Goessling, Wolfram

    2014-01-01

    SUMMARY The liver and pancreas arise from common endodermal progenitors. How these distinct cell fates are specified is poorly understood. Here, we describe prostaglandin E2 (PGE2) as a regulator of endodermal fate specification during development. Modulating PGE2 activity has opposing effects on liver-versus-pancreas specification in zebrafish embryos as well as mouse endodermal progenitors. The PGE2 synthetic enzyme cox2a and receptor ep2a are patterned such that cells closest to PGE2 synthesis acquire a liver fate whereas more distant cells acquire a pancreas fate. PGE2 interacts with the bmp2b pathway to regulate fate specification. At later stages of development, PGE2 acting via the ep4a receptor promotes outgrowth of both the liver and pancreas. PGE2 remains important for adult organ growth, as it modulates liver regeneration. This work provides in vivo evidence that PGE2 may act as a morphogen to regulate cell fate decisions and outgrowth of the embryonic endodermal anlagen. PMID:24530296

  20. Changes in the plasma prostaglandin F2 alpha metabolite before and during spontaneous labor and labor induced by amniotomy, oxytocin and prostaglandin E2.

    Science.gov (United States)

    Nagata, I; Sunaga, H; Furuya, K; Makimura, N; Kato, K

    1987-04-01

    To elucidate the role of endogenous prostaglandin F2 alpha in spontaneous and induced labor, plasma concentrations of 13, 14-dihydro-15-keto-prostaglandin F2 alpha (PGFM) were determined before the onset of labor, at onset of labor, during active labor, at the crowning of the fetal head, and 1 and 2 hours after delivery. Patients in spontaneous labor and labor induced by amniotomy, oxytocin, and prostaglandin E2 were studied. The levels of plasma PGFM in patients who entered spontaneous labor fell 2 to 3 weeks before delivery, whereas those in the induced labor group did not change until the time of induction. Although the levels of PGFM rose gradually with the progress of labor in all cases, the levels in the spontaneous labor were significantly lower in each stage than in the corresponding stage of induced labor. These results suggest that endogenous prostaglandin F2 alpha (PGF2 alpha) production decreases 2-3 weeks prior to the spontaneous onset of labor and is increased again as labor progresses, that the patterns of PGF2 alpha production are similar to each other during spontaneous labor and labor induced by various methods. Therefore, it is felt that endogenous PGF2 alpha may participate in the progress of all kinds of labor.

  1. Prostaglandin E2 protects murine lungs from bleomycin-induced pulmonary fibrosis and lung dysfunction

    Science.gov (United States)

    Dackor, Ryan T.; Cheng, Jennifer; Voltz, James W.; Card, Jeffrey W.; Ferguson, Catherine D.; Garrett, Ryan C.; Bradbury, J. Alyce; DeGraff, Laura M.; Lih, Fred B.; Tomer, Kenneth B.; Flake, Gordon P.; Travlos, Gregory S.; Ramsey, Randle W.; Edin, Matthew L.; Morgan, Daniel L.

    2011-01-01

    Prostaglandin E2 (PGE2) is a lipid mediator that is produced via the metabolism of arachidonic acid by cyclooxygenase enzymes. In the lung, PGE2 acts as an anti-inflammatory factor and plays an important role in tissue repair processes. Although several studies have examined the role of PGE2 in the pathogenesis of pulmonary fibrosis in rodents, results have generally been conflicting, and few studies have examined the therapeutic effects of PGE2 on the accompanying lung dysfunction. In this study, an established model of pulmonary fibrosis was used in which 10–12-wk-old male C57BL/6 mice were administered a single dose (1.0 mg/kg) of bleomycin via oropharyngeal aspiration. To test the role of prostaglandins in this model, mice were dosed, via surgically implanted minipumps, with either vehicle, PGE2 (1.32 μg/h), or the prostacyclin analog iloprost (0.33 μg/h) beginning 7 days before or 14 days after bleomycin administration. Endpoints assessed at 7 days after bleomycin administration included proinflammatory cytokine levels and measurement of cellular infiltration into the lung. Endpoints assessed at 21 days after bleomycin administration included lung function assessment via invasive (FlexiVent) analysis, cellular infiltration, lung collagen content, and semiquantitative histological analysis of the degree of lung fibrosis (Ashcroft method). Seven days after bleomycin administration, lymphocyte numbers and chemokine C-C motif ligand 2 expression were significantly lower in PGE2- and iloprost-treated animals compared with vehicle-treated controls (P bleomycin challenge, PGE2 also protected against the decline in lung static compliance, lung fibrosis, and collagen production that is associated with 3 wk of bleomycin exposure. However, PGE2 had no therapeutic effect on these parameters when administered 14 days after bleomycin challenge. In summary, PGE2 prevented the decline in lung static compliance and protected against lung fibrosis when it was administered

  2. Prostaglandin E-2 Synthesizing Enzymes in Rheumatoid Arthritis B Cells and the Effects of B Cell Depleting Therapy on Enzyme Expression

    NARCIS (Netherlands)

    Gheorghe, Karina Roxana; Thurlings, Rogier M.; Westman, Marie; Boumans, Maartje J.; Malmström, Vivianne; Trollmo, Christina; Korotkova, Marina; Jakobsson, Per-Johan; Tak, Paul-Peter

    2011-01-01

    Introduction: B cells may play an important role in promoting immune activation in the rheumatoid synovium and can produce prostaglandin E-2 (PGE(2)) when activated. In its turn, PGE(2) formed by cyclooxygenase (COX) and microsomal prostaglandin E-2 synthase 1 (MPGES1) contributes to the rheumatoid

  3. Induction of labour: a comparison of a single prostaglandin E2 vaginal tablet with amniotomy and intravenous oxytocin.

    Science.gov (United States)

    Kennedy, J H; Stewart, P; Barlow, D H; Hillan, E; Calder, A A

    1982-09-01

    In a randomized controlled study of 100 women of low parity and favourable induction features, induction of labour by means of a single vaginal tablet containing 3 mg of prostaglandin E2 (PGE2) was compared with the conventional method of amniotomy and intravenous oxytocin. Four of the patients (8%) who received the prostaglandin tablet required additional intravenous oxytocin to achieve delivery. The prostaglandin group had a longer mean overall induction-delivery interval but a shorter amniotomy-delivery interval than the oxytocin group. One patient in the PGE2 group and two in the oxytocin group required caesarean section. The PGE2 treated patients expressed a higher level of satisfaction with their method of induction, they required less analgesia, had less blood loss at delivery and their babies had a lower incidence of neonatal jaundice.

  4. Cardioprotective actions of curcumin on the pathogenic NFAT/COX-2/prostaglandin E2pathway induced during Trypanosoma cruzi infection.

    Science.gov (United States)

    Hernández, Matías; Wicz, Susana; Corral, Ricardo S

    2016-11-15

    Diverse cardiovascular signaling routes have been considered critical for Chagas cardiomyopathy caused by the protozoan parasite Trypanosoma cruzi. Along this line, T. cruzi infection and endothelin-1 (ET-1) have been shown to cooperatively activate the Ca 2+ /NFAT cascade in cardiomyocytes, leading to cyclooxygenase type 2 (COX-2) induction and increased release of prostanoids and prohypertrophic peptides. To determine whether the well-known cardioprotective and anti-inflammatory effects of curcumin (Cur) could be helpful to interfere with this key machinery for pathogenesis of Chagas myocarditis. Cur treatment was evaluated through in vivo studies using a murine model of acute T. cruzi infection and in vitro experiments using ET-1-stimulated and parasite-infected mouse cardiomyocytes. Cur-treated and untreated infected mice were followed-up to estimate survival postinfection and heart tissues from both groups were analyzed for inflammatory infiltration by histopathology, whereas parasite load, induction of arachidonic acid pathway and natriuretic peptide expression were determined by real-time PCR. Molecular analysis of Cur myocardial targets included intracellular calcium measurement, NFAT and COX-2 induction in transfected cells, and assessment of NFAT, COX-2 and microsomal prostaglandin E synthase-1 (mPGES-1) levels by immunoblotting, prostaglandin E 2 (PGE 2 ) by ELISA, b-type natriuretic peptide (BNP) by real-time PCR, and PGE 2 /EP4 receptor/BNP interaction by transwell experiments. Cur treatment of acute Chagas mice enhanced survival and proved to hinder relevant inflammatory processes in the heart, including leukocyte recruitment, activation of the eicosanoid pathway and BNP overexpression, without modifying parasite burden in the organ. Cur was capable of blocking Ca 2+ -dependent NFATc1 transcriptional activity, COX-2 and mPGES-1 induction, and subsequent PGE 2 production in ET-1-stimulated and parasite-infected cardiomyocytes. Furthermore, the decline

  5. On the mechanism of noradrenaline-induced prostaglandin E2-Synthesis in primary cell cultures from rabbit splenic pulpa.

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

    1981-10-01

    The role of Ca2+ and phospholipase A2 in alpha-adrenoceptor mediated stimulation of prostaglandin (PG)E2-release was investigated in primary cell cultures of rabbit splenic pulpa. Noradrenaline enhanced PGE2-release only in the presence of extracellular Ca2+. In contrast, PGE2-release induced by arachidonic acid was unchanged when Ca2+ was omitted. In the presence of Ca2+, the ionophore A 23187 increased PGE2-release concentration-dependently. During incubation in Ca2+-free medium, the ionophore was ineffective. Inhibitors of phospholipase A2 (mepacrine, p-bromophenacyl bromide) abolished the noradrenaline-induced PGE2-release and reduced the effect of A 23187; the stimulation of PGE2-release by arachidonic acid was not affected. Addition of exogenous phospholipase A2 enhances release of PGE2. From these results we suggest that noradrenaline-induced PGE2-release in rabbit splenic fibroblasts via alpha-adrenoceptors involves the following steps: influx of Ca2+, activation of a Ca2+-dependent phospholipase and liberation of arachidonic acid which is transformed into PGs.

  6. Penetration effect of prostaglandin E2 gel on oral mucosa of rats

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    Rafinus Arifin

    2012-09-01

    Full Text Available Background: Several researches reported that Prostaglandin E2 (PGE2 injection on buccal mucosa combined with orthodontic pressure can faster tooth movement but has disadvantages such as high alveolar bone and root resorption furthermore pain from injection needle. PGE2 gel was made to better replace the lacks of injectable PGE2. Purpose: This research was aimed to prove that PGE 2 gel can penetrate rat’s oral mucosa effecting the appearance of PMN cells. Methods: This research was an in vivo laboratory experiment using 36 Sprague Dawley rats which were divided into 3 groups: normal group, topical PGE2 gel group after 1, 2, 4, 8 hours (4 subgroups, and topical gel without PGE2 group after 1, 2, 4, 8 hours (4 subgroups. Each group consists of 4 rats, therefore the total sample for all research groups were 36 rats. Gel with 25 µg/mL of PGE2 and gel without PGE2 were applied on oral mucosa for 2 minutes. Then, the rats were sacrificed after 1 hour, 2 hours, 4 hours, and 8 hours application. After that, the samples were prepared for histological examination with Hematoxyllin and Eosin. The picture were taken with OptiLab View and PMN cells amount were counted with light microscope, set 400 times of magnification. Results: Penetration effect of PGE2 gel on rat’s oral mucosa result in PMN inflammation cells distribution. One-way ANOVA showed no significant difference on PMN cells count in rats’ lower jaws between groups of normal and gel without PGE2. There was significant difference between groups of PGE2 gel and gel without PGE2 (p=0,001. PGE2 gel application showed PGE2 as inflammatory media, even though administered topically. Conclusion: PGE2 gel can penetrate rat’s oral mucosa, effecting PMN cells 1, 2, 4 and 8 hours after application of PGE2 gel.Latar belakang: Beberapa penelitian melaporkan bahwa injeksi (Prostaglandin E2 PGE2pada mukosa bukal yang dikombinasikan dengan tekanan ortodonti dapat mempercepat pergerakan gigi, tapi

  7. Activating prostaglandin E2 receptor subtype EP4 increases secreted mucin from airway goblet cells.

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    Akaba, Tomohiro; Komiya, Kosaku; Suzaki, Isao; Kozaki, Yuji; Tamaoki, Jun; Rubin, Bruce K

    2017-11-09

    Prostaglandin E2 (PGE2) is a ligand of the E-type prostanoid receptors, EP1-4. PGE2 secretion is increased in the airways of patients with asthma by secretory phospholipases A2, which also increases MUC5AC mucin in goblet cells. We hypothesized that PGE2 would also increase MUC5AC mRNA and secreted protein through specific EP receptor activation. We sought to assess the effect of specific EP receptor activation on MUC5AC secretion from ciliated-enriched cells or goblet-enriched cells induced by IL-13. We develop an enriched goblet cell epithelium by growing normal human bronchial epithelial cells at air liquid interface for 14 days in the presence of IL-13. We examined exposure to 4 specific EP receptor agonists at 24 h and 14 days in cells grown with or without IL-13 exposure, and measured MUC5AC mRNA and secreted protein, as well as airway culture morphology, and EP receptor expression. In ciliated-enriched cells grown in the absence of IL-13, the EP4 receptor agonist modestly increased both MUC5AC mRNA and secretion (p receptor agonist greatly increased both MUC5AC mRNA and protein (p receptor had no effect on secreted mucin. EP4 receptor mRNA and protein were significantly increased in goblet-enriched cells, while the other receptor mRNA were decreased. We conclude that PGE2 stimulates airway mucin production predominantly by EP4 receptor activation in association with increased EP4 receptor expression. This may contribute to mucus hypersecretion as seen in severe asthma. Copyright © 2017. Published by Elsevier Ltd.

  8. Regulation of sulfated glycosaminoglycan production by prostaglandin E2 in cultured lung fibroblasts

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    Karlinsky, J.B.; Goldstein, R.H. (Boston Univ. School of Medicine, MA (USA))

    1989-08-01

    Prostaglandin E2 (PGE2) has been shown to increase the synthesis of hyaluronic acid in cultured fibroblasts by increasing the activity of hyaluronate synthetase, a group of plasma membrane-bound synthetic enzymes. We examined whether PGE2 also increased the activity of those enzyme systems involved in the synthesis of sulfated glycosaminoglycan in the human embryonic lung fibroblast. Exposure of cells to PGE2 resulted in dose-dependent increases in glucosamine incorporation into all sulfated glycosaminoglycan subtypes. PGE2 at 10(-7) mol/L increased total glycosaminoglycan per dish to 21.6 +/- 3.1 micrograms versus 12.0 +/- 2.5 micrograms in control untreated cultures. Stimulation of endogenous PGE2 production by bradykinin had a similar effect on glycosaminoglycan synthesis. To examine whether PGE2 affected sulfated glycosaminoglycan protein core production, cells were labeled with tritiated glucosamine in the presence of cycloheximide. Under these conditions, incorporation of radiolabel into all glycosaminoglycan subtypes was reduced. However, when exogenous sulfated glycosaminoglycan chain initiator (p-nitrophenyl beta-D-xyloside) was added, incorporation of tritiated glucosamine into sulfated glycosaminoglycan increased but not to levels found in control cultures. Application of PGE2 to cultures treated with cycloheximide alone, or to cultures treated with cycloheximide plus xyloside, increased tritiated glucosamine incorporation into chondroitin, dermatan sulfate, and to a lesser extent into heparan sulfate. We conclude that PGE2 stimulates synthesis of all sulfated glycosaminoglycan even in the absence of new protein core production, probably by increasing activities of sulfated glycosaminoglycan synthetase enzymes. PGE2 stimulation of heparan sulfate synthesis is partially dependent on the availability of heparan sulfate-specific protein core.

  9. Prostaglandin E2 Indicates Therapeutic Efficacy of Mesenchymal Stem Cells in Experimental Traumatic Brain Injury.

    Science.gov (United States)

    Kota, Daniel J; Prabhakara, Karthik S; Toledano-Furman, Naama; Bhattarai, Deepa; Chen, Qingzheng; DiCarlo, Bryan; Smith, Philippa; Triolo, Fabio; Wenzel, Pamela L; Cox, Charles S; Olson, Scott D

    2017-05-01

    Traumatic brain injury (TBI) is soon predicted to become the third leading cause of death and disability worldwide. After the primary injury, a complex set of secondary injuries develops hours and days later with prolonged neuroinflammation playing a key role. TBI and other inflammatory conditions are currently being treated in preclinical and clinical trials by a number of cellular therapies. Mesenchymal stem cells (MSC) are of great interest due to their widespread usage, safety, and relative ease to isolate and culture. However, there has been a wide range in efficacy reported using MSC clinically and in preclinical models, likely due to differences in cell preparations and a significant amount of donor variability. In this study, we seek to find a correlation between in vitro activity and in vivo efficacy. We designed assays to explore the responsiveness of MSC to immunological cues to address the immunomodulatory properties of MSC, one of their primary modes of therapeutic activity in TBI. Our results showed intrinsic differences in the immunomodulatory capacity of MSC preparations from different bone marrow and amniotic fluid donors. This difference mirrored the therapeutic capacity of the MSC in an experimental model of TBI, an effect confirmed using siRNA knockdown of COX2 followed by overexpressing COX2. Among the immunomodulatory factors assessed, the therapeutic benefit correlated with the secretion of prostaglandin E2 (PGE2 ) by MSC prior to treatment, suggesting that measurement of PGE2 could be a very useful potency marker to create an index of predicted efficacy for preparations of MSC to treat TBI. Stem Cells 2017;35:1416-1430. © 2017 AlphaMed Press.

  10. Janus kinase 2 activation participates in prostaglandin E2-induced hyperalgesia.

    Science.gov (United States)

    Vieira, André Schwambach; Araldi, Dionéia; Dias, Elayne Vieira; do Prado, Filipe César; Tambeli, Claudia Herrera; Parada, Carlos Amilcar

    2016-12-01

    Prostaglandin E2 (PGE2) is one of the major signaling molecules involved in hyperalgesia, acting directly on nociceptors and resulting in the activation of PKA and PKC. Once active, these kinases phosphorylate many cellular proteins, resulting in changes on nociceptors sensorial transduction properties. The Janus Kinases (JAKs) are a family of intracellular signaling molecules generally associated with cytokine signaling, and their activity can be increased in nociceptors after peripheral inflammation. However, there are no evidences of JAKs direct involvement in PGE2 mediated sensitization of nociceptors. Therefore, the aim of the present study was to explore a possible role for JAKs in PGE2 mediated sensitization. In cultured dorsal root ganglion (DRG) neurons, we observed that the administration of PGE2 increases capsaicin induced calcium transients, and a pre-incubation of DRG cells with the JAK inhibitor AG490 blocks this PGE2 in vitro effect. Intrathecal administration of AG490 to ten-weeks-old male Wistar rats reduces the hyperalgesia induced by the intraplantar administration of PGE2 or carrageenan in the right hind paw. We also observed that carrageenan administration in the right hind paw induced an increase in membrane associated PKCepsilon in the ipsilateral L5 DRG, and this increase was blocked by intrathecal AG490 administration. In conclusion the present study indicates that the JAKs expressed in the DRG and spinal cord may have a role in the sensitization of nociceptors by a peripheral inflammatory event. Moreover, the inhibition of JAKs may be a possible novel pharmacological target for the control of the inflammatory hyperalgesia. Copyright © 2016. Published by Elsevier Inc.

  11. Cyclic Mechanical Stretching Induces Autophagic Cell Death in Tenofibroblasts Through Activation of Prostaglandin E2 Production

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    Hua Chen

    2015-04-01

    Full Text Available Background/Aims: Autophagic cell death has recently been implicated in the pathophysiology of tendinopathy. Prostaglandin E2 (PGE2, a known inflammatory mediator of tendinitis, inhibits tenofibroblast proliferation in vitro; however, the underlying mechanism is unclear. The present study investigated the relationship between PGE2 production and autophagic cell death in mechanically loaded human patellar tendon fibroblasts (HPTFs in vitro. Methods: Cultured HPTFs were subjected to exogenous PGE2 treatment or repetitive cyclic mechanical stretching. Cell death was determined by flow cytometry with acridine orange/ethidium bromide staining. Induction of autophagy was assessed by autophagy markers including the formation of autophagosomes and autolysosomes (by electron microscopy, AO staining, and formation of GPF-LC3-labeled vacuoles and the expression of LC3-II and BECN1 (by western blot. Stretching-induced PGE2 release was determined by ELISA. Results: Exogenous PGE2 significantly induced cell death and autophagy in HPTFs in a dose-dependent manner. Blocking autophagy using inhibitors 3-methyladenine and chloroquine, or small interfering RNAs against autophagy genes Becn-1 and Atg-5 prevented PGE2-induced cell death. Cyclic mechanical stretching at 8% and 12% magnitudes for 24 h significantly stimulated PGE2 release by HPTFs in a magnitude-dependent manner. In addition, mechanical stretching induced autophagy and cell death. Blocking PGE2 production using COX inhibitors indomethacin and celecoxib significantly reduced stretching-induced autophagy and cell death. Conclusion: Taken together, cyclic mechanical stretching induces autophagic cell death in tenofibroblasts through activation of PGE2 production.

  12. Vitamin D modulates prostaglandin E2 synthesis and degradation in human lung fibroblasts.

    Science.gov (United States)

    Liu, Xiangde; Nelson, Amy; Wang, Xingqi; Farid, Maha; Gunji, Yoko; Ikari, Jun; Iwasawa, Shun; Basma, Hesham; Feghali-Bostwick, Carol; Rennard, Stephen I

    2014-01-01

    Vitamin D insufficiency has been increasingly recognized in the general population worldwide and has been associated with several lung diseases, including asthma, chronic obstructive pulmonary disease (COPD), and respiratory tract infections. Fibroblasts play a critical role in tissue repair and remodeling, which is a key feature of COPD and asthma. Fibroblasts modulate tissue repair by producing and modifying extracellular matrix components and by releasing mediators that act as autocrine or paracrine modulators of tissue remodeling. The current study was designed to investigate if vitamin D alters fibroblast release of key autocrine/paracrine repair factors. First, we demonstrated that human fetal lung (HFL)-1 cells express the vitamin D receptor (VDR) and that vitamin D, 25-hydroxyvitamin D [25(OH)D], or 1,25-dihydroxyvitamin D [1,25(OH)2D] induce VDR nuclear translocation and increase VDR-DNA binding activity. We next demonstrated that vitamin D, 25(OH)D, and 1,25(OH)2D significantly reduced prostaglandin (PG)E2 production by human lung fibroblasts (HFL-1) but had no effect on transforming growth factor β1, vascular endothelial growth factor, or fibronectin production. Vitamin D, 25(OH)D, and 1,25(OH)2D significantly inhibited IL-1β-induced microsomal PGE synthase (mPGES)-1 expression; in contrast, all three forms of vitamin D stimulated 15-hydroxy PG dehydrogenase, an enzyme that degrades PGE2. Cyclooxygenase-1 and -2 and the other two PGE2 synthases (mPGES-2 and cytosolic PGE synthase) were not altered by vitamin D, 25(OH)D, or 1,25(OH)2D. Finally, the effect of PGE2 inhibition by 25(OH)D was observed in adult lung fibroblasts. These findings suggest that vitamin D can regulate PGE2 synthesis and degradation and by this mechanism can modulate fibroblast-mediated tissue repair function.

  13. Presence of crevicular fluid Prostaglandin E2 in relation with clinical and radiographic periodontal status

    Directory of Open Access Journals (Sweden)

    Javier Elpidio Monzón

    2016-07-01

    Full Text Available Background and Objectives: Prostaglandin E2 (PGE2 is present in gingival crevicular fluid the (GCF and is evidenced in periodontal disease (PD. However, there are no enough reports to correlate the PGE2 concentrations in GCF in periodontal health and disease with clinical and radiographic indicators, age and gender. Hence, the present study is aimed to estimate the levels of PGE2 in GCF of subjects without periodontal disease (SEP and periodontal disease (CEP. Materials and Methods: 99 subjects were selected, 33 without PD (G1 and 66 with PD, 33 with gingivitis (G2 and 33 with periodontitis (G3, which were submitted to a clinical and radiographic diagnosis, registering samples FGC, being stored, centrifuged and refrigerated for preservation. Subsequently the concentration of crevicular PGE2 was measured by using the enzyme linked immunosorbent assay (ELISA, determining the concentration of each subject. Results: PGE2 was detected in all the samples. The G1 presented a concentration of 28.82 ± 2.88 pg / mL, G2 44.91 ± 4.37 pg / mL and G3 148.67 ± 74.74 pg / mL (0.0001. PGE2 levels were significantly correlated with bleeding on probing, probing depth, attachment loss and bone loss (0.05. PGE2 levels were modified by age, but not gender. Conclusion: It is well known that activated inflammatory cells produce inflammatory mediators that stimulate the production of PGE2. The findings of this study demonstrate an increased concentration of PGE2 in FCG according to the presence of greater severity of PD. PGE2 may be considered as a biomarker in PD progression. However, controlled, longitudinal studies are needed to confirm this possibility.

  14. Carnosol and carnosic acids from Salvia officinalis inhibit microsomal prostaglandin E2 synthase-1.

    Science.gov (United States)

    Bauer, Julia; Kuehnl, Susanne; Rollinger, Judith M; Scherer, Olga; Northoff, Hinnak; Stuppner, Hermann; Werz, Oliver; Koeberle, Andreas

    2012-07-01

    Prostaglandin E(2) (PGE(2)), the most relevant eicosanoid promoting inflammation and tumorigenesis, is formed by cyclooxygenases (COXs) and PGE(2) synthases from free arachidonic acid. Preparations of the leaves of Salvia officinalis are commonly used in folk medicine as an effective antiseptic and anti-inflammatory remedy and possess anticancer activity. Here, we demonstrate that a standard ethyl acetate extract of S. officinalis efficiently suppresses the formation of PGE(2) in a cell-free assay by direct interference with microsomal PGE(2) synthase (mPGES)-1. Bioactivity-guided fractionation of the extract yielded closely related fractions that potently suppressed mPGES-1 with IC(50) values between 1.9 and 3.5 μg/ml. Component analysis of these fractions revealed the diterpenes carnosol and carnosic acid as potential bioactive principles inhibiting mPGES-1 activity with IC(50) values of 5.0 μM. Using a human whole-blood assay as a robust cell-based model, carnosic acid, but not carnosol, blocked PGE(2) generation upon stimulation with lipopolysaccharide (IC(50) = 9.3 μM). Carnosic acid neither inhibited the concomitant biosynthesis of other prostanoids [6-keto PGF(1α), 12(S)-hydroxy-5-cis-8,10-trans-heptadecatrienoic acid, and thromboxane B(2)] in human whole blood nor affected the activities of COX-1/2 in a cell-free assay. Together, S. officinalis extracts and its ingredients carnosol and carnosic acid inhibit PGE(2) formation by selectively targeting mPGES-1. We conclude that the inhibitory effect of carnosic acid on PGE(2) formation, observed in the physiologically relevant whole-blood model, may critically contribute to the anti-inflammatory and anticarcinogenic properties of S. officinalis.

  15. Prostaglandin E2 resistance in granulocytes from patients with aspirin-exacerbated respiratory disease.

    Science.gov (United States)

    Laidlaw, Tanya M; Cutler, Anya J; Kidder, Molly S; Liu, Tao; Cardet, Juan Carlos; Chhay, Heng; Feng, Chunli; Boyce, Joshua A

    2014-06-01

    Aspirin-exacerbated respiratory disease (AERD) is an inflammatory condition of the respiratory tract and is characterized by overproduction of leukotrienes (LT) and large numbers of circulating granulocyte-platelet complexes. LT production can be suppressed by prostaglandin E(2) (PGE(2)) and the cyclic AMP-dependent protein kinase A (PKA). To determine if PGE(2)-dependent control of LT production by granulocytes is dysregulated in AERD. Granulocytes from well-characterized patients with and without AERD were activated ex vivo and subjected to a range of functional and biochemical analyses. Granulocytes from subjects with AERD generated more LTB4 and cysteinyl LTs than did granulocytes from controls with aspirin-tolerant asthma and controls without asthma. When compared with controls, granulocytes from subjects with AERD had comparable levels of EP(2) protein expression and PGE(2)-mediated cAMP accumulation, yet were resistant to PGE(2)-mediated suppression of LT generation. Percentages of platelet-adherent neutrophils correlated positively with LTB4 generation and inversely with responsiveness to PGE(2)-mediated suppression of LTB(4). The PKA inhibitor H89 potentiated LTB4 generation by control granulocytes but was inactive in granulocytes from individuals with AERD and had no effect on platelet P-selectin induction. Both tonic PKA activity and levels of PKA catalytic gamma subunit protein were significantly lower in granulocytes from individuals with AERD relative to those from controls. Impaired granulocyte PKA function in AERD may lead to dysregulated control of 5-lipoxygenase activity by PGE(2), whereas adherent platelets lead to increased production of LTs, which contributes to the features of persistent respiratory tract inflammation and LT overproduction. Copyright © 2014 American Academy of Allergy, Asthma & Immunology. Published by Mosby, Inc. All rights reserved.

  16. Perspective of microsomal prostaglandin E2 synthase-1 as drug target in inflammation-related disorders.

    Science.gov (United States)

    Koeberle, Andreas; Werz, Oliver

    2015-11-01

    Prostaglandin (PG)E2 encompasses crucial roles in pain, fever, inflammation and diseases with inflammatory component, such as cancer, but is also essential for gastric, renal, cardiovascular and immune homeostasis. Cyclooxygenases (COX) convert arachidonic acid to the intermediate PGH2 which is isomerized to PGE2 by at least three different PGE2 synthases. Inhibitors of COX - non-steroidal anti-inflammatory drugs (NSAIDs) - are currently the only available therapeutics that target PGE2 biosynthesis. Due to adverse effects of COX inhibitors on the cardiovascular system (COX-2-selective), stomach and kidney (COX-1/2-unselective), novel pharmacological strategies are in demand. The inducible microsomal PGE2 synthase (mPGES)-1 is considered mainly responsible for the excessive PGE2 synthesis during inflammation and was suggested as promising drug target for suppressing PGE2 biosynthesis. However, 15 years after intensive research on the biology and pharmacology of mPGES-1, the therapeutic value of mPGES-1 as drug target is still vague and mPGES-1 inhibitors did not enter the market so far. This commentary will first shed light on the structure, mechanism and regulation of mPGES-1 and will then discuss its biological function and the consequence of its inhibition for the dynamic network of eicosanoids. Moreover, we (i) present current strategies for interfering with mPGES-1-mediated PGE2 synthesis, (ii) summarize bioanalytical approaches for mPGES-1 drug discovery and (iii) describe preclinical test systems for the characterization of mPGES-1 inhibitors. The pharmacological potential of selective mPGES-1 inhibitor classes as well as dual mPGES-1/5-lipoxygenase inhibitors is reviewed and pitfalls in their development, including species discrepancies and loss of in vivo activity, are discussed. Copyright © 2015 Elsevier Inc. All rights reserved.

  17. Prostaglandin E2 potentiation of P2X3 receptor mediated currents in dorsal root ganglion neurons

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    Huang Li-Yen

    2007-08-01

    Full Text Available Abstract Prostaglandin E2 (PGE2 is a well-known inflammatory mediator that enhances the excitability of DRG neurons. Homomeric P2X3 and heteromeric P2X2/3 receptors are abundantly expressed in dorsal root ganglia (DRG neurons and participate in the transmission of nociceptive signals. The interaction between PGE2 and P2X3 receptors has not been well delineated. We studied the actions of PGE2 on ATP-activated currents in dissociated DRG neurons under voltage-clamp conditions. PGE2 had no effects on P2X2/3 receptor-mediated responses, but significantly potentiated fast-inactivating ATP currents mediated by homomeric P2X3 receptors. PGE2 exerted its action by activating EP3 receptors. To study the mechanism underlying the action of PGE2, we found that the adenylyl cyclase activator, forskolin and the membrane-permeable cAMP analogue, 8-Br-cAMP increased ATP currents, mimicking the effect of PGE2. In addition, forskolin occluded the enhancement produced by PGE2. The protein kinase A (PKA inhibitors, H89 and PKA-I blocked the PGE2 effect. In contrast, the PKC inhibitor, bisindolymaleimide (Bis did not change the potentiating action of PGE2. We further showed that PGE2 enhanced α,β-meATP-induced allodynia and hyperalgesia and the enhancement was blocked by H89. These observations suggest that PGE2 binds to EP3 receptors, resulting in the activation of cAMP/PKA signaling pathway and leading to an enhancement of P2X3 homomeric receptor-mediated ATP responses in DRG neurons.

  18. [Various effects of prostaglandin E2 on reabsorption of water and urea in the amphibia osmosis-regulating epithelium].

    Science.gov (United States)

    Parnova, R G; Bakhteeva, V T; Lavrova, E A

    2001-12-01

    Principal similarities between molecular pathways providing the enhancement of water and urea reabsorption under the action of argininvasotocin (AVT) in amphibian urinary bladder suggest that prostaglandin E2 (PGE2) could be a negative regulator of urea transport. To analyse this hypothesis, the role of PGE2 in regulation of urea transport was studied in isolated frog (Rana temporaria L.) urinary bladder. The urea permeability (Pu) was determined from the rate of efflux of (14) Curea from mucosal to serosal solution in isoosmotic conditions. The water permeability was measured in separate experiments in presence of an osmotic gradient. In contrast to water permeability, we were unable to demonstrate any inhibitory effect of 10-1000 nM PGE2 on AVT-stimulated urea transport using a variety of protocols. It was found that basolateral PGE2 exposure (10 nM-1 microM) caused an increase in Pu with no effect on osmotic water flow. The PGE2 effect was markedly inhibited by phloretin, a specific inhibitor of urea transporter. Sulprostone, an EP1/EP3 prostaglandin E2 receptor agonist, had no effect on Pu suggesting the contribution of EP2/EP4 receptor subtypes. In presence of osmotic water flow, the AVT-induced urea transport was significantly higher. This water flow-dependent urea permeability was inhibited by PGE2 although the inhibitory effect was less pronounced in comparison to the action of PGE2 on osmotic water flow. On the basis of these results we can make a conclusion that PGE2 has different role in regulation of water and urea transport in the frog urinary bladder. PGE2 could be considered as a stimulator of urea transport and an inhibitor of osmotic water flow activated by the AVT. The ability of PGE2 to regulate various types of cAMP-dependent transport by different mechanisms seems to be based on the presence of multiple basolateral PGE2 receptor subtypes in amphibian osmosis-regulatory epithelium.

  19. Prostaglandin E2 receptor subtype EP-2 is not involved in the induction of non-pregnant guinea pig uterine contractions associated with terminal pregnancy.

    Science.gov (United States)

    Lebel, Wes; Riccardi, Keith; Grasser, W A; Terry, Ketti; Thompson, David; Paralkar, V M

    2004-12-01

    Prostaglandin E2 (PGE2) exerts its biological effects through 4 different receptor subtypes, EP-1, EP-2, EP-3, and EP-4. Recently we have demonstrated the importance of the prostaglandin E2 receptor subtype EP-2 in the healing of bone defects and fractures. This discovery led to the identification of CP-533,536, an EP-2 selective agonist, a promising therapeutic alternative for the enhancement of bone healing and the treatment of fractures (J Bone Miner Res 18 (2003) 2033). PGE2 has a myriad of effects throughout the body including the induction of uterine contractions, which results in termination of pregnancies. Our objective in this study was to determine the role of the EP-2 receptor and specifically that of CP-533,536, an EP-2 specific agonist, to induce uterine contractions and terminate pregnancy in guinea pigs, an animal model of human pregnancy. Preliminary experiments confirmed earlier reports that the guinea pig uterus was more sensitive than that of the rat. The guinea pig uterus contains the four PGE2 receptor subtypes, and ex vivo treatment of the uterus with PGE2 as expected causes profound uterine contractions. However, using receptor selective prostaglandin agonists including CP-533,536 we showed that the EP-1 and 3 receptors not the EP-2 receptor is responsible for the induction of uterine contractions of PGE2. Further, CP-533,536 did not antagonize the ability of PGE2 to induce uterine contractions in this model.

  20. Perubahan Kadar Prostaglandin E2 (PGE2) Setelah Aplikasi Ekstrak Gambir (Uncaria Gambir ROXB) Pada Kasus Pulpitis Ireversible.

    OpenAIRE

    Samad, Rasmidar

    2017-01-01

    The dental pulp was soft tissue, reside in the cental of tooth, enclosed by, email, dentine and cementum, Inflammation of dental pulp was called pulpitis. Two groups of pulpitis, among these pulpitis, irreversible pulpitis. Design of this researc pre and post test to evaluate change the levels of prostaglandin E2 (PGE2) post application gambier (Uncaria Gambier Roxb) extract, in January-April 2016 in the Biofarmaca Laboratory Research Center Activities Faclty of Pharmacy.

  1. LXR modulation blocks prostaglandin E2 production and matrix degradation in cartilage and alleviates pain in a rat osteoarthritis model

    OpenAIRE

    Li, Ning; Rivéra-Bermúdez, Moisés A.; ZHANG, MEI; Tejada, Julio; Glasson, Sonya S.; Collins-Racie, Lisa A.; LaVallie, Edward R; Wang, Yihe; Chang, Ken C. N.; Nagpal, Sunil; Morris, Elisabeth A; Flannery, Carl R; Yang, Zhiyong

    2010-01-01

    Osteoarthritis (OA), the most common arthritic condition in humans, is characterized by the progressive degeneration of articular cartilage accompanied by chronic joint pain. Inflammatory mediators, such as cytokines and prostaglandin E2 (PGE2) that are elevated in OA joints, play important roles in the progression of cartilage degradation and pain-associated nociceptor sensitivity. We have found that the nuclear receptor family transcription factors Liver X Receptors (LXRα and -β) are expres...

  2. Retrograde and local destination transfer of uterine prostaglandin E2 in early pregnant sow and its physiological consequences.

    Science.gov (United States)

    Stefańczyk-Krzymowska, Stanisława; Wasowska, Barbara; Chłopek, Jolanta; Gilun, Przemysław; Grzegorzewski, Waldemar; Radomski, Michał

    2006-10-01

    The local destination transfer of prostaglandin E2 (PGE2) from the uterine lymph to arterial blood supplying the ovary and its retrograde transfer to arterial blood supplying the uterine horn and the effect of additional delivery of PGE2 into the ovary on the secretion of steroid hormones was studied in early pregnant gilts. The injection of PGE2 under the perimetrium caused an increase (Ppregnancy during (Ppregnancy after infusion (Pearly pregnant gilts.

  3. Production of prostaglandin E2 in monocytes stimulated in vitro by Chlamydia trachomatis, Chlamydophila pneumoniae, and Mycoplasma fermentans.

    Science.gov (United States)

    Krausse-Opatz, Birgit; Schmidt, Cornelia; Fendrich, Ursula; Bialowons, Anke; Kaever, Volkhard; Zeidler, Henning; Kuipers, Jens; Köhler, Lars

    2004-09-01

    Chlamydia trachomatis (CT) as well as Chlamydophila pneumoniae (CP) cause chronic inflammatory diseases in humans. Persistently infected monocytes are involved in the pathogenesis by inducing mediators of inflammation. An in vitro system of chlamydial persistence in human peripheral blood monocytes (HPBM) was used to investigate prostaglandin E(2) (PGE(2)) production and the expression of the key enzyme for prostaglandin production, cyclooxygenase-2 (COX-2). PGE(2) production was determined by PGE(2)-ELISA of HPBM-culture supernatants. Cox-2 mRNA expression was measured by real-time RT-PCR of total RNA isolated from HPBM. Both, CT and CP, stimulated PGE(2) production of HPBM in vitro. Equivalent numbers of CT per host cell induced a higher PGE(2)-response compared to CP. The amount of synthesized PGE(2) depended on the chlamydial multiplicity of infection (MOI). Even at an MOI of 10 the amount of CT- and CP-induced prostaglandin, respectively, was lower than the amount of prostaglandin induced by E. coli lipopolysaccharide (LPS) at a concentration of 10microg/ml. In contrast to stimulation with LPS, Chlamydia-induced PGE(2) production as well as cox-2 mRNA decreased after day 1 post infection (p.i.). These data indicate that Chlamydia stimulate PGE(2) production in human monocytes. Since Chlamydia are often contaminated by mycoplasma, the influence of mycoplasma on the prostaglandin production was investigated additionally. Mycoplasma fermentans (MF) also stimulated PGE(2) production. The co-infection of mycoplasma and Chlamydia resulted in an additive effect in the production of PGE(2). Thus it is important to use host cells and Chlamydia free of mycoplasma contamination for the analysis of Chlamydia-induced prostaglandin production.

  4. Comparison of plasma oxytocin levels during spontaneous labor and labor induced by amniotomy, prostaglandin F2 alpha, and prostaglandin E2.

    Science.gov (United States)

    Nagata, I; Kato, K; Makimura, N; Uesato, T; Seki, K; Kikuchi, Y

    1983-10-01

    Plasma concentrations of oxytocin in nine spontaneous labors (group 1), nine amniotomy-induced labors (group 2), six prostaglandin F2 alpha-induced labors (group 3), and five prostaglandin E2-induced labors (group 4) were determined at the stages of 1 to 7 days preceding the onset of labor, onset of labor, and established labor, by means of unextracted radioimmunoassay. The levels of oxytocin in the stage preceding the onset of labor in group 1 were not significantly different from the levels of oxytocin in the corresponding stages in groups 2, 3, and 4. However, the levels of oxytocin in the stages of onset of labor and established labor in group 1 were significantly higher than those in the corresponding stages in groups 2, 3, and 4. These results suggest that oxytocin plays a leading role in the onset and progress of spontaneous labor, whereas something other than oxytocin might be involved in the labor induced by amniotomy alone or by prostaglandins.

  5. Characterization of biosynthesis and modes of action of prostaglandin E2 and prostacyclin in guinea pig mesenteric lymphatic vessels.

    Science.gov (United States)

    Rehal, Sonia; Blanckaert, Pauline; Roizes, Simon; von der Weid, Pierre-Yves

    2009-12-01

    Rhythmical transient constrictions of the lymphatic vessels provide the means for efficient lymph drainage and interstitial tissue fluid balance. This activity is critical during inflammation, to avoid or limit oedema resulting from increased vascular permeability, mediated by the release of various inflammatory mediators. In this study, we investigated the mechanisms by which prostaglandin E(2) (PGE(2)) and prostacyclin modulate lymphatic contractility in isolated guinea pig mesenteric lymphatic vessels. Quantitative RT-PCR was used to assess the expression of mRNA for enzymes and receptors involved in the production and action of PGE(2) and prostacyclin in mesenteric collecting lymphatic vessels. Frequency and amplitude of lymphatic vessel constriction were measured in the presence of these prostaglandins and the role of their respective EP and IP receptors assessed. Prostaglandin E(2) and prostacyclin decreased concentration-dependently the frequency, without affecting the amplitude, of lymphatic constriction. Data obtained in the presence of the EP(4) receptor antagonists, GW627368x (1 microM) and AH23848B (30 microM) and the IP receptor antagonist CAY10441 (0.1 microM) suggest that PGE(2) predominantly activates EP(4), whereas prostacyclin mainly stimulates IP receptors. Inhibition of responses to either prostaglandin with H89 (10 microM) or glibenclamide (1 microM) suggested a role for the activation of protein kinase A and ATP-sensitive K(+) channels. Our findings characterized the inhibition of lymphatic pumping induced by PGE(2) or prostacyclin in guinea pig mesenteric lymphatics. This action is likely to impair oedema resolution and to contribute to the pro-inflammatory actions of these prostaglandins.

  6. Anabolic Responses of an Adult Cancellous Bone Site to Prostaglandin E2 in the Rat

    Science.gov (United States)

    Ito, Hiroshi; Ke, Hua Zhu; Jee, Webster S. S.; Sakou, Takashi

    1993-01-01

    The objects of this study were to determine: (1) the response of a non-growing cancellous bone site to daily prostaglandin E2 (PGE2) administration; and (2) the differences in the effects of daily PGE2, administration in growing (proximal tibial metaphysis, PTM) and non-growing cancellous bone sites (distal tibial metaphysis, DTM). Seven-month-old male Sprague-Dawley rats were given daily subcutaneous injections of 0, 1, 3 and 6 mg PGE2/kg per day for 60, 120 and 180 days. The static and dynamic histomorphometric analyses were performed on double-fluorescent labeled undecalcified distal tibial metaphyses (DTM). No age-related changes were found in static and dynamic histomorphometry of DTM cancellous bone between 7 and 13 months of age. The DTM of 7-month-old (basal controls) rats consisted of a 24.5 +/- 7.61%-metaphyseal cancellous bone mass, and a thick trabeculae (92 +/- 12 micro-m). It also had a very low tissue-base bone formation rate (3.0 +/- 7.31%/year). Exogenous PGE2 administration produced the following transient changes in a dose-response manner between zero and 60 days: (1) increased trabecular bone mass and improved architecture (increased trabecular bone area, width and number, and decreased trabecular separation); (2) increased trabecular interconnections: (3) increased bone formation parameters; and (4) decreased eroded perimeter. A new steady state with more cancellous bone mass and higher bone turnover was observed from day 60 onward, The elevated bone mass induced by the first 60 days of PGE2 treatment was maintained by another 60 and 120 days with continuous daily PGE2 treatment. When these findings were compared to those previously reported for the PTM, we found that the DTM was much more responsive to PGE2 treatment than the PTM. Percent trabecular bone area and tissue based bone formation rate increased significantly more in DTM as compared to PTM after the 60 days of 6 mg PGE2 treatment. These observations indicate that a non

  7. Impaired neonatal macrophage phagocytosis is not explained by overproduction of prostaglandin E2

    Directory of Open Access Journals (Sweden)

    Ballinger Megan N

    2011-12-01

    Full Text Available Abstract Background Neonates and young infants manifest increased susceptibility to bacterial, viral and fungal lung infections. Previous work has identified a role for eicosanoids in mediating host defense functions of macrophages. This study examines the relationship between alveolar macrophage (AM host defense and production of lipid mediators during the neonatal period compared to adult AMs. Methods AMs were harvested from young (day 7 and day 14 and adult (~10 week rats. The functionality of these cells was assessed by examining their ability to phagocytose opsonized targets, produce cytokines, eicosanoids and intracellular cAMP measured by enzyme immunoassays, and gene expression of proteins, enzymes and receptors essential for eicosanoid generation and phagocytosis measured by real time RT-PCR. Results AMs from young animals (day 7 and 14 were defective in their ability to phagocytose opsonized targets and produce tumor necrosis factor (TNF- α. In addition, young AMs produce more prostaglandin (PG E2, a suppressor of host defense, and less leukotriene (LT B4, a promoter of host defense. Young AMs express higher levels of enzymes responsible for the production of PGE2 and LTB4; however, there was no change in the expression of E prostanoid (EP receptors or LT receptors. Despite the similar EP profiles, young AMs are more responsive to PGE2 as evidenced by their increased production of the important second messenger, cyclic AMP. In addition, young AMs express higher levels of PDE3B and lower levels of PDE4C compared to adult AMs. However, even though the young AMs produced a skewed eicosanoid profile, neither the inhibition of PGE2 by aspirin nor the addition of exogenous LTB4 rescued the defective opsonized phagocytosis. Examination of a receptor responsible for mediating opsonized phagocytosis showed a significant decrease in the gene expression levels of the Fcgamma receptor in young (day 7 AMs compared to adult AMs. Conclusion These

  8. Prostaglandin E2 in tick saliva regulates macrophage cell migration and cytokine profile

    Science.gov (United States)

    2013-01-01

    Background Ticks are obligate hematophagous ectoparasites that suppress the host’s immune and inflammatory responses by secreting immuno-modulatory and anti-inflammatory molecules in their saliva. In previous studies we have shown that tick salivary gland extract (SGE) and saliva from Dermacentor variabilis have distinct effects on platelet-derived growth factor (PDGF)-stimulated IC-21 macrophage and NIH3T3-L1 fibroblast migration. Since tick saliva contains a high concentration of prostaglandin E2 (PGE2), a potent modulator of inflammation, we used a PGE2 receptor antagonist to evaluate the role of PGE2 in the different migratory responses induced by saliva and its impact on macrophage cytokine profile. Methods Adult ticks were fed on female New Zealand white rabbits for 5-8 days. Female ticks were stimulated with dopamine/theophylline to induce salivation and saliva was pooled. Competitive enzyme immunoassays (EIA) were used to measure saliva PGE2 content and the changes in macrophage intracellular cyclic adenosine monophosphate (cAMP) levels. The effects of tick saliva on macrophage and fibroblast migration were assessed in the absence and presence of the PGE2 receptor antagonist, AH 6809, using blind well chamber assays. A cytokine antibody array was used to examine the effects of tick saliva on macrophage cytokine secretion. Statistical significance was determined by one-way ANOVA; Student Newman-Kuels post-test was used for multiple comparisons. Results The saliva-induced increase in PDGF-stimulated macrophage migration was reversed by AH 6809. The inhibition of PDGF-stimulated fibroblast migration by saliva was also antagonist-sensitive. Tick saliva induced macrophages to secrete copious amounts of PGE2, and conditioned medium from these cells caused an AH 6809-sensitive inhibition of stimulated fibroblast migration, showing that macrophages can regulate fibroblast activity. We show that tick saliva decreased the secretion of the pro

  9. Increased jejunal prostaglandin E2 concentrations in patients with acute cholera

    NARCIS (Netherlands)

    Speelman, P.; Rabbani, G. H.; Bukhave, K.; Rask-Madsen, J.

    1985-01-01

    Supraphysiologic doses of prostaglandins (PGs) mimic the effect of cholera toxin and cAMP in the small intestine, but not all observations are explicable in terms of the theory that links PGs to cAMP. Because no data exist on endogenous PGs in human cholera we measured PGE2 concentrations in jejunal

  10. Activation of prostaglandin E2 EP1 receptor increases arteriolar tone and blood pressure in mice with type 2 diabetes

    Science.gov (United States)

    Rutkai, Ibolya; Feher, Attila; Erdei, Nora; Henrion, Daniel; Papp, Zoltan; Edes, Istvan; Koller, Akos; Kaley, Gabor; Bagi, Zsolt

    2009-01-01

    Aims Type 2 diabetes mellitus is frequently associated with hypertension, but the underlying mechanisms are not completely understood. We tested the hypothesis that activation of type 1 prostaglandin E2 (PGE2) receptor (EP1) increases skeletal muscle arteriolar tone and blood pressure in mice with type 2 diabetes. Methods and results In 12-week-old, male db/db mice (with homozygote mutation in leptin receptor), systolic blood pressure was significantly elevated, compared with control heterozygotes. Isolated, pressurized gracilis muscle arterioles (∼90 µm) of db/db mice exhibited an enhanced pressure- and angiotensin II (0.1–10 nM)-induced tone, which was reduced by the selective EP1 receptor antagonist, AH6809 (10 µM), to the level observed in arterioles of control mice. Exogenous application of PGE2 (10 pM–100 nM) or the selective agonist of the EP1 receptor, 17-phenyl-trinor-PGE2 (10 pM–100 nM), elicited arteriolar constrictions that were significantly enhanced in db/db mice (max: 31 ± 4 and 29 ± 5%), compared with controls (max: 20 ± 2 and 14 ± 3%, respectively). In the aorta of db/db mice, an increased protein expression of EP1, but not EP4, receptor was also detected by western immunoblotting. Moreover, we found that oral administration of the EP1 receptor antagonist, AH6809 (10 mg/kg/day, for 4 days), significantly reduced the systolic blood pressure in db/db, but not in control mice. Conclusion Activation of EP1 receptors increases arteriolar tone, which could contribute to the development of hypertension in the db/db mice. PMID:19299433

  11. A prostaglandin E2 receptor antagonist prevents pregnancies during a preclinical contraceptive trial with female macaques.

    Science.gov (United States)

    Peluffo, M C; Stanley, J; Braeuer, N; Rotgeri, A; Fritzemeier, K-H; Fuhrmann, U; Buchmann, B; Adevai, T; Murphy, M J; Zelinski, M B; Lindenthal, B; Hennebold, J D; Stouffer, R L

    2014-07-01

    Can administration of a prostaglandin (PG) E2 receptor 2 (PTGER2) antagonist prevent pregnancy in adult female monkeys by blocking periovulatory events in the follicle without altering menstrual cyclicity or general health? This is the first study to demonstrate that a PTGER2 antagonist can serve as an effective non-hormonal contraceptive in primates. The requirement for PGE2 in ovulation and the release of an oocyte surrounded by expanded cumulus cells (cumulus-oocyte expansion; C-OE) was established through the generation of PTGS2 and PTGER2 null-mutant mice. A critical role for PGE2 in primate ovulation is supported by evidence that intrafollicular injection of indomethacin in rhesus monkeys suppressed follicle rupture, whereas co-injection of PGE2 with indomethacin resulted in ovulation. First, controlled ovulation protocols were performed in adult, female rhesus monkeys to analyze the mRNA levels for genes encoding PGE2 synthesis and signaling components in the naturally selected pre-ovulatory follicle at different times after the ovulatory hCG stimulus (0, 12, 24, 36 h pre-ovulation; 36 h post-ovulation, n = 3-4/time point). Second, controlled ovarian stimulation cycles were utilized to obtain multiple cumulus-oocyte complexes (COCs) from rhesus monkeys to evaluate the role of PGE2 in C-OE in vitro (n = 3-4 animals/treatment; ≥3 COCs/animal/treatment). Third, adult cycling female cynomolgus macaques were randomly assigned (n = 10/group) to vehicle (control) or PTGER2 antagonist (BAY06) groups to perform a contraceptive trial. After the first treatment cycle, a male of proven fertility was introduced into each group and they remained housed together for the duration of the 5-month contraceptive trial that was followed by a post-treatment reversibility trial. Quantitative real-time PCR, COC culture and expansion, immunofluorescence/confocal microscopy, enzyme immunoassay, contraceptive trial, ultrasonography, complete blood counts, serum biochemistry tests

  12. A prostaglandin E2 receptor antagonist prevents pregnancies during a preclinical contraceptive trial with female macaques

    Science.gov (United States)

    Peluffo, M.C.; Stanley, J.; Braeuer, N.; Rotgeri, A.; Fritzemeier, K.-H.; Fuhrmann, U.; Buchmann, B.; Adevai, T.; Murphy, M.J.; Zelinski, M.B.; Lindenthal, B.; Hennebold, J.D.; Stouffer, R.L.

    2014-01-01

    STUDY QUESTION Can administration of a prostaglandin (PG) E2 receptor 2 (PTGER2) antagonist prevent pregnancy in adult female monkeys by blocking periovulatory events in the follicle without altering menstrual cyclicity or general health? SUMMARY ANSWER This is the first study to demonstrate that a PTGER2 antagonist can serve as an effective non-hormonal contraceptive in primates. WHAT IS KNOWN ALREADY The requirement for PGE2 in ovulation and the release of an oocyte surrounded by expanded cumulus cells (cumulus–oocyte expansion; C-OE) was established through the generation of PTGS2 and PTGER2 null-mutant mice. A critical role for PGE2 in primate ovulation is supported by evidence that intrafollicular injection of indomethacin in rhesus monkeys suppressed follicle rupture, whereas co-injection of PGE2 with indomethacin resulted in ovulation. STUDY DESIGN, SIZE, DURATION First, controlled ovulation protocols were performed in adult, female rhesus monkeys to analyze the mRNA levels for genes encoding PGE2 synthesis and signaling components in the naturally selected pre-ovulatory follicle at different times after the ovulatory hCG stimulus (0, 12, 24, 36 h pre-ovulation; 36 h post-ovulation, n = 3–4/time point). Second, controlled ovarian stimulation cycles were utilized to obtain multiple cumulus–oocyte complexes (COCs) from rhesus monkeys to evaluate the role of PGE2 in C-OE in vitro (n = 3–4 animals/treatment; ≥3 COCs/animal/treatment). Third, adult cycling female cynomolgus macaques were randomly assigned (n = 10/group) to vehicle (control) or PTGER2 antagonist (BAY06) groups to perform a contraceptive trial. After the first treatment cycle, a male of proven fertility was introduced into each group and they remained housed together for the duration of the 5-month contraceptive trial that was followed by a post-treatment reversibility trial. PARTICIPANTS/MATERIALS, SETTING, METHODS Quantitative real-time PCR, COC culture and expansion, immunofluorescence

  13. Prostaglandin E2 and its methyl ester reduce cataplexy in canine narcolepsy.

    Science.gov (United States)

    Nishino, S; Mignot, E; Fruhstorfer, B; Dement, W C; Hayaishi, O

    1989-04-01

    The effects of intravenous administration of prostaglandins (PGs) were investigated in genetically narcoleptic Doberman pinschers. The treatment of narcoleptic dogs with PGE2 and PGE2 methyl ester, but not PGD2 and PGD2 methyl ester, induced a dose-dependent reduction of canine cataplexy, a dissociated manifestation of rapid-eye-movement sleep. The effect was specific and not associated with any change in other behavior. Furthermore, the effect was long-lasting (up to 2 hr) and could not be explained by the acute cardiovascular changes seen after intravenous PG administration. PGE2 methyl ester, a lipophilic derivative of PGE2 with more central penetration than PGE2, was 4 times more potent than PGE2. These results indicate that PGE2 modifies cataplexy through a central effect and suggest that this prostaglandin may play a role in rapid-eye-movement sleep regulation.

  14. Activation of α7 nicotinic acetylcholine receptor by nicotine selectively up-regulates cyclooxygenase-2 and prostaglandin E2 in rat microglial cultures

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    Minghetti Luisa

    2005-01-01

    Full Text Available Abstract Background Nicotinic acetylcholine (Ach receptors are ligand-gated pentameric ion channels whose main function is to transmit signals for the neurotransmitter Ach in peripheral and central nervous system. However, the α7 nicotinic receptor has been recently found in several non-neuronal cells and described as an important regulator of cellular function. Nicotine and ACh have been recently reported to inhibit tumor necrosis factor-α (TNF-α production in human macrophages as well as in mouse microglial cultures. In the present study, we investigated whether the stimulation of α7 nicotinic receptor by the specific agonist nicotine could affect the functional state of activated microglia by promoting and/or inhibiting the release of other important pro-inflammatory and lipid mediator such as prostaglandin E2. Methods Expression of α7 nicotinic receptor in rat microglial cell was examined by RT-PCR, immunofluorescence staining and Western blot. The functional effects of α7 receptor activation were analyzed in resting or lipopolysaccharide (LPS stimulated microglial cells pre-treated with nicotine. Culture media were assayed for the levels of tumor necrosis factor, interleukin-1β, nitric oxide, interleukin-10 and prostaglandin E2. Total RNA was assayed by RT-PCR for the expression of COX-2 mRNA. Results Rat microglial cells express α7 nicotinic receptor, and its activation by nicotine dose-dependently reduces the LPS-induced release of TNF-α, but has little or no effect on nitric oxide, interleukin-10 and interleukin-1β. By contrast, nicotine enhances the expression of cyclooxygenase-2 and the synthesis of one of its major products, prostaglandin E2. Conclusions Since prostaglandin E2 modulates several macrophage and lymphocyte functions, which are instrumental for inflammatory resolution, our study further supports the existence of a brain cholinergic anti-inflammatory pathway mediated by α7 nicotinic receptor that could be

  15. Prostaglandin E2 and its methyl ester reduce cataplexy in canine narcolepsy.

    OpenAIRE

    Nishino, S.; Mignot, E.; Fruhstorfer, B; Dement, W C; Hayaishi, O

    1989-01-01

    The effects of intravenous administration of prostaglandins (PGs) were investigated in genetically narcoleptic Doberman pinschers. The treatment of narcoleptic dogs with PGE2 and PGE2 methyl ester, but not PGD2 and PGD2 methyl ester, induced a dose-dependent reduction of canine cataplexy, a dissociated manifestation of rapid-eye-movement sleep. The effect was specific and not associated with any change in other behavior. Furthermore, the effect was long-lasting (up to 2 hr) and could not be e...

  16. Cyclooxygenase 2 and Prostaglandin E2 are not Involved in N-Nitrosodiethylamine-Initiated Early Rat Hepatocarcinogenesis

    Science.gov (United States)

    Ogawa, Kumiko; Pitchakarn, Pornsiri; Takahashi, Satoru; Asamoto, Makoto; Shirai, Tomoyuki

    2009-01-01

    The present study was undertaken to investigate the effect of dietary supplementation with nimesulide or eugenol on N-nitrosodiethylamine (DEN)-initiated early hepatocarcinogenesis in F344 male rats. Both compounds did not alter the expression of cytochrome P450 (CYP) 2E1, the enzyme that plays a major role in the activation of DEN to genotoxic products; however, nimesulide induced the expression of CYP1A1. Western blot analysis revealed that COX-1 and COX-2 protein expressions were not modulated by DEN compared with normal controls. Furthermore, post-initiation feeding with nimesulide or eugenol did not modulate COX-2 protein expression in normal or DEN-treated rats, whereas eugenol significantly increased the liver prostaglandin E2 (PGE2) levels of DEN-injected animals compared with the DEN controls. Ultimately, nimesulide or eugenol did not modify DEN-induced hepatocarcinogenesis as evidenced by insignificant changes in the number and size of preneoplastic placental glutathione S-transferase (GST-P) positive liver foci compared with the DEN controls. These results suggest that COX-2, as well as prostaglandin E2, may play no role in the post-initiation development of DEN-induced rat hepatocarcinogenesis at an early stage. PMID:22272001

  17. Arginase I, polyamine, and prostaglandin E2 pathways suppress the inflammatory response and contribute to diffuse cutaneous leishmaniasis.

    Science.gov (United States)

    França-Costa, Jaqueline; Van Weyenbergh, Johan; Boaventura, Viviane S; Luz, Nívea F; Malta-Santos, Hayna; Oliveira, Murilo Cezar Souza; Santos de Campos, Daniela Conceição; Saldanha, Ana Cristina; dos-Santos, Washington L C; Bozza, Patrícia T; Barral-Netto, Manoel; Barral, Aldina; Costa, Jackson M; Borges, Valeria M

    2015-02-01

    Diffuse cutaneous leishmaniasis (DCL) is a rare clinical manifestation of tegumentary leishmaniasis. The molecular mechanisms underlying DCL pathogenesis remain unclear, and there is no efficient treatment available. This study investigated the systemic and in situ expression of the inflammatory response that might contribute to suppression in DCL. The plasma levels of arginase I, ornithine decarboxylase (ODC), transforming growth factor β (TGF-β), and prostaglandin E2 (PGE2) were higher in patients with DCL, compared with patients with localized cutaneous leishmaniasis (LCL) or with controls from an area of endemicity. In situ transcriptomic analyses reinforced the association between arginase I expression and enzymes involved in prostaglandin and polyamine synthesis. Immunohistochemistry confirmed that arginase I, ODC, and cyclooxygenase2 expression was higher in lesion biopsy specimens from patients with DCL than in those from patients with LCL. Inhibition of arginase I or ODC abrogates L. amazonensis replication in infected human macrophages. Our data implicate arginase I, ODC, PGE2, and TGF-β in the failure to mount an efficient immune response and suggest perspectives in the development of new strategies for therapeutic intervention for patients with DCL. © The Author 2014. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

  18. The Prostaglandin E2-EP3 Receptor Axis Regulates Anaplasma phagocytophilum-Mediated NLRC4 Inflammasome Activation.

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    Xiaowei Wang

    2016-08-01

    Full Text Available Rickettsial agents are sensed by pattern recognition receptors but lack pathogen-associated molecular patterns commonly observed in facultative intracellular bacteria. Due to these molecular features, the order Rickettsiales can be used to uncover broader principles of bacterial immunity. Here, we used the bacterium Anaplasma phagocytophilum, the agent of human granulocytic anaplasmosis, to reveal a novel microbial surveillance system. Mechanistically, we discovered that upon A. phagocytophilum infection, cytosolic phospholipase A2 cleaves arachidonic acid from phospholipids, which is converted to the eicosanoid prostaglandin E2 (PGE2 via cyclooxygenase 2 (COX2 and the membrane associated prostaglandin E synthase-1 (mPGES-1. PGE2-EP3 receptor signaling leads to activation of the NLRC4 inflammasome and secretion of interleukin (IL-1β and IL-18. Importantly, the receptor-interacting serine/threonine-protein kinase 2 (RIPK2 was identified as a major regulator of the immune response against A. phagocytophilum. Accordingly, mice lacking COX2 were more susceptible to A. phagocytophilum, had a defect in IL-18 secretion and exhibited splenomegaly and damage to the splenic architecture. Remarkably, Salmonella-induced NLRC4 inflammasome activation was not affected by either chemical inhibition or genetic ablation of genes associated with PGE2 biosynthesis and signaling. This divergence in immune circuitry was due to reduced levels of the PGE2-EP3 receptor during Salmonella infection when compared to A. phagocytophilum. Collectively, we reveal the existence of a functionally distinct NLRC4 inflammasome illustrated by the rickettsial agent A. phagocytophilum.

  19. Effect of flunixin meglumine or prostaglandin E2 treatment 15 days after breeding on fertility in Saanen does.

    Science.gov (United States)

    Cetin, Yunus; Kocamuftuoglu, Mesih; Ozyurtlu, Nihat; Kucukaslan, Ibrahim; Sendag, Sait; Wehrend, Axel

    2014-02-01

    The objective of this study was to determine the effects of timely injections of flunixin meglumine (FM) or vaginal application of prostaglandin E2 (PgE2) on pregnancy, fertility, fecundity, and prolificacy rates in Saanen goats. One hundred and sixty-three nonlactating Saanen does were treated with a flugestone acetate (20 mg)-containing intravaginal sponge for 12 days. They also received eCG (400 IU) and a PGF2α analogue (50 μg) 10 days after progestagen priming. Does detected in estrus were mated and assigned randomly to one of three treatment groups. The PgE2 group (N = 40) received PgE2 (2.5 mg) intravaginally 15 days after mating. The FM group (N = 54) received flunixin meglumine (total dose, 100 mg) intramuscularly 15 days after mating. Flunixin meglumine was administered at 9:00 AM. Animals in the control group (N = 69) received no treatment. Pregnancy was diagnosed using transrectal ultrasonography (B-mode at 8 MHz) 30 days after mating. The pregnancy rate was significantly greater (P < 0.01) after 30 days in goats treated with PgE2 and also in the control group than in those treated with FM (67.5%, 59.4%, and 42.5%, respectively). The pregnancy rate did not differ between the PgE2 and the control group. The pregnancy and fertility rate were lowest in the FM group compared with the other groups. There was no significant difference in the prolificacy rate among experimental groups. In conclusion, our results showed that FM administration during a late luteal phase is detrimental to early pregnancy in goats. Copyright © 2014 Elsevier Inc. All rights reserved.

  20. The Multiple Faces of Prostaglandin E2 G-Protein Coupled Receptor Signaling during the Dendritic Cell Life Cycle

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    Alessandra Cambi

    2013-03-01

    Full Text Available Many processes regulating immune responses are initiated by G-protein coupled receptors (GPCRs and report biochemical changes in the microenvironment. Dendritic cells (DCs are the most potent antigen-presenting cells and crucial for the regulation of innate and adaptive immune responses. The lipid mediator Prostaglandin E2 (PGE2 via four GPCR subtypes (EP1-4 critically regulates DC generation, maturation and migration. The role of PGE2 signaling in DC biology was unraveled by the characterization of EP receptor subtype expression in DC progenitor cells and DCs, the identification of the signaling pathways initiated by these GPCR subtypes and the classification of DC responses to PGE2 at different stages of differentiation. Here, we review the advances in PGE2 signaling in DCs and describe the efforts still to be made to understand the spatio-temporal fine-tuning of PGE2 responses by DCs.

  1. Prostaglandin E2 receptor expression in the rat trigeminal-vascular system and other brain structures involved in pain

    DEFF Research Database (Denmark)

    Myren, Maja; Olesen, Jes; Gupta, Saurabh

    2012-01-01

    receptors in both peripheral and central structures involved in pain transmission and perception in migraine: dura mater, cerebral arteries, trigeminal ganglion, trigeminal nucleus caudalis, periaqueductal grey, thalamus, hypothalamus, cortex, pituitary gland, hippocampus and cerebellum. In the trigeminal......Prostaglandin E(2) (PGE(2)) is considered to be a key mediator in migraine pathophysiology. PGE(2) acts via four receptors (EP(1)-EP(4)) but their distribution in the brain districts implicated in migraine has yet to be delineated. We quantified amount of mRNA and protein expression for the EP...... than in dorsal root ganglia (peripheral control), whereas the EP(2) mRNA and protein were highly abundant in the pituitary gland. EP(3) mRNA was mainly found in thalamus and hypothalamus. The most robust mRNA and protein expression for EP(4) receptor was seen in the dorsal root ganglion. In conclusion...

  2. Valnemulin downregulates nitric oxide, prostaglandin E2, and cytokine production via inhibition of NF-kappaB and MAPK activity.

    Science.gov (United States)

    Zhang, Xuemei; Li, Hongyu; Feng, Haihua; Xiong, Huanzhang; Zhang, Lei; Song, Yu; Yu, Lu; Deng, Xuming

    2009-07-01

    Valnemulin is a pleuromutilin antibiotic used in clinics for the treatment of various infections. We studied the in vitro anti-inflammatory effects of valnemulin and associated signal transduction mechanisms in lipopolysaccharide (LPS)-stimulated RAW 264.7 macrophages. We found that valnemulin inhibited nitric oxide (NO), prostaglandin E2 (PGE2), tumour necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6), and increased interleukin-10 (IL-10) production. Inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) protein expression were also inhibited by valnemulin. We further observed that valnemulin prevented the LPS-induced NF-kappaB translocation from the cytoplasm into the nucleus. Valnemulin also blocked phosphorylation of three mitogen-activated protein kinases (MAPKs): extracellular signal receptor-activated kinase (ERK) 1/2, p38, and c-Jun N-terminal kinase (JNK). Our data indicate that valnemulin may have therapeutic anti-inflammatory effects independent of its antibacterial activity.

  3. Tissue inhibitor of metalloproteinases-2 (TIMP-2) in rat liver cells is increased by lipopolysaccharide and prostaglandin E2.

    Science.gov (United States)

    Roeb, E; Rose-John, S; Erren, A; Edwards, D R; Matern, S; Graeve, L; Heinrich, P C

    1995-01-02

    To explore the functional role of TIMP-2 in liver, we determined TIMP-2 mRNA levels in primary rat hepatocytes and in total rat liver. Rat hepatocytes constitutively express TIMP-2 mRNA at a low level. Incubation with dexamethasone, prostaglandin E2 and a combination of inflammatory cytokines leads to an up-regulation of TIMP-2 mRNA. In rats in vivo we found a dramatic increase of TIMP-2 expression after intraperitoneal injection of lipopolysaccharide. Compared to our previous findings on TIMP-1 we conclude that TIMP-2 mRNA expression is regulated in a distinct and partially opposite manner. Over-production of TIMP-2 could inhibit the activity of metalloproteinases and thus lead to matrix accumulation. Dysregulation of TIMP-2 synthesis might be involved in the development of liver fibrosis.

  4. Prostaglandin (E2) induces immediate migraine-like attack in migraine patients without aura

    DEFF Research Database (Denmark)

    Antonova, Maria; Wienecke, Troels; Olesen, Jes

    2012-01-01

    without aura were randomly allocated to receive 0.4 µg/kg/min PGE(2) (Prostin®E2, dinoprostone) or placebo over 25 minutes in a two-way, crossover study. Headache intensity was recorded on a verbal rating scale, middle cerebral artery blood flow velocity (V(MCA)) was measured by transcranial Doppler (TCD...

  5. Comparison of Extra-Amniotic Normal Saline Infusion plus Hydrocortisone versus Prostaglandin E2 Suppository for Pregnancy Termination

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    Farahnaz Keshavarzi

    2012-08-01

    Full Text Available Background and Aim: Pregnancy termination before onset of labor is one of the midwifery problems. The aim of the present study was to compare extra-amniotic normal saline infusion plus hydrocortisone effect versus prostaglandin E2 suppository for cervical ripening and second- trimester pregnancy termination.   Materials and Methods: This randomized clinical-trial study was performed on 50 pregnant women with gestation age of 14 to 28 weeks and Bishops Score ≤ 2 who required pregnancy termination for fetal indications. Half of the cases received extra-amniotic normal saline infusion plus 100 mg hydrocortisone (EASI+ H and the other half received two doses of 3mg prostaglandin E2 suppository every 4 hours. Six hours later, induction of labor was started by means of a high dose of Oxytocin according to of Alabama University Protocol for Mid-trimester Abortion. The obtained data was analyzed by using statistical softwares Chi-square, Fisher and T-test.   Results: There were no differences between the two groups regarding maternal age, parity, gestational age, Primary Bishops Score and indication of pregnancy termination. In the EASI+H group, the mean interval between initiation of labor induction and fetal expulsion was 23.04 ± 4.47 hours and in PGE2 group was 28.65 ± 2.87 hours (P=0.001. The success rate in the EASI+H group was 100% and in PGE2 group 80 % (P =0.04. Complications such as fever, nausea, vomiting, diarrhea, increase of blood pressure and need to curettage in PGE2 group were statistically and significantly more abundant.   Conclusion: Extra-amniotic normal saline infusion plus hydrocortisone is an effective and safe method that is suggested for cervical ripening and second- trimester pregnancy termination.

  6. A randomized prospective trial comparing single dose prostaglandin E2 vaginal gel with forewater amniotomy for induction of labour.

    Science.gov (United States)

    Mahmood, T A; Rayner, A; Smith, N C; Beat, I

    1995-02-01

    A prospective randomized parallel-group study was carried out to compare the efficacy of a single dose vaginal prostaglandin E2 gel with forewater amniotomy for induction of labour at term in 260 parturients (110 primigravid and 150 parous women) with low risk pregnancy and favourable cervix. In the prostaglandin E2 (PGE2) managed group, the primigravidae were treated with 2 mg PGE2 gel and parous patients with 1 mg PGE2 gel. Forewater amniotomy was performed 4 h later, or sooner if women requested analgesia. In the amniotomy group, artificial forewater amniotomy was carried out and a repeat cervical assessment done 4 h later, or sooner if women requested analgesia. In both groups, intravenous oxytocin was established if there was evidence of disordered uterine activity, 6 h after the start of initial intervention. An assessment of consumers' views was carried out by using a standardized questionnaire completed 48 h after delivery. There was a significant reduction in the requirement for oxytocin augmentation in women treated with PGE2: primigravidae, odds ratio (OR), 0.27 and 95% confidence interval (CI), 0.12-0.61; multiparae, OR, 0.19 and 95% CI, 0.08-0.45. Fewer primigravidae managed with PGE2 gel required epidural analgesia (OR, 0.16; 95% CI, 0.06-1.00). Fewer parous women managed with PGE2 gel required parenteral opiates (OR, 0.44; 95% CI, 0.23-0.85) and more women required inhalation analgesia or no analgesia (OR, 2.22; 95% CI, 1.76-2.79). The intervention to delivery intervals were shortened in PGE2 groups independent of parity but the differences were not significant.(ABSTRACT TRUNCATED AT 250 WORDS)

  7. A cyclooxygenase-2-dependent prostaglandin E2 biosynthetic system in the Golgi apparatus.

    Science.gov (United States)

    Yuan, Chong; Smith, William L

    2015-02-27

    Cyclooxygenases (COXs) catalyze the committed step in prostaglandin (PG) biosynthesis. COX-1 is constitutively expressed and stable, whereas COX-2 is inducible and short lived. COX-2 is degraded via endoplasmic reticulum (ER)-associated degradation (ERAD) following post-translational glycosylation of Asn-594. COX-1 and COX-2 are found in abundance on the luminal surfaces of the ER and inner membrane of the nuclear envelope. Using confocal immunocytofluorescence, we detected both COX-2 and microsomal PGE synthase-1 (mPGES-1) but not COX-1 in the Golgi apparatus. Inhibition of trafficking between the ER and Golgi retarded COX-2 ERAD. COX-2 has a C-terminal STEL sequence, which is an inefficient ER retention signal. Substituting this sequence with KDEL, a robust ER retention signal, concentrated COX-2 in the ER where it was stable and slowly glycosylated on Asn-594. Native COX-2 and a recombinant COX-2 having a Golgi targeting signal but not native COX-1 exhibited efficient catalytic coupling to mPGES-1. We conclude that N-glycosylation of Asn-594 of COX-2 occurs in the ER, leading to anterograde movement of COX-2 to the Golgi where the Asn-594-linked glycan is trimmed prior to retrograde COX-2 transport to the ER for ERAD. Having an inefficient ER retention signal leads to sluggish Golgi to ER transit of COX-2. This permits significant Golgi residence time during which COX-2 can function catalytically. Cytosolic phospholipase A2α, which mobilizes arachidonic acid for PG synthesis, preferentially translocates to the Golgi in response to physiologic Ca(2+) mobilization. We propose that cytosolic phospholipase A2α, COX-2, and mPGES-1 in the Golgi comprise a dedicated system for COX-2-dependent PGE2 biosynthesis. © 2015 by The American Society for Biochemistry and Molecular Biology, Inc.

  8. The roles of prostaglandin E2 and D2 in lipopolysaccharide-mediated changes in sleep.

    Science.gov (United States)

    Oishi, Yo; Yoshida, Kyoko; Scammell, Thomas E; Urade, Yoshihiro; Lazarus, Michael; Saper, Clifford B

    2015-07-01

    When living organisms become sick as a result of a bacterial infection, a suite of brain-mediated responses occur, including fever, anorexia and sleepiness. Systemic administration of lipopolysaccharide (LPS), a common constituent of bacterial cell walls, increases body temperature and non-rapid eye movement (NREM) sleep in animals and induces the production of pro-inflammatory prostaglandins (PGs). PGE2 is the principal mediator of fever, and both PGE2 and PGD2 regulate sleep-wake behavior. The extent to which PGE2 and PGD2 are involved in the effect of LPS on NREM sleep remains to be clarified. Therefore, we examined LPS-induced changes in body temperature and NREM sleep in mice with nervous system-specific knockouts (KO) for the PGE2 receptors type EP3 or EP4, in mice with total body KO of microsomal PGE synthase-1 or the PGD2 receptor type DP, and in mice treated with the cyclooxygenase (COX) inhibitor meloxicam. We observed that LPS-induced NREM sleep was slightly attenuated in mice lacking EP4 receptors in the nervous system, but was not affected in any of the other KO mice or in mice pretreated with the COX inhibitor. These results suggest that the effect of LPS on NREM sleep is partially dependent on PGs and is likely mediated mainly by other pro-inflammatory substances. In addition, our data show that the main effect of LPS on body temperature is hypothermia in the absence of nervous system EP3 receptors or in the presence of a COX inhibitor. Copyright © 2014 Elsevier Inc. All rights reserved.

  9. Outpatient Foley catheter versus inpatient prostaglandin E2 gel for induction of labour: a randomised trial

    Directory of Open Access Journals (Sweden)

    Henry Amanda

    2013-01-01

    Full Text Available Abstract Background Induction of labour (IOL is one of the commonest obstetric interventions, with significant impact on both the individual woman and health service delivery. Outpatient IOL is an attractive option to reduce these impacts. To date there is little data comparing outpatient and inpatient IOL methods, and potential safety concerns (hyperstimulation if prostaglandins, the standard inpatient IOL medications, are used in the outpatient setting. The purpose of this study was to assess feasibility, clinical effectiveness and patient acceptability of outpatient Foley catheter (OPC vs. inpatient vaginal PGE2 (IP for induction of labour (IOL at term. Methods Women with an unfavourable cervix requiring IOL at term (N = 101 were randomised to outpatient care using Foley catheter (OPC, n = 50 or inpatient care using vaginal PGE2 (IP, n = 51. OPC group had Foley catheter inserted and were discharged overnight following a reassuring cardiotocograph. IP group received 2 mg/1 mg vaginal PGE2 if nulliparous or 1 mg/1 mg if multiparous. Main outcome measures were inpatient stay (prior to birth, in Birthing Unit, total, mode of birth, induction to delivery interval, adverse reactions and patient satisfaction. Results OPC group had shorter hospital stay prior to birth (21.3 vs. 32.4 hrs, p  Conclusions OPC was feasible and acceptable for IOL of women with an unfavourable cervix at term compared to IP, however did not show a statistically significant reduction in total inpatient stay and was associated with increased oxytocin IOL. Trial registration Australian New Zealand Clinical Trials Registry, ACTRN:12609000420246.

  10. Regulation of rat intrapulmonary arterial tone by arachidonic acid and prostaglandin E2 during hypoxia.

    Directory of Open Access Journals (Sweden)

    Gaoliang Yan

    Full Text Available Arachidonic acid (AA and its metabolites, prostaglandins (PG are known to be involved in regulation of vascular homeostasis including vascular tone and vessel wall tension, but their potential role in Hypoxic pulmonary vasoconstriction (HPV remains unclear. In this study, we examined the effects of AA and PGE2 on the hypoxic response in isolated rat intrapulmonary arteries (IPAs.We carried out the investigation on IPAs by vessel tension measurement. Isotetrandrine (20 µM significantly inhibited phase I, phase IIb and phase IIc of hypoxic vasoconstriction. Both indomethacin (100 µM and NS398 attenuated KPSS-induced vessel contraction and phase I, phase IIb and phase IIc of HPV, implying that COX-2 plays a primary role in the hypoxic response of rat IPAs. PGE2 alone caused a significant vasoconstriction in isolated rat IPAs. This constriction is mediated by EP4. Blockage of EP4 by L-161982 (1 µM significantly inhibited phase I, phase IIb and phase IIc of hypoxic vasoconstriction. However, AH6809 (3 µM, an antagonist of EP1, EP2, EP3 and DP1 receptors, exerted no effect on KPSS or hypoxia induced vessel contraction. Increase of cellular cAMP by forskolin could significantly reduce KPSS-induced vessel contraction and abolish phase I, phase II b and phase II c of HPV.Our results demonstrated a vasoconstrictive effect of PGE2 on rat IPAs and this effect is via activation of EP4. Furthermore, our results suggest that intracellular cAMP plays dual roles in regulation of vascular tone, depending on the spatial distribution of cAMP and its coupling with EP receptor and Ca(2+ channels.

  11. N-Acetylcysteine enhances the action of anti-inflammatory drugs as suppressors of prostaglandin production in monocytes

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    Erica Hoffer

    2002-01-01

    Full Text Available The anti-inflammatory effect of non-steroidal anti-inflammatory drugs (NSAIDs is associated with inhibition of cyclooxygenase (COX, the rate-limiting enzyme responsible for the synthesis of prostaglandins. Since oxygen free radicals can act as second cellular messengers, especially to modulate the metabolism of arachidonic acid and the prostaglandin tract, it seems plausible that antioxidants might affect the production of prostaglandin by activated cells. This research is focused on the effect of the antioxidant N-acetylcysteine (NAC on the inhibition of prostaglandin E2 formation in activated monocytes by specific and non-specific COX inhibitors. We found that lipopolysaccharide-induced prostaglandin E2 formation was significantly reduced by rofecoxib and by diclofenac, two NSAIDs. Addition of NAC to each of these drugs enhanced the effect of the NSAIDs. These results suggest that one might expect either a potentiation of the anti-inflammatory effect of COX inhibitors by their simultaneous administration with NAC, or obtaining the same anti-inflammatory at lower drug levels.

  12. Immunolocalization of Prostaglandin E2 Receptor Subtype 4 (EP4 in the Cervix of Cyclic Bitches and Those with Pyometra

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    P Linharattanaruksa1, K Chatdarong1, S Ponglowhapan1, M Khalid3 and S Srisuwatanasagul2*

    2013-07-01

    Full Text Available Cervix is an important part of the reproductive tract; in non-pregnant animals it remains closed during anestrus and diestrus and is open only during estrus. In pathological conditions like pyometra, the cervix may be open or closed but the control mechanism is not clearly known. Prostaglandin E2 (PGE2 is considered to be involved in changes of extracellular matrix via coupling to prostaglandin E receptor subtype 4 (EP4. This study investigated the expression of EP4 in the cervices of bitches during different stages of estrous cycle and those with pyometra. After ovariohysterectomy, cervices were collected from anestrus (n=6, estrus (n=12 and diestrus (n=6, open- (n=10 and closed-cervix pyometra (n=10 bitches. Cervical EP4 expression was observed at all the layers and the stages but the differences in EP4 expression either among bitches in different stages of the estrous cycle and between open- and closed-cervix pyometra were limited to only surface epithelium (SE. In cyclic bitches during estrus and in open-cervix pyometra bitches, significantly higher (P<0.05 EP4 expression was found in SE of uterine part than vaginal part. In SE of the uterine part, the expression was higher in the bitches during estrus than in anestrus and diestrus, and in the bitches affected by open-cervix than those with closed-cervix pyometra. The results suggest that regulation of cervical dilation appeared in the uterine part of the cervix. Moreover, EP4 may be involved in stimulating dilation of the cervix in both estrus and open-cervix pyometra bitches.

  13. Long Term Consumption of Flaxseed Enriched Diet Decreased Ovarian Cancer Incidence and Prostaglandin E2 in Hens

    Science.gov (United States)

    Eilati, Erfan; Bahr, Janice M.; Hales, Dale Buchanan

    2013-01-01

    Objective Ovarian cancer is the most lethal gynecological malignancy. Prevention may be the best approach to reduce ovarian cancer. Flaxseed is the richest vegetable source of omega-3 fatty acids which may be effective in the prevention of ovarian cancer. Prostaglandin E2 (PGE2) is the most proinflammatory ecoisanoid and one of the downstream products of two isoforms of cyclooxygenase (COX) enzymes: COX-1 and COX-2. Our objective was to determine if long-term consumption of a flaxseed enriched diet decreased ovarian cancer severity and incidence in the laying hen and to investigate its potential correlation with the expression of COX enzymes and PGE2 concentration. Methods White Leghorn hens were fed 10% flaxseed-enriched or standard diet for 4 years. The severity and incidence of ovarian cancer were determined by gross pathology and histology. COX-1 and COX-2 protein and mRNA expression and PGE2 concentrations in ovaries were measured by Western blot, quantitative real-time PCR and ELISA, respectively. Results The results demonstrated that there was a reduction in ovarian cancer severity and incidence in hens fed flaxseed diet. In correlation with decreased ovarian cancer severity and incidence, concentration of PGE2 and expression of COX-2 were diminished in ovaries of hens fed flaxseed. Conclusions Our findings suggest that the lower levels of COX-2 and PGE2 are the main contributing factors in the chemo-suppressive role of long-term flaxseed consumption in ovarian cancer in laying hens. These findings may provide the basis for clinical trials of dietary intervention targeting prostaglandin biosynthesis for the prevention and treatment of ovarian cancer. PMID:23707669

  14. Effect of Inhaled Prostaglandin E2 on Methacholine and Leukotriene D4 Airway Responsiveness in Asthmatic Subjects

    Directory of Open Access Journals (Sweden)

    Wil Hm Stevens

    1996-01-01

    Full Text Available Previous studies in asthmatics have demonstrated that the endogenous release of inhibitory prostaglandins limits the bronchoconstrictor response to repeated challenges with exercise and histamine, and that inhaled prostaglandin (PG E2 attenuates allergen-induced asthmatic responses and exercise bronchoconstriction in asthmatics. Inhaled PGE2 does not significantly attenuate methacholine airway responsiveness. These results, taken together, indicate that inhaled PGE2 attenuates the bronchoconstriction caused by stimuli, such as allergen and exercise, that result in bronchoconstriction through cysteinyl leukotriene (LT release. The purpose of this study was to determine whether inhaled PGE2 could selectively attenuate LTD4-induced bronchoconstriction in seven stable asthmatic subjects. Each subject was studied on four different study days. On two occasions the subjects inhaled 100 mg PGE2, 30 mins before a methacholine, or LTD4 challenge test. On the other two study days, the subjects were pretreated with its diluent. Results were expressed as the provocation concentration causing a 20% fall in forced expiratory volume in 1 s (FEV1 (PC20. PGE2 pretreatment significantly increased the LTD4 PC20, but not the methacholine PC20. The mean LTD4 PC20 increased from 2.00 mg/mL (%SEM 1.65 after diluent pretreatment to 3.01 mg/mL (%SEM 1.64 after PGE2 pretreatment (P=0.008. The mean methacholine PC20 was 1.28 mg/mL (%SEM 1.68 after diluent pretreatment and 1.62 mg/mL (%SEM 1.46 after PGE2 pretreatment (P=0.28. These results suggest that PGE2 partially attenuates LTD4-induced bronchoconstriction; however, the magnitude of the effect is unlikely to account for its attenuation of exercise and allergen-induced bronchoconstriction.

  15. Effects of prostaglandin F2 alpha on bone formation and resorption in cultured neonatal mouse calvariae: Role of prostaglandin E2 production

    Energy Technology Data Exchange (ETDEWEB)

    Raisz, L.G.; Alander, C.B.; Fall, P.M.; Simmons, H.A. (Univ. of Connecticut Health Center, Farmington (USA))

    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.

  16. Differential modulation of T helper type 1 (Th1) and T helper type 2 (Th2) cytokine secretion by prostaglandin E2 critically depends on interleukin-2

    NARCIS (Netherlands)

    Hilkens, C. M.; Vermeulen, H. [=Hans; van Neerven, R. J.; Snijdewint, F. G.; Wierenga, E. A.; Kapsenberg, M. L.

    1995-01-01

    Prostaglandin E2 (PGE2) favors T helper type 2 (Th2)-like cytokine secretion profiles in murine and human CD4+ T cells by inhibiting the production of the Th1-associated cytokines interleukin-2 (IL-2) and interferon-gamma (IFN-gamma) and up-regulating the production of the Th2-associated cytokines

  17. Evolution of insulin-like growth factor-1, prostaglandin E2, and mitogenic activity of bovine mammary primary lymph during the dry period and lactogenesis.

    Science.gov (United States)

    Lacasse, P; Block, E; Turner, J; Woodward, T; Couture, Y; Petitclerc, D

    1996-10-01

    Four pregnant cows near the end of lactation were fitted with a catheter in a lymph duct afferent to the supramammary lymph node. Cows were dried off 3 d after surgery, and samples of lymph were collected daily from the day of surgery until 4 d postpartum. Samples of blood and mammary secretions were taken before and after drying off and at parturition. Concentrations of most metabolites were lower in lymph than in serum. Concentrations of IGF-I and prostaglandin E2 were not affected at drying off but decreased and increased, respectively, at parturition. All IGF-binding proteins that were present in serum were also present in lymph fluid, but the binding activity was lower. Mitogenic activities of lymph samples taken at various physiological stages were determined on mammary epithelial (MAC-T) and fibroblast cell lines. Lymph was mitogenic, but mitogenic activity was not related to physiological stages. The correlation was high between mitogenic activity of lymph on MAC-T cells and the content of prostaglandin E2 in lymph. Supplementation of lymph with additional prostaglandin E2 increased mitogenic activity, and neutralization of lymph by antibodies reduced mitogenic activity. Basal medium conditioned by the epithelial cell line contained 100 to 250 pg/ml of immunoassayable prostaglandin E2.

  18. Expression of Prostaglandin E2 Enzymes in the Synovium of Arthralgia Patients at Risk of Developing Rheumatoid Arthritis and in Early Arthritis Patients

    NARCIS (Netherlands)

    de Hair, Maria J. H.; Leclerc, Patrick; Newsum, Elize C.; Maijer, Karen I.; van de Sande, Marleen G. H.; Ramwadhdoebe, Tamara H.; van Schaardenburg, Dirkjan; van Baarsen, Lisa G. M.; Korotkova, Marina; Gerlag, Danielle M.; Tak, Paul-Peter; Jakobsson, Per-Johan

    2015-01-01

    Arthralgia may precede the development of synovial inflammation in autoantibody-positive individuals at risk of developing rheumatoid arthritis (RA). A major pathway involved in pain is the prostaglandin (PG) E2 pathway. We investigated this pathway in the synovium of individuals with RA-specific

  19. Cost-effectiveness of induction of labour at term with a Foley catheter compared to vaginal prostaglandin E2 gel (PROBAAT trial)

    NARCIS (Netherlands)

    van Baaren, G. J.; Jozwiak, M.; Opmeer, B. C.; Rengerink, K. Oude; Benthem, M.; Dijksterhuis, M. G. K.; van Huizen, M. E.; van der Salm, P. C. M.; Schuitemaker, N. W. E.; Papatsonis, D. N. M.; Perquin, D. A. M.; Porath, M.; van der Post, J. A. M.; Rijnders, R. J. P.; Scheepers, H. C. J.; Spaanderman, M.; van Pampus, M. G.; de Leeuw, J. W.; Mol, B. W. J.; Bloemenkamp, K. W. M.

    Objective To assess the economic consequences of labour induction with Foley catheter compared to prostaglandin E2 gel. Design Economic evaluation alongside a randomised controlled trial. Setting Obstetric departments of one university and 11 teaching hospitals in the Netherlands. Population Women

  20. Estradiol-17beta, prostaglandin E2 (PGE2), and the PGE2 receptor are involved in PGE2 positive feedback loop in the porcine endometrium.

    Science.gov (United States)

    Waclawik, Agnieszka; Jabbour, Henry N; Blitek, Agnieszka; Ziecik, Adam J

    2009-08-01

    Before implantation, the porcine endometrium and trophoblast synthesize elevated amounts of luteoprotective prostaglandin estradiol-17beta (E(2)) (PGE(2)). We hypothesized that embryo signal, E(2), and PGE(2) modulate expression of key enzymes in PG synthesis: PG-endoperoxide synthase-2 (PTGS2), microsomal PGE synthase (mPGES-1), PGF synthase (PGFS), and PG 9-ketoreductase (CBR1) as well as PGE(2) receptor (PTGER2 and -4) expression and signaling within the endometrium. We determined the site of action of PGE(2) in endometrium during the estrous cycle and pregnancy. Endometrial tissue explants obtained from gilts (n = 6) on d 11-12 of the estrous cycle were treated with vehicle (control), PGE(2) (100 nM), E(2) (1-100 nm), or phorbol 12-myristate 13-acetate (100 nm, positive control). E(2) increased PGE(2) secretion through elevating expression of mPGES-1 mRNA and PTGS2 and mPGES-1 protein in endometrial explants. By contrast, E(2) decreased PGFS and CBR1 protein expression. E(2) also stimulated PTGER2 but not PTGER4 protein content. PGE(2) enhanced mPGES-1 and PTGER2 mRNA as well as PTGS2, mPGES-1, and PTGER2 protein expression. PGE(2) had no effect on PGFS, CBR1, and PTGER4 expression and PGF(2alpha) release. Treatment of endometrial tissue with PGE(2) increased cAMP production. Cotreatment with PTGER2 antagonist (AH6809) but not PTGER4 antagonist (GW 627368X) inhibited significantly PGE(2)-mediated cAMP production. PTGER2 protein was localized in luminal and glandular epithelium and blood vessels of endometrium and was significantly up-regulated on d 11-12 of pregnancy. Our results suggest that E(2) prevents luteolysis through enzymatic modification of PG synthesis and that E(2), PGE(2), and endometrial PTGER2 are involved in a PGE(2) positive feedback loop in porcine endometrium.

  1. The Effect of HIV and HPV Co-infection on Cervical COX-2 Expression and Systemic Prostaglandin E2 Levels

    Science.gov (United States)

    Fitzgerald, Daniel W.; Bezak, Karl; Ocheretina, Oksana; Riviere, Cynthia; Wright, Thomas C.; Milne, Ginger L.; Zhou, Xi Kathy; Du, Baoheng; Subbaramaiah, Kotha; Byrt, Erin; Goodwin, Matthew L.; Rafii, Arash; Dannenberg, Andrew J.

    2011-01-01

    Human immunodeficiency virus (HIV-1) infection causes chronic inflammation. COX-2 derived prostaglandin E2 (PGE2) has been linked to both inflammation and carcinogenesis. We hypothesized that HIV-1 could induce COX-2 in cervical tissue and increase systemic PGE2 levels and that these alterations could play a role in AIDS-related cervical cancer. Levels of cervical COX-2 mRNA and urinary PGE-M, a biomarker of systemic PGE2 levels, were determined in 17 HIV-negative women with a negative cervical HPV test, 18 HIV-infected women with a negative HPV test, and 13 HIV-infected women with cervical HPV and high-grade squamous intraepithelial lesions on cytology. Cervical COX-2 levels were significantly associated with HIV and HPV status (P=0.006 and 0.002, respectively). Median levels of urinary PGE-M were increased in HIV-infected compared to uninfected women (11.2 ng/mg creatinine vs. 6.8 ng/mg creatinine, P=0.02). Among HIV infected women, urinary PGE-M levels were positively correlated with plasma HIV-1 RNA levels (Pinfection is associated with increased cervical COX-2 and elevated systemic PGE2 levels. Drugs that inhibit the synthesis of PGE2 may prove useful in reducing the risk of cervical cancer or systemic inflammation in HIV infected women. PMID:22135046

  2. Saliva, Serum Levels of Interleukin-21, -33 and Prostaglandin E2 in Patients with Generalised Aggressive or Chronic Periodontitis.

    Science.gov (United States)

    Gümüş, Pınar; Nizam, Nejat; Nalbantsoy, Ayşe; Özçaka, Özgün; Buduneli, Nurcan

    This cross-sectional study aims to evaluate saliva, serum levels of interleukin-21 (IL-21), IL-33, and prostaglandin E2 (PGE2) in patients with generalised chronic periodontitis or aggressive periodontitis. Before initiation of any periodontal treatment, saliva and serum samples were collected and clinical periodontal measurements were recorded from 94 participants (25 aggressive periodontitis patients, 25 chronic periodontitis patients, 44 periodontally healthy individuals). IL-21, IL-33 and PGE2 levels in serum and saliva samples were determined by ELISA. Data were tested statistically using Kruskal-Wallis, Mann-Whitney U-, and Spearman-rho rank tests. Saliva IL-33 levels were statistically significantly higher in the chronic than the aggressive group (p periodontitis groups. Saliva IL-33 levels correlated with age in the chronic periodontitis group (p periodontitis groups (p aggressive periodontitis, but the present findings support the role of these cytokines in periodontitis. Statistically significantly higher saliva IL-33 levels in the chronic periodontitis group warrant further research.

  3. Reactivity of blood vessels in response to prostaglandin E2 in placentas from pregnancies complicated by fetal growth restriction.

    Science.gov (United States)

    Luria, Oded; Bar, Jacob; Barnea, Ofer; Golan, Abraham; Kovo, Michal

    2012-05-01

    The authors aimed to study the contractility responses of normal and fetal growth restriction (FGR) placentas to prostaglandin E(2) (PGE(2) ) and to correlate the results to subsequent placental histological analysis. A dual-perfused single cotyledon model was used. Placentas from pregnancies complicated by FGR and from normal pregnancies were obtained. Selected cotyledons were cannulated and dually perfused. Following stabilization, three concentrations of PGE(2) (0.05, 0.1, and 0.15 mg/mL) were administered to the fetal arterial side causing contraction/relaxation response. Fetal perfusion pressure was measured continuously during these contraction and relaxation phases. Following the perfusion experiments, the placentas were analyzed for fetal or maternal origin vascular lesions. A total of 21 complete experiments were performed (16 normal, 5 FGR). In response to PGE(2) , FGR placentas exhibited lower change in the perfusion pressure and lower relaxation time constant. Basal perfusion pressure did not differ significantly between the two groups. Placental histopathology lesions, fetal or maternal origin, were more common in the FGR compared with the controls placentas, 80% versus 25%, respectively, P=  0.047. The lower vascular reactivity in response to PGE(2) and the presence of fetal and maternal vascular placental lesions suggest a mechanism explaining the altered vascular supply in FGR. © 2012 John Wiley & Sons, Ltd.

  4. Effects of NSAIDs on the Release of Calcitonin Gene-Related Peptide and Prostaglandin E2 from Rat Trigeminal Ganglia

    Directory of Open Access Journals (Sweden)

    Vittorio Vellani

    2017-01-01

    Full Text Available Nonsteroidal anti-inflammatory drugs (NSAIDs are frequently used to treat migraine, but the mechanisms of their effects in this pathology are not fully elucidated. The trigeminal ganglia and calcitonin gene-related peptide (CGRP have been implicated in the pathophysiology of migraine. The release of CGRP and prostaglandin E2 (PGE2 from freshly isolated rat trigeminal ganglia was evaluated after oral administration of nimesulide, etoricoxib, and ketoprofen, NSAIDs with different pharmacological features. Thirty minutes after oral administration, nimesulide, 10 mg/Kg, decreased the GCRP release induced by an inflammatory soup, while the other NSAIDs were ineffective at this point in time. Two hours after oral nimesulide (5 and 10 mg/Kg and ketoprofen (10 mg/Kg, but not of etoricoxib, a significant decrease in the CGRP release was observed. All drugs reduced PGE2, although with some differences in timing and doses, and the action on CGRP does not seem to be related to PGE2 inhibition. The reduction of CGRP release from rat trigeminal ganglia after nimesulide and ketoprofen may help to explain the mechanism of action of NSAIDs in migraine. Since at 30 minutes only nimesulide was effective in reducing CGRP release, these results suggest that this NSAID may exert a particularly rapid effect in patients with migraine.

  5. Design of group IIA secreted/synovial phospholipase A(2 inhibitors: an oxadiazolone derivative suppresses chondrocyte prostaglandin E(2 secretion.

    Directory of Open Access Journals (Sweden)

    Jean-Edouard Ombetta

    Full Text Available Group IIA secreted/synovial phospholipase A(2 (GIIAPLA(2 is an enzyme involved in the synthesis of eicosanoids such as prostaglandin E(2 (PGE(2, the main eicosanoid contributing to pain and inflammation in rheumatic diseases. We designed, by molecular modeling, 7 novel analogs of 3-{4-[5(indol-1-ylpentoxy]benzyl}-4H-1,2,4-oxadiazol-5-one, denoted C1, an inhibitor of the GIIAPLA(2 enzyme. We report the results of molecular dynamics studies of the complexes between these derivatives and GIIAPLA(2, along with their chemical synthesis and results from PLA(2 inhibition tests. Modeling predicted some derivatives to display greater GIIAPLA(2 affinities than did C1, and such predictions were confirmed by in vitro PLA(2 enzymatic tests. Compound C8, endowed with the most favorable energy balance, was shown experimentally to be the strongest GIIAPLA(2 inhibitor. Moreover, it displayed an anti-inflammatory activity on rabbit articular chondrocytes, as shown by its capacity to inhibit IL-1beta-stimulated PGE(2 secretion in these cells. Interestingly, it did not modify the COX-1 to COX-2 ratio. C8 is therefore a potential candidate for anti-inflammatory therapy in joints.

  6. Effect of prostaglandins E1, E2, and F2 alpha on osteoclast formation in mouse bone marrow cultures

    Energy Technology Data Exchange (ETDEWEB)

    Collins, D.A.; Chambers, T.J. (St. George' s Hospital Medical School, London (United Kingdom))

    1991-02-01

    Prostaglandins (PG) act as direct inhibitors of mature osteoclasts, but although resorption-inhibition is also observed initially PG increase bone resorption in organ culture. This suggests that PG influence bone resorption in organ culture through actions on cell types other than mature osteoclasts. We have therefore tested the effects of PG E1, E2, and F2 alpha on the differentiation of osteoclastic phenotype in mouse bone marrow cultures using bone resorption and calcitonin receptors (CTR) as markers of osteoclastic differentiation. We found that PGE2 (10{sup {minus} 6}-10{sup {minus} 9} M) and PGE1 (10{sup {minus} 6} - 10{sup {minus} 7} M) induced a significant increase in CTR-positive cell numbers, to levels five to eight times those seen in controls and similar to the number induced by 1,25-dihydroxyvitamin D3 (1,25-(OH)2D3). Bone resorption was increased (10{sup {minus} 7} M PGE2 and 10{sup {minus} 6} M PGE1) in association with the increased CTR-positive cell numbers, suggesting that the PG also induced resorptive function. 1,25-(OH)2D3 increased both the number of CTR-positive cells and the extent of resorption per cell; the additional presence of PG did not affect the number of CTR-positive cells but did reduce bone resorption compared with 1,25-(OH)2D3 alone. PGF2 alpha had no significant effect on CTR-positive cell induction or bone resorption. The results suggest that PGE1 and E2 induce osteoclastic differentiation in mouse bone marrow cultures and inhibit the function of the osteoclasts thus formed.

  7. Peptidylarginine deiminase from Porphyromonas gingivalis contributes to infection of gingival fibroblasts and induction of prostaglandin E2 -signaling pathway.

    Science.gov (United States)

    Gawron, K; Bereta, G; Nowakowska, Z; Lazarz-Bartyzel, K; Lazarz, M; Szmigielski, B; Mizgalska, D; Buda, A; Koziel, J; Oruba, Z; Chomyszyn-Gajewska, M; Potempa, J

    2014-12-01

    Porphyromonas gingivalis (P. gingivalis) expres-ses the enzyme peptidylarginine deiminase (PPAD), which has a strong preference for C-terminal arginines. Due to the combined activity of PPAD and Arg-specific gingipains, P. gingivalis on the cell surface is highly citrullinated. To investigate the contribution of PPAD to the interaction of P. gingivalis with primary human gingival fibroblasts (PHGF) and P. gingivalis-induced synthesis of prostaglandin E2 (PGE2 ), PHGF were infected with wild-type P. gingivalis ATCC 33277, an isogenic PPAD-knockout strain (∆ppad) or a mutated strain (C351A) expressing an inactive enzyme in which the catalytic cysteine has been mutated to alanine (PPAD(C351A) ). Cells were infected in medium containing the mutants alone or in medium supplemented with purified, active PPAD. PHGF infection was assessed by colony-forming assay, microscopic analysis and flow cytometry. Expression of cyclo-oxygenase 2 (COX-2) and microsomal PGE synthase-1 (mPGES-1), key factors in the prostaglandin synthesis pathway, was examined by quantitative reverse transcription polymerase chain reaction (qRT-PCR), while PGE2 synthesis was evaluated by enzyme immunoassay. PHGF were infected more efficiently by wild-type P. gingivalis than by the ∆ppad strain, which correlated with strong induction of COX-2 and mPGES-1 expression by wild-type P. gingivalis, but not by the PPAD activity-null mutant strains (Δppad and C351A). The impaired ability of the Δppad strain to adhere to and/or invade PHGF and both Δppad and C351A to stimulate the PGE2 -synthesis pathway was fully restored by the addition of purified PPAD. The latter effect was strongly inhibited by aspirin. Collectively, our results implicate PPAD activity, but not PPAD itself, as an important factor for gingival fibroblast infection and activation of PGE2 synthesis, the latter of which may strongly contribute to bone resorption and eventual tooth loss. © 2014 John Wiley & Sons A/S. Published by John

  8. Colonic Saturated Fatty Acid Concentrations and Expression of COX-1, but not Diet, Predict Prostaglandin E2 in Normal Human Colon Tissue.

    Science.gov (United States)

    Sidahmed, ElKhansa; Sen, Ananda; Ren, Jianwei; Patel, Arsh; Turgeon, D Kim; Ruffin, Mack T; Brenner, Dean E; Djuric, Zora

    2016-10-01

    Prostaglandin E2 (PGE2) in the colon is a pro-inflammatory mediator that is associated with increased risk of colon cancer. In this study, expression of genes in the PGE2 pathway were quantified in colon biopsies from a trial of a Mediterranean versus a Healthy Eating diet in 113 individuals at high risk for colon cancer. Colon biopsies were obtained before and after 6 months of intervention. Quantitative, real-time PCR was used to measure mRNA expression of prostaglandin H synthases (PTGS1 and 2), prostaglandin E synthases (PTGES1 and 3), prostaglandin dehydrogenase (HPGD), and PGE2 receptors (PTGER2, PTGER4). The most highly expressed genes were HPGD and PTGS1. In multivariate linear regression models of baseline data, both colon saturated fatty acid concentrations and PTGS1 expression were significant, positive predictors of colon PGE2 concentrations after controlling for nonsteroidal anti-inflammatory drug use, gender, age, and smoking status. The effects of dietary intervention on gene expression were minimal with small increases in expression noted for PTGES3 in both arms and in PTGER4 in the Mediterranean arm. These results indicate that short-term dietary change had little effect on enzymes in the prostaglandin pathway in the colon and other factors, such as differences in fatty acid metabolism, might be more influential.

  9. Early effects of prostaglandin E2 on bone formation and resorption in different bone sites of rats.

    Science.gov (United States)

    Lin, C H; Jee, W S; Ma, Y F; Setterberg, R B

    1995-10-01

    The aim of this study was to determine early effects of prostaglandin E2 (PGE2) on bone mass, formation and resorption in a growing cancellous bone site (the proximal tibial metaphysis, PTM), non-growing cancellous bone site (the distal tibial metaphysis, DTM), and cortical bone site (the tibial shaft, TX) with histomorphometric analysis. Six mg PGE2/kg/d was given s.c. to 6-month-old Sprague-Dawley female rats for 5, 10 or 16 days. Double fluorescent labels were given to 0, 10- and 16-day PGE2 treatment and 16-day control groups. Significant increase in bone mass was found after 16 days treatment in cancellous bone sites but not in the cortical bone site. Stimulated bone formation, indicated by the increase in osteoid perimeter, was observed as early as 5 days post-treatment in all 3 bone sites. Bone formation indices were increased after 10 days of treatment, however, there was no difference in selected bone formation indices between 10 and 16 days PGE2 treatments at all 3 bone sites. Significant increase in eroded surface and eroded surface covered with osteoid was observed in cancellous bone sites after 5 days, but decreased after 10 days of treatment. Although the eroded surface was not elevated in TX at the 5th day, the eroded surface covered with osteoid was increased on endocortical surface which indicated that PGE2 stimulated bone resorption on this surface prior to day 5. We concluded that PGE2 stimulated the bone formation and resorption as early as 5 days post-treatment. The levels of stimulated bone formation was TX > DTM > PTM.(ABSTRACT TRUNCATED AT 250 WORDS)

  10. Long-term leptin treatment exerts a pro-apoptotic effect on renal tubular cells via prostaglandin E2 augmentation.

    Science.gov (United States)

    Hsu, Yung-Ho; Cheng, Chung-Yi; Chen, Yen-Cheng; Chen, Tso-Hsiao; Sue, Yuh-Mou; Tsai, Wei-Lun; Chen, Cheng-Hsien

    2012-08-15

    Adipokine leptin reportedly acts on the kidney in pathophysiological states. However, the influence of leptin on renal tubular epithelial cells is still unclear. Gentamicin, a widely used antibiotic for the treatment of bacterial infection, can cause nephrotoxicity. This study aims to investigate the influence of long-term leptin treatment on gentamicin-induced apoptosis in rat renal tubular cells (NRK-52E) and mice. We monitored apoptosis and molecular mechanisms using annexin V/ propidium iodide staining and small interfering RNA transfection. In NRK-52E cells, leptin reduced gentamicin-induced apoptosis at 24h, but significantly increased apoptosis at 48 h. Long-term treatment of leptin decreased Bcl-x(L) expression and increased caspase activity in gentamicin-treated NRK-52E cells. Leptin also increased the expression of cyclooxygenase-2 (COX-2) and its product, prostaglandin E(2) (PGE(2)), in a dose-dependent manner. The COX-2 inhibitor, NS398 (N-[2-(Cyclohexyloxy)-4- nitrophenyl]methanesulfonamide), blocked PGE(2) augmentation and the pro-apoptotic effects of leptin. The addition of PGE(2) recovered the pro-apoptotic effect of leptin in NS398-treated NRK-52E cells. In a mouse animal model, a 10 day leptin treatment significantly increased gentamicin-induced apoptotic cells in proximal tubules. NS398 treatment inhibited this in vivo pro-apoptotic effect of leptin. Results reveal that long-term elevation of leptin induces COX-2-mediated PGE(2) augmentation in renal tubular cells, and then increases these cells' susceptibility to gentamicin-induced apoptosis. Copyright © 2012 Elsevier B.V. All rights reserved.

  11. The effect of watermelon frost on prostaglandin E2 (PGE2 in inflamed pulp tissue (in vitro study

    Directory of Open Access Journals (Sweden)

    Dennis Dennis

    2009-06-01

    Full Text Available Background: Pulp inflammation can be marked by the increase of prostaglandin E2(PGE2 level compared to normal pulp. The increase of PGE2 may lead to vasodilatation, increase of vascular permeability, pain and bone resorption. Watermelon frost has been well known in Chinese society for pain relief and inflammation in oral cavity and teeth. Purpose: The aim of this study was to investigate that watermelon frost can be used to decrease the PGE2 level. Method: 27 samples of pulp tissues used in this in-vitro study, were extirpated from the patients’ teeth with symptomatic irreversible pulpitis referred to clinic of Conservative Dentistry, RSPGM Faculty of Dentistry, USU. Trial materials were applied to 27 samples i.e. watermelon frost as a trial material and commercial watermelon frost and eugenol to observe their effect on PGE2. PGE2 level of each material was detected through ELISA method by measuring and comparing the absorbance reading of the wells of the samples against standards with a micro plate reader at W1 = 650 nm and W2 = 490 nm. Result: The result showed the biggest effect was found in the third group (eugenol, mean 4.6933, followed by the first group (watermelon frost as a trial material, mean 18,1578 then the second group (commercial watermelon frost, mean 82,2689. OneWay ANOVA revealed that there were significant differences among all trial materials (p < 0.001 on PGE2 level. Conclusion: This study demonstrated that watermelon frost can be used to decrease the PGE2 level in inflamed pulp tissue and led to the acceptance of traditional medicine and natural products as an alternative form of dental care.

  12. Febrile response induced by cecal ligation and puncture (CLP) in rats: involvement of prostaglandin E2 and cytokines.

    Science.gov (United States)

    Figueiredo, Maria José; Soares, Denis Melo; Soares, Denis de Melo; Martins, Juliano Manvailer; Machado, Renes de Resende; Sorgi, Carlos Arterio; Faccioli, Lucia Helena; Melo, Miriam Cristina Contin de; de Melo, Miriam Cristina Contin; Malvar, David do Carmo; Souza, Glória E P

    2012-05-01

    The purpose of the present study was to better understand the events involved in the febrile response induced by cecal ligation and puncture (CLP), a complex infectious process. To this end, we conducted in vivo experiments in rats examining (1) fever development, (2) bacterial number in the infection focus and in blood, (3) peripheral and hypothalamic synthesis of cytokines, (4) hypothalamic and cerebrospinal fluid (CSF) synthesis of prostaglandin E(2) (PGE(2)), (5) the effect of anti-IL-6 antibody on fever, and (6) the effect of celecoxib on fever and hypothalamic synthesis of PGE(2) after CLP induction. We found that CLP promotes fever and animal death depending on the number of punctures. The peak of CLP-induced fever overlapped with the maximal increase in the number of bacteria in the infectious focus and blood, which occurred at 6 and 12 h. The peak of the febrile response also coincided with increased amounts of interleukin (IL)-1β, IL-6 and IL-10 in the peritoneal exudate and serum; IL-6 in the hypothalamus and PGE(2) in the CSF and predominantly in the hypothalamus. Moreover, intracerebroventricularly injected anti-IL-6 antibody reduced the febrile response while celecoxib reduced the fever and PGE(2) amount in the hypothalamus induced by CLP. Tumor necrosis factor (TNF)-α peaked at 3 h at all sites studied. Conversely, IL-10 concentration decreased in the hypothalamus. These findings show that the peak of CLP-induced fever is accompanied by an increase of bacteria in peritoneal fluid (local infection) and blood; local synthesis of pyrogenic (IL-1β, IL-6) and antipyretic (IL-10) cytokines and central production of IL-6 and PGE(2), suggesting that these last are the central mediators of this response.

  13. Efferocytosis promotes suppressive effects on dendritic cells through prostaglandin E2 production in the context of autoimmunity.

    Directory of Open Access Journals (Sweden)

    Irma Pujol-Autonell

    Full Text Available INTRODUCTION: Efferocytosis is a crucial process by which apoptotic cells are cleared by phagocytes, maintaining immune tolerance to self in the absence of inflammation. Peripheral tolerance, lost in autoimmune processes, may be restored by the administration of autologous dendritic cells loaded with islet apoptotic cells in experimental type 1 diabetes. OBJECTIVE: To evaluate tolerogenic properties in dendritic cells induced by the clearance of apoptotic islet cells, thus explaining the re-establishment of tolerance in a context of autoimmunity. METHODS: Bone marrow derived dendritic cells from non-obese diabetic mice, a model of autoimmune diabetes, were generated and pulsed with islet apoptotic cells. The ability of these cells to induce autologous T cell proliferation and to suppress mature dendritic cell function was assessed, together with cytokine production. Microarray experiments were performed using dendritic cells to identify differentially expressed genes after efferocytosis. RESULTS: Molecular and functional changes in dendritic cells after the capture of apoptotic cells were observed. 1 Impaired ability of dendritic cells to stimulate autologous T cell proliferation after the capture of apoptotic cells even after proinflammatory stimuli, with a cytokine profile typical for immature dendritic cells. 2 Suppressive ability of mature dendritic cell function. 3 Microarray-based gene expression profiling of dendritic cells showed differential expression of genes involved in antigen processing and presentation after efferocytosis. 4 Prostaglandin E2 increased production was responsible for immunosuppressive mechanism of dendritic cells after the capture of apoptotic cells. CONCLUSIONS: The tolerogenic behaviour of dendritic cells after islet cells efferocytosis points to a mechanism of silencing potential autoreactive T cells in the microenvironment of autoimmunity. Our results suggest that dendritic cells may be programmed to induce

  14. Cycloxygenase-2 is expressed in vasculature of normal and ischemic adult human kidney and is colocalized with vascular prostaglandin E2 EP4 receptors

    DEFF Research Database (Denmark)

    Therland, Karina L; Stubbe, Jane; Thiesson, Helle C

    2004-01-01

    . COX-2 had a similar localization in fetal kidney and was additionally observed in Henle's loop and macula densa. Human tissue arrays displayed COX-2 labeling of vascular smooth muscle in multiple extrarenal tissues. Vascular COX-2 expression was significantly increased in kidneys with arterial...... stenosis. COX-1 was colocalized with microsomal prostaglandin E(2) synthase (PGES) in collecting ducts, and PGES was also detected in macula densa cells. Vascular COX-2 was colocalized with prostaglandin E(2) EP4 receptors but not with EP2 receptors. Thus, renovascular COX-2 expression was a constitutive...... feature encountered in human kidneys at all ages, whereas COX-2 was seen in macula densa only in fetal kidney. Vascular COX-2 activity in human kidney and extrarenal tissues may support blood flow and affect vascular wall-blood interaction....

  15. The Antinociceptive Effect of Light-Emitting Diode Irradiation on Incised Wounds Is Correlated with Changes in Cyclooxygenase 2 Activity, Prostaglandin E2, and Proinflammatory Cytokines.

    Science.gov (United States)

    Chia, Yuan-Yi; Liu, Chien-Cheng; Feng, Guan-Ming; Tseng, Chia-Chih Alex; Hung, Kuo-Chuan; Chen, Chih-Chieh; Tan, Ping-Heng

    2017-01-01

    Background. Light-emitting diode (LED) phototherapy has been reported to relieve pain and enhance tissue repair through several mechanisms. However, the analgesic effect of LED on incised wounds has never been examined. Objectives. We examined the analgesic effect of LED therapy on incision pain and the changes in cyclooxygenase 2 (COX-2), prostaglandin E2 (PGE2), and the proinflammatory cytokines interleukin 6 (IL-6), IL-1β, and tumor necrosis factor α (TNF-α). Methods. Rats received LED therapy on incised skin 6 days before incision (L-I group) or 6 days after incision (I-L group) or from 3 days before incision to 3 days after incision (L-I-L group). Behavioral tests and analysis of skin tissue were performed after LED therapy. Results. LED therapy attenuated the decrease in thermal withdrawal latency in all the irradiated groups and the decrease in the mechanical withdrawal threshold in the L-I group only. The expression levels of COX-2, PGE2, and IL-6 were significantly decreased in the three LED-treated groups, whereas IL-1β and TNF-α were significantly decreased only in the L-I group compared with their levels in the I groups (p incised skin.

  16. Prostaglandin E2 is an endogenous modulator of cerebellar development and complex behavior during a sensitive postnatal period.

    Science.gov (United States)

    Dean, Shannon L; Knutson, Jessica F; Krebs-Kraft, Desiree L; McCarthy, Margaret M

    2012-04-01

    Prostaglandins are lipid-derived molecules that mediate the generation of fever in the central nervous system. In addition to their proinflammatory role, prostaglandins also impact neuronal development and synaptic plasticity, sometimes in a sex-specific manner. The cerebellum has a high expression of prostaglandin receptors during development, but the role that these molecules play during normal cerebellar maturation is unknown. We demonstrate here that disrupting prostaglandin synthesis with cyclo-oxygenase inhibitors during a time-sensitive window in early postnatal life alters cerebellar Purkinje cell development in rats, resulting in initially increased dendritic growth in both sexes. We show that this results in later cerebellar atrophy in males only, resulting in a sex-specific loss of cerebellar volume. Further, although performance in motor tasks is spared, social interaction and the sensory threshold are altered in males developmentally exposed to cyclo-oxygenase inhibitors. This work demonstrates a previously unknown role for prostaglandins in cerebellar development and emphasizes the role that the cerebellum plays outside motor tasks, in cognitive and sensory domains that may help to explain its connection to complex neurodevelopmental disorders such as autism. © 2012 The Authors. European Journal of Neuroscience © 2012 Federation of European Neuroscience Societies and Blackwell Publishing Ltd.

  17. Aqueous prostaglandin E(2) of cataract patients at trough ketorolac and bromfenac levels after 2 days dosing.

    Science.gov (United States)

    Bucci, Frank A; Waterbury, L David

    2009-06-01

    Ketorolac 0.4% administered four times daily (q.i.d.) has long been used safely and effectively for the alleviation of ocular inflamation and pain and the prevention of intraoperative miosis in patients undergoing cataract surgery. Bromfenac ophthalmic solution 0.09% was recently developed as an ocular anti-inflammatory drug with a twice-daily (b.i.d.) dosing regimen. This study was designed to evaluate if b.i.d. dosing with bromfenac 0.09%, in comparison with q.i.d. dosing with ketorolac 0.4%, provides adequate trough nonsteroidal anti-inflammatory drug levels that were effective enough to reduce aqueous prostaglandin (PG) E(2) levels of patients after cataract surgery toward the end of its dosing cycle. In this single-center, investigator-masked trial, patients undergoing cataract surgery were randomized to receive either ketorolac 0.4% q.i.d. or bromfenac 0.09% b.i.d. for 2 days preoperatively. Aqueous humor was collected at the start of surgery 6 hours after the last dose of ketorolac 0.4% and 12 hours after the last dose of bromfenac 0.09%. Aqueous PGE(2) levels and drug concentrations were evaluated by a competitive enzyme immunoassay and reverse-phase HPLC-mass spectroscopy, respectively. A total of 61 patients received ketorolac 0.4% (n=30) or bromfenac 0.09% (n=31). The mean (+/-SD) aqueous PGE(2) level was 285.6+/-141.9 pg/mL in patients treated with ketorolac 0.4% and 386.2+/-131.0 pg/mL in patients treated with bromfenac 0.09% (P=0.006). The mean (+/-SD) aqueous concentrations of ketorolac and bromfenac were 83.6+/-73.8 ng/mL and 9.2+/-6.6 ng/mL, respectively (P<0.001). Ketorolac 0.4% maintained significantly higher aqueous concentrations and lowered aqueous PGE(2) levels significantly more than bromfenac 0.09% at trough levels. Ketorolac 0.4% administered q.i.d. may provide a more sustained control of intraocular inflammation and pain than bromfenac 0.09% administered b.i.d.

  18. Tumor necrosis factor-alpha induces Cl- and K+ secretion in human distal colon driven by prostaglandin E2.

    Science.gov (United States)

    Schmitz, H; Fromm, M; Bode, H; Scholz, P; Riecken, E O; Schulzke, J D

    1996-10-01

    Increased levels of tumor necrosis factor-alpha (TNF-alpha) have been found in, for example, inflammatory bowel disease (IBD) and human immunodeficiency virus (HIV) infection. To investigate a possible contribution of TNF-alpha to the pathogenesis of diarrhea in these diseases, ion transport of human distal colon was studied in the Ussing chamber in vitro. Serosal addition of TNF-alpha increased short-circuit current (Isc) of partially stripped tissues in a dose-dependent manner. Maximum Isc increase of 1.8 +/- 0.2 mumol.h-1.cm-2 was reached after 60 +/- 9 min at 200 ng/ml TNF-alpha. Bidirectional tracer flux measurements revealed that TNF-alpha induced an increase in 36 Cl serosal-to-mucosal flux, a decrease in 36Cl- mucosal-to-serosal flux, and a slight increase in K+ secretion indicated by an increased secretory 86Rb net flux. In the highly differentiated colonic epithelial cell line HT-29/B6, TNF-alpha had no effect on Isc, suggesting a mediation step located in the subepithelium. This supposition was supported by measurements on totally stripped human tissues, since removal of subepithelial layers by total stripping reduced the TNF-alpha effect by 40%. Experiments with tetrodotoxin (10(-6)M) indicated that the TNF-alpha effect was not mediated by the enteric nervous system. The specific 5-lipoxygenase blocker ICI-230487 (5 x 10(-8)M) also had no effect on TNF-alpha action. In contrast, inhibition of cyclooxygenase by indomethacin (10(-6)M inhibited the effect of TNF-alpha. Radioimmunoassay of prostaglandin E2 (PGE2) in the serosal bathing solution revealed an increase in PGE2 production/release after addition of TNF-alpha, which paralleled the Isc response. We conclude that TNF-alpha changed Cl- and K+ transport toward secretion in human colon. This effect was mediated by PGE2 produced by subepithelial cells. Thus TNF-alpha could be a mediator of diarrhea during intestinal inflammation, e.g., in IBD and HIV infection.

  19. Misoprostol inhibits gastric mucosal release of endogenous prostaglandin E2 and thromboxane B2 in healthy volunteers

    DEFF Research Database (Denmark)

    Mertz-Nielsen, A; Eskerod, O; Bukhave, K

    1995-01-01

    blind, cross over design. In each subject misoprostol or placebo was instilled in randomised order into the stomach, which was subsequently perfused with isotonic mannitol. Misoprostol significantly decreased basal as well as acid stimulated output of PGE2 and TXB2, without affecting output of LTB4......Prostaglandin analogues of the E-series theoretically offer the ideal antiulcer drugs. Peptic ulcer healing with prostaglandin analogues is, however, no better than would be predicted from their ability to inhibit gastric acid secretion and they are less effective than histamine H2 receptor...

  20. Prostaglandin E2 Induces Prorenin-Dependent Activation of (Pro)renin Receptor and Upregulation of Cyclooxygenase-2 in Collecting Duct Cells.

    Science.gov (United States)

    Salinas-Parra, Nicolás; Reyes-Martínez, Cristian; Prieto, Minolfa C; Gonzalez, Alexis A

    2017-09-01

    Prostaglandin E2 (PGE2) regulates renin expression in renal juxtaglomerular cells. PGE2 acts through E-prostanoid (EP) receptors in the renal collecting duct (CD) to regulate sodium and water balance. CD cells express EP1 and EP4, which are linked to protein kinase C (PKC) and PKA downstream pathways, respectively. Previous studies showed that the presence of renin in the CD, and that of PKC and PKA pathways, activate its expression. The (pro)renin receptor (PRR) is also expressed in CD cells, and its activation enhances cyclooxygenase-2 (COX-2) through extracellular signal-regulated kinase (ERK). We hypothesized that PGE2 stimulates prorenin and renin synthesis leading to subsequent activation of PRR and upregulation of COX-2. We used a mouse M-1 CD cell line that expresses EP1, EP3 and EP4 but not EP2. PGE2 (10(-6)M) treatment increased prorenin and renin protein levels at 4 and 8 hours. No differences were found at 12-hour after PGE2 treatment. Phospho-ERK was significantly augmented after 12 hours. COX-2 expression was decreased after 4 hours of PGE2 treatment, but increased after 12 hours. Interestingly, the full-length form of the PRR was upregulated only at 12 hours. PGE2-mediated phospho-ERK and COX-2 upregulation was suppressed by PRR silencing. Our results suggest that PGE2 induces biphasic regulation of COX-2 through renin-dependent PRR activation via EP1 and EP4 receptors. PRR-mediated increases in COX-2 expression may enhance PGE2 synthesis in CD cells serving as a buffer mechanism in conditions of activated renin-angiotensin system. Copyright © 2017 Southern Society for Clinical Investigation. Published by Elsevier Inc. All rights reserved.

  1. The role of EP and TP receptors in the response to prostaglandin E2 in the aorta of WKY and spontaneously hypertensive rats

    DEFF Research Database (Denmark)

    Tang, Eva Hc; Jensen, Boye; Skøtt, Ole

    2007-01-01

    AIM: The present study examined the hypothesis that prostaglandin E(2) (PGE(2)) through activation of prostaglandin E (EP) receptor contributes to endothelium-dependent contractions. Methods and Results Western blotting revealed that the protein expression of EP1 receptor was significantly down......-regulated in the aorta of the spontaneously hypertensive rat (SHR), but there was no significant difference in the expression of EP2, EP4 and total EP3 receptors between preparations of Wistar Kyoto rats (WKY) and SHR. Isometric tension studies showed that low concentrations of PGE(2) caused endothelium......-dependent relaxations in WKY but not in aortas of the SHR. High concentrations of PGE(2) evoked contractions predominately through the activation of thromboxane-prostanoid (TP) receptors in the WKY, but involves the dual activation EP and TP receptors in the SHR. SQ29,548, BAYu3405 and Terutroban (TP receptor...

  2. Obesity-associated systemic interleukin-6 promotes pre-adipocyte aromatase expression via increased breast cancer cell prostaglandin E2 production.

    Science.gov (United States)

    Bowers, Laura W; Brenner, Andrew J; Hursting, Stephen D; Tekmal, Rajeshwar R; deGraffenried, Linda A

    2015-01-01

    Obesity is associated with a worse breast cancer prognosis, particularly in estrogen receptor alpha (ERα) positive, postmenopausal patients. We hypothesized that this is mediated in part by an elevation in breast cancer cell cyclooxygenase-2 (COX-2) expression and prostaglandin E2 (PGE2) production that results in greater local pre-adipocyte aromatase expression. We utilized an in vitro model of the obese patient's tumor microenvironment in which cultured MCF-7 breast cancer cells and pre-adipocytes were exposed to pooled serum from obese (OB; BMI ≥ 30.0 kg/m(2)) or normal weight (N; BMI 18.5-24.9 kg/m(2)) postmenopausal women. Exposure to OB versus N sera significantly increased MCF-7 cell COX-2 expression and PGE2 production. Pre-adipocyte aromatase expression was 89 % greater following culture in conditioned media (CM) from MCF-7 cells exposed to OB versus N sera (OB-CM and N-CM, respectively), a difference nullified by MCF-7 cell treatment with the COX-2 inhibitor celecoxib. Previous analysis of the sera revealed significantly higher interleukin-6 (IL-6) concentrations in the OB versus N samples. Depletion of IL-6 from the sera neutralized the difference in pre-adipocyte aromatase expression stimulated by OB-CM versus N-CM. Finally, CM from pre-adipocyte/MCF-7 cell co-cultures exposed to OB sera stimulated greater MCF-7 and T47D breast cancer cell ERα activity and proliferation in comparison to N sera. This study indicates that obesity-associated systemic IL-6 indirectly enhances pre-adipocyte aromatase expression via increased breast cancer cell PGE2 production. Investigation regarding the efficacy of a COX-2 inhibitor/aromatase inhibitor combination therapy in the obese postmenopausal patient population is warranted.

  3. Prostaglandin E2 and Transforming Growth Factor-β Play a Critical Role in Suppression of Allergic Airway Inflammation by Adipose-Derived Stem Cells.

    Directory of Open Access Journals (Sweden)

    Kyu-Sup Cho

    Full Text Available The role of soluble factors in the suppression of allergic airway inflammation by adipose-derived stem cells (ASCs remains to be elucidated. Moreover, the major soluble factors responsible for the immunomodulatory effects of ASCs in allergic airway diseases have not been well documented. We evaluated the effects of ASCs on allergic inflammation in asthmatic mice treated with a prostaglandin E2 (PGE2 inhibitor or transforming growth factor-β (TGF-β neutralizing antibodies.Asthmatic mice were injected intraperitoneally with a PGE2 inhibitor or TGF-β neutralizing antibodies at approximately the same time as ASCs injection and were compared with non-treated controls. In asthmatic mice, ASCs significantly reduced airway hyperresponsiveness, the number of total inflammatory cells and eosinophils in the bronchoalveolar lavage fluid (BALF, eosinophilic inflammation, goblet cell hyperplasia, and serum total and allergen-specific IgE and IgG1. ASCs significantly inhibited Th2 cytokines, such as interleukin (IL-4, IL-5, and IL-13, and enhanced the Th1 cytokine (Interferon-γ and regulatory cytokines (IL-10 and TGF-β in the BALF and lung draining lymph nodes (LLNs. ASCs engraftment caused significant increases in the regulatory T cell (Treg and IL-10+ T cell populations in LLNs. However, blocking PGE2 or TGF-β eliminated the immunosuppressive effect of ASCs in allergic airway inflammation.ASCs are capable of secreting PGE2 and TGF-β, which may play a role in inducing Treg expansion. Furthermore, treatment with a PGE2 inhibitor or TGF-β neutralizing antibodies eliminated the beneficial effect of ASCs treatment in asthmatic mice, suggesting that PGE2 and TGF-β are the major soluble factors responsible for suppressing allergic airway inflammation.

  4. Distinct phospholipase A2 enzymes regulate prostaglandin E2 and F2alpha production by bovine endometrial epithelial cells

    Directory of Open Access Journals (Sweden)

    Elgayyar Mona

    2007-04-01

    Full Text Available Abstract Background The rate-limiting step in prostaglandin (PG biosynthesis is catalyzed by phospholipase A2 (PLA2 enzymes which hydrolyze arachidonic acid from membrane phospholipids. Despite their importance in uterine PG production, little is known concerning the specific PLA2 enzymes that regulate arachidonic acid liberation in the uterine endometrium. The objectives of this study were to evaluate the expression and activities of calcium-independent Group VI and Group IVC PLA2 (PLA2G6 and PLA2G4C and calcium-dependent Group IVA PLA2 (PLA2G4A enzymes in the regulation of bovine uterine endometrial epithelial cell PG production. Methods Bovine endometrial epithelial cells in culture were treated with oxytocin, interferon-tau and the PLA2G6 inhibitor bromoenol lactone, alone and in combination. Concentrations of PGF2alpha and PGE2 released into the medium were analyzed. Western blot analysis was performed on cellular protein to determine the effects of treatments on expression of PLA2G4A, PLA2G6 and PLA2G4C. Group-specific PLA2 activity assays were performed on cell lysates following treatment with oxytocin, interferon-tau or vehicle (control, alone and in combination. To further evaluate the role of specific PLA2 enzymes in uterine cell PG biosynthesis, cells were transfected with cDNAs encoding human PLA2G6 and PLA24C, treated as described above and PG assays performed. Results Constitutive cell production of PGF2alpha was about two-fold higher than PGE2. Oxytocin stimulated production of both PGs but the increase of PGF2alpha was significantly greater. Interferon-tau diminished oxytocin stimulation of both PGs. The PLA2G6 inhibitor, bromoenol lactone, abolished oxytocin-stimulated production of PGF2alpha. Treatments had little effect on PLA2G4A protein expression. In contrast, oxytocin enhanced expression of PLA2G6 and this effect was diminished in the presence of interferon-tau. Expression of PLA2G4C was barely detectable in control and

  5. Variation of prostaglandin E2 concentrations in ovaries and its effects on ovarian maturation and oocyte proliferation in the giant fresh water prawn, Macrobrachium rosenbergii.

    Science.gov (United States)

    Sumpownon, Chanudporn; Engsusophon, Attakorn; Siangcham, Tanapan; Sugiyama, Eiji; Soonklang, Nantawan; Meeratana, Prasert; Wanichanon, Chaitip; Hanna, Peter J; Setou, Mitsutoshi; Sobhon, Prasert

    2015-11-01

    Prostaglandins (PGs) are important bioactive mediators for many physiological functions. In some decapod crustaceans, prostaglandin E2 (PGE2) has been detected in reproductive organs, and may play a role in the control of ovarian maturation. However, in the freshwater prawn, Macrobrachium rosenbergii, the presences of PGE2 and key enzymes for PGE2 biosynthesis, as well as its effects on ovarian maturation have not yet been investigated. In this study we reported the presence of PGE2, cyclooxygenase1 (COX1) and prostaglandin E synthase (PGES) in the ovarian tissues of M. rosenbergii, using immunohistochemistry. Intense immunoreactivities of PGE2 (PGE2-ir), COX1 (Cox1-ir) and PGES (PGES-ir) were detected in previtellogenic oocytes (Oc1 and Oc2), while the immunoreactivities were absent in the late vitellogenic oocytes (Oc4). This finding supports the hypothesis that the PGE2 biosynthesis occurs in the ovary of this prawn. To ascertain this finding we used LC-MS/MS to quantitate PGE2 concentrations during ovarian developmental cycle. The levels of PGE2 were significantly higher in the early ovarian stages (St I and II) than in the late stages (St III and IV). Moreover, we found that administration of PGE2 stimulated the ovarian maturation in this species by shortening the length of the ovarian cycle, increasing ovarian-somatic index, oocyte proliferation, and vitellogenin (Vg) level in the hemolymph. Copyright © 2015 Elsevier Inc. All rights reserved.

  6. The role of prostaglandins E1 and E2, dinoprostone, and misoprostol in cervical ripening and the induction of labor: a mechanistic approach.

    Science.gov (United States)

    Bakker, Ronan; Pierce, Stephanie; Myers, Dean

    2017-08-01

    Prostaglandins play a critical role in cervical ripening by increasing inflammatory mediators in the cervix and inducing cervical remodeling. Prostaglandin E1 (PGE1) and prostaglandin E2 (PGE2) exert different effects on these processes and on myometrial contractility. These mechanistic differences may affect outcomes in women treated with dinoprostone, a formulation identical to endogenous PGE2, compared with misoprostol, a PGE1 analog. The objective of this review is to evaluate existing evidence regarding mechanistic differences between PGE1 and PGE2, and consider the clinical implications of these differences in patients requiring cervical ripening for labor induction. We conducted a critical narrative review of peer-reviewed articles identified using PubMed and other online databases. While both dinoprostone and misoprostol are effective in cervical ripening and labor induction, they differ in their clinical and pharmacological profiles. PGE2 has been shown to stimulate interleukin-8, an inflammatory cytokine that promotes the influx of neutrophils and induces remodeling of the cervical extracellular matrix, and to induce functional progesterone withdrawal. Misoprostol has been shown to elicit a dose-dependent effect on myometrial contractility, which may affect rates of uterine tachysystole in clinical practice. Differences in the mechanism of action between misoprostol and PGE2 may contribute to their variable effects in the cervix and myometrium, and should be considered to optimize outcomes.

  7. Gastric bicarbonate secretion and release of prostaglandin E2 are increased in duodenal ulcer patients, but not in Helicobacter pylori positive healthy subjects

    DEFF Research Database (Denmark)

    A, Mertz-Nielsen; Hillingsø, Jens; Frøkiær, Hanne

    1996-01-01

    Background: Duodenal ulcer (DU) patients have impaired proximal duodenal mucosal bicarbonate secretion at rest and in response to luminal acid with higher acid-stimulated mucosal release of prostaglandin (PG) E(2) than healthy subjects. Our purpose was to determine whether this abnormality...... was present also in the stomach of DU patients. Methods: Simultaneous determinations of gastric and duodenal bicarbonate secretion and luminal release of PGE(2) were performed in 16 healthy volunteers (5 Helicobacter pylori-positive) and 8 inactive DU patients (all H. pylori-positivr). Results: In healthy...

  8. Gastric bicarbonate secretion and release of prostaglandin E2 are increased in duodenal ulcer patients but not in Helicobacter pylori-positive healthy subjects

    DEFF Research Database (Denmark)

    Mertz-Nielsen, A; Hillingsø, Jens; Frøkiaer, H

    1996-01-01

    BACKGROUND: Duodenal ulcer (DU) patients have impaired proximal duodenal mucosal bicarbonate secretion at rest and in response to luminal acid with higher acid-stimulated mucosal release of prostaglandin (PG) E2 than healthy subjects. Our purpose was to determine whether this abnormality...... was present also in the stomach of DU patients. METHODS: Simultaneous determinations of gastric and duodenal bicarbonate secretion and luminal release of PGE2 were performed in 16 healthy volunteers (5 Helicobacter pylori-positive) and 8 inactive DU patients (all H. pylori-positive). RESULTS: In healthy...

  9. The pharmacological effect of BGC20-1531, a novel prostanoid EP4 receptor antagonist, in the prostaglandin E2 human model of headache

    DEFF Research Database (Denmark)

    Antonova, Maria; Wienecke, Troels; Maubach, Karen

    2011-01-01

    Using a human Prostaglandin E(2) (PGE(2)) model of headache, we examined whether a novel potent and selective EP(4) receptor antagonist, BGC20-1531, may prevent headache and dilatation of the middle cerebral (MCA) and superficial temporal artery (STA). In a three-way cross-over trial, eight healthy...... of the MCA or the STA (P > 0.05) with either dose of BGC20-1531 relative to placebo, although putative therapeutic exposures were not reached in all volunteers. In conclusion, these data suggest that the other EP receptors may be involved in PGE(2) induced headache and dilatation in normal subjects....

  10. Promoter-dependent and -independent activation of insulin-like growth factor binding protein-5 gene expression by prostaglandin E2 in primary rat osteoblasts

    Science.gov (United States)

    McCarthy, T. L.; Casinghino, S.; Mittanck, D. W.; Ji, C. H.; Centrella, M.; Rotwein, P.

    1996-01-01

    Insulin-like growth factor (IGF) action is mediated by high affinity cell surface IGF receptors and modulated by a family of secreted IGF binding proteins (IGFBPs). IGFBP-5, the most conserved of six IGFBPs characterized to date, uniquely potentiates the anabolic actions of IGF-I for skeletal cells. In osteoblasts, IGFBP-5 production is stimulated by prostaglandin E2 (PGE2), a local factor that mediates certain effects induced by parathyroid hormone, cytokines such as interleukin-1 and transforming growth factor-beta, and mechanical strain. In this study, we show that transcriptional and post-transcriptional events initiated by PGE2 collaborate to enhance IGFBP-5 gene expression in primary fetal rat osteoblast cultures. PGE2 treatment stimulated up to a 7-fold rise in steady-state levels of IGFBP-5 mRNA throughout 32 h of incubation. Analysis of nascent IGFBP-5 mRNA suggested that PGE2 had only a modest stimulatory effect on IGFBP-5 gene transcription, and transient transfection studies with IGFBP-5 promoter-reporter genes confirmed that PGE2 enhanced promoter activity by approximately 2-fold. Similar stimulatory effects were seen with forskolin. A DNA fragment with only 51 base pairs of the 5'-flanking sequence retained hormonal responsiveness, which may be mediated by a binding site for transcription factor AP-2 located at positions -44 to -36 in the proximal IGFBP-5 promoter. Incubation of osteoblasts with the mRNA transcriptional inhibitor 5,6-dichloro-1-beta-D-ribofuranosylbenzimidazole demonstrated that PGE2 enhanced IGFBP-5 mRNA stability by 2-fold, increasing the t1/2 from 9 to 18 h. The effects of PGE2 on steady-state IGFBP-5 transcripts were abrogated by preincubating cells with cycloheximide, indicating that the effects of PGE2 on both gene transcription and mRNA stability required ongoing protein synthesis. Therefore, both promoter-dependent and -independent pathways converge to enhance IGFBP-5 gene expression in response to PGE2 in osteoblasts.

  11. DNA damage response proteins and oxygen modulate prostaglandin E2 growth factor release in response to low and high LET ionizing radiation

    Directory of Open Access Journals (Sweden)

    Christopher P. Allen

    2015-12-01

    Full Text Available Common cancer therapies employ chemicals or radiation that damage DNA. Cancer and normal cells respond to DNA damage by activating complex networks of DNA damage sensor, signal transducer, and effector proteins that arrest cell cycle progression, and repair damaged DNA. If damage is severe enough, the DNA damage response (DDR triggers programmed cell death by apoptosis or other pathways. Caspase 3 is a protease that is activated upon damage and triggers apoptosis, and production of prostaglandin E2 (PGE2, a potent growth factor that can enhance growth of surviving cancer cells leading to accelerated tumor repopulation. Thus, dying tumor cells can promote growth of surviving tumor cells, a pathway aptly named Phoenix Rising. In the present study we surveyed Phoenix Rising responses in a variety of normal and established cancer cell lines, and in cancer cell lines freshly derived from patients. We demonstrate that IR induces a Phoenix Rising response in many, but not all cell lines, and that PGE2 production generally correlates with enhanced growth of cells that survive irradiation, and of unirradiated cells co-cultured with irradiated cells. We show that PGE2 production is stimulated by low and high LET ionizing radiation, and can be enhanced or suppressed by inhibitors of key DNA damage response proteins. PGE2 is produced downstream of Caspase 3 and the cyclooxygenases COX1 and COX2, and we show that the pan COX1-2 inhibitor indomethacin blocks IR-induced PGE2 production in the presence or absence of DDR inhibitors. COX1-2 require oxygen for catalytic activity, and we further show that PGE2 production is markedly suppressed in cells cultured under low (1% oxygen concentration. Thus, Phoenix Rising is most likely to cause repopulation of tumors with relatively high oxygen, but not in hypoxic tumors. This survey lays a foundation for future studies to further define tumor responses to radiation and inhibitors of the DDR and Phoenix Rising to

  12. Gastric bicarbonate secretion and release of prostaglandin E2 are increased in duodenal ulcer patients but not in Helicobacter pylori-positive healthy subjects

    DEFF Research Database (Denmark)

    Mertz-Nielsen, A; Hillingsø, Jens; Frøkiaer, H

    1996-01-01

    BACKGROUND: Duodenal ulcer (DU) patients have impaired proximal duodenal mucosal bicarbonate secretion at rest and in response to luminal acid with higher acid-stimulated mucosal release of prostaglandin (PG) E2 than healthy subjects. Our purpose was to determine whether this abnormality was pres...... for the abnormally high gastric secretion of bicarbonate in inactive DU patients. The defective duodenal secretion of bicarbonate observed in these patients may be a consequence of previous ulceration rather than the mere presence of H. pylori infection.......BACKGROUND: Duodenal ulcer (DU) patients have impaired proximal duodenal mucosal bicarbonate secretion at rest and in response to luminal acid with higher acid-stimulated mucosal release of prostaglandin (PG) E2 than healthy subjects. Our purpose was to determine whether this abnormality...... was present also in the stomach of DU patients. METHODS: Simultaneous determinations of gastric and duodenal bicarbonate secretion and luminal release of PGE2 were performed in 16 healthy volunteers (5 Helicobacter pylori-positive) and 8 inactive DU patients (all H. pylori-positive). RESULTS: In healthy...

  13. Tetra- and pentacyclic triterpene acids from the ancient anti-inflammatory remedy frankincense as inhibitors of microsomal prostaglandin E(2) synthase-1.

    Science.gov (United States)

    Verhoff, Moritz; Seitz, Stefanie; Paul, Michael; Noha, Stefan M; Jauch, Johann; Schuster, Daniela; Werz, Oliver

    2014-06-27

    The microsomal prostaglandin E2 synthase (mPGES)-1 is the terminal enzyme in the biosynthesis of prostaglandin (PG)E2 from cyclooxygenase (COX)-derived PGH2. We previously found that mPGES-1 is inhibited by boswellic acids (IC50 = 3-30 μM), which are bioactive triterpene acids present in the anti-inflammatory remedy frankincense. Here we show that besides boswellic acids, additional known triterpene acids (i.e., tircuallic, lupeolic, and roburic acids) isolated from frankincense suppress mPGES-1 with increased potencies. In particular, 3α-acetoxy-8,24-dienetirucallic acid (6) and 3α-acetoxy-7,24-dienetirucallic acid (10) inhibited mPGES-1 activity in a cell-free assay with IC50 = 0.4 μM, each. Structure-activity relationship studies and docking simulations revealed concrete structure-related interactions with mPGES-1 and its cosubstrate glutathione. COX-1 and -2 were hardly affected by the triterpene acids (IC50 > 10 μM). Given the crucial role of mPGES-1 in inflammation and the abundance of highly active triterpene acids in frankincence extracts, our findings provide further evidence of the anti-inflammatory potential of frankincense preparations and reveal novel, potent bioactivities of tirucallic acids, roburic acids, and lupeolic acids.

  14. Tetra- and Pentacyclic Triterpene Acids from the Ancient Anti-inflammatory Remedy Frankincense as Inhibitors of Microsomal Prostaglandin E2 Synthase-1

    Science.gov (United States)

    2014-01-01

    The microsomal prostaglandin E2 synthase (mPGES)-1 is the terminal enzyme in the biosynthesis of prostaglandin (PG)E2 from cyclooxygenase (COX)-derived PGH2. We previously found that mPGES-1 is inhibited by boswellic acids (IC50 = 3–30 μM), which are bioactive triterpene acids present in the anti-inflammatory remedy frankincense. Here we show that besides boswellic acids, additional known triterpene acids (i.e., tircuallic, lupeolic, and roburic acids) isolated from frankincense suppress mPGES-1 with increased potencies. In particular, 3α-acetoxy-8,24-dienetirucallic acid (6) and 3α-acetoxy-7,24-dienetirucallic acid (10) inhibited mPGES-1 activity in a cell-free assay with IC50 = 0.4 μM, each. Structure–activity relationship studies and docking simulations revealed concrete structure-related interactions with mPGES-1 and its cosubstrate glutathione. COX-1 and -2 were hardly affected by the triterpene acids (IC50 > 10 μM). Given the crucial role of mPGES-1 in inflammation and the abundance of highly active triterpene acids in frankincence extracts, our findings provide further evidence of the anti-inflammatory potential of frankincense preparations and reveal novel, potent bioactivities of tirucallic acids, roburic acids, and lupeolic acids. PMID:24844534

  15. Effect of central and peripheral injection of prostaglandin E2 and F2α on feeding and the crop-emptying rate in chicks.

    Science.gov (United States)

    Tachibana, Tetsuya; Nakai, Yasua; Makino, Ryosuke; Khan, Md Sakirul Islam; Cline, Mark A

    2017-05-01

    Prostaglandins (PGs) have been shown to cause several physiological changes in mammals including anorexia, awakening and sleeping, change in digestive function, and activation of the hypothalamus-pituitary-adrenal gland (HPA) axis. However, there is a paucity of information about the effect of PGs on physiological parameters in birds. The purpose of the present study was to clarify whether intracerebroventricular (ICV) and intraperitoneal (IP) injections of prostaglandin E2 (PGE2) and prostaglandin F2α (PGF2α) affect feeding, voluntary movement, crop-emptying rate, and corticosterone release in chicks (Gallus gallus). ICV injection of either PGE2 or PGF2α (2 and 4μg) significantly decreased food intake in chicks. The anorexigenic effect was also observed after IP injection of the PGs. Voluntary movement was significantly suppressed by ICV injection of PGE2 or PGF2α, although the time-course change was different between the two. In contrast, IP injection of the PGs had no or less effect on voluntary movement. Both ICV and IP injection of PGE2 significantly retarded the crop-emptying rate, whereas PGF2α significantly lowered the crop-emptying rate only after IP injection. The plasma corticosterone concentration significantly increased after ICV and IP injection of PGE2, whereas PGF2α had no effect. These results suggest that central and peripheral PGs are involved in the regulation of appetite, voluntary movement, food passage in the digestive tract, and activation of the HPA axis in chicks, although the effects depend on the site of action and type of PGs. Copyright © 2017 Elsevier Inc. All rights reserved.

  16. Increased potential for wound activated production of Prostaglandin E2 and related toxic compounds in non-native populations of Gracilaria vermiculophylla.

    Science.gov (United States)

    Hammann, Mareike; Rempt, Martin; Pohnert, Georg; Wang, Gaoge; Boo, Sung Min; Weinberger, Florian

    2016-01-01

    The capacity of the East Asian seaweed Gracilaria vermiculophylla ("Ogonori") for production of prostaglandin E2 from arachidonic acid occasionally causes food poisoning after ingestion. During the last two decades the alga has been introduced to Europe and North America. Non-native populations have been shown to be generally less palatable to marine herbivores than native populations. We hypothesized that the difference in palatability among populations could be due to differences in the algal content of prostaglandins. We therefore compared the capacity for wound-activated production of prostaglandins and other eicosatetraenoid oxylipins among five native populations in East Asia and seven non-native populations in Europe and NW Mexico, using a targeted metabolomics approach. In two independent experiments non-native populations exhibited a significant tendency to produce more eicosatetraenoids than native populations after acclimation to identical conditions and subsequent artificial wounding. Fourteen out of 15 eicosatetraenoids that were detected in experiment I and all 19 eicosatetraenoids that were detected in experiment II reached higher mean concentrations in non-native than in native specimens. Wounding of non-native specimens resulted on average in 390% more 15-keto-PGE2, in 90% more PGE2, in 37% more PGA2 and in 96% more 7,8-di-hydroxy-eicosatetraenoic acid than wounding of native specimens. Not only PGE2, but also PGA2 and dihydroxylated eicosatetraenoic acid are known to deter various biological enemies of G. vermiculophylla that cause tissue or cell wounding, and in the present study the latter two compounds also repelled the mesograzer Littorina brevicula. Non-native populations of G. vermiculophylla are thus more defended against herbivory than native populations. This increased capacity for activated chemical defense may have contributed to their invasion success and at the same time it poses an elevated risk for human food safety. Copyright

  17. Role of pathogen-derived cell wall carbohydrates and prostaglandin E2 in immune response and suppression of fish immunity by the oomycete Saprolegnia parasitica.

    Science.gov (United States)

    Belmonte, Rodrigo; Wang, Tiehui; Duncan, Gary J; Skaar, Ida; Mélida, Hugo; Bulone, Vincent; van West, Pieter; Secombes, Christopher J

    2014-11-01

    Saprolegnia parasitica is a freshwater oomycete that is capable of infecting several species of fin fish. Saprolegniosis, the disease caused by this microbe, has a substantial impact on Atlantic salmon aquaculture. No sustainable treatment against saprolegniosis is available, and little is known regarding the host response. In this study, we examined the immune response of Atlantic salmon to S. parasitica infection and to its cell wall carbohydrates. Saprolegnia triggers a strong inflammatory response in its host (i.e., induction of interleukin-1β1 [IL-1β1], IL-6, and tumor necrosis factor alpha), while severely suppressing the expression of genes associated with adaptive immunity in fish, through downregulation of T-helper cell cytokines, antigen presentation machinery, and immunoglobulins. Oomycete cell wall carbohydrates were recognized by fish leukocytes, triggering upregulation of genes involved in the inflammatory response, similar to what is observed during infection. Our data suggest that S. parasitica is capable of producing prostaglandin [corrected] E2 (PGE2) in vitro, a metabolite not previously shown to be produced by oomycetes, and two proteins with homology to vertebrate enzymes known to play a role in prostaglandin biosynthesis have been identified in the oomycete genome. Exogenous PGE2 was shown to increase the inflammatory response in fish leukocytes incubated with cell wall carbohydrates while suppressing genes involved in cellular immunity (gamma interferon [IFN-γ] and the IFN-γ-inducible protein [γ-IP]). Inhibition of S. parasitica zoospore germination and mycelial growth by two cyclooxygenase inhibitors (aspirin and indomethacin) also suggests that prostaglandins may be involved in oomycete development. Copyright © 2014, American Society for Microbiology. All Rights Reserved.

  18. Arg126 and Asp49 Are Essential for the Catalytic Function of Microsomal Prostaglandin E2 Synthase 1 and Ser127 Is Not.

    Directory of Open Access Journals (Sweden)

    Joan Raouf

    Full Text Available Prostaglandins are signaling molecules that regulate different physiological processes, involving allergic and inflammatory responses and cardiovascular control. They are involved in several pathophysiological processes, including inflammation and cancer. The inducible terminal enzyme, microsomal prostaglandin E synthase 1 (MPGES1, catalyses prostaglandin E2 production during inflammation. MPGES1 has therefore been intensively studied as a pharmaceutical target and many competitive inhibitors targeting its active site have been developed. However, little is known about its catalytic mechanism.The objective of this study was to investigate which amino acids play a key role in the catalytic mechanism of MPGES1.Based on results and predictions from previous structural studies, the amino acid residues Asp49, Arg73, Arg126, and Ser127 were chosen and altered by site-directed mutagenesis. The mutated enzyme variants were cloned and expressed in both the E. coli and the Baculovirus expression systems. Their catalytic significance was evaluated by activity measurements with prostanoid profiling.Our study shows that Arg126 and Asp49 are absolutely required for the catalytic activity of MPGES1, as when exchanged, the enzyme variants loose activity. Ser127 and Arg73 on the other hand, don't seem to be central to the catalytic mechanism because when exchanged, their variants retain considerable activity. Our finding that the Ser127Ala variant retains activity was surprising since high-resolution structural data supported a role in glutathione activation. The close proximity of Ser127 to the active site is, however, supported since the Ser127Cys variant displays 80% lowered activity.

  19. Prostaglandin E2 Exerts Multiple Regulatory Actions on Human Obese Adipose Tissue Remodeling, Inflammation, Adaptive Thermogenesis and Lipolysis.

    Science.gov (United States)

    García-Alonso, Verónica; Titos, Esther; Alcaraz-Quiles, Jose; Rius, Bibiana; Lopategi, Aritz; López-Vicario, Cristina; Jakobsson, Per-Johan; Delgado, Salvadora; Lozano, Juanjo; Clària, Joan

    2016-01-01

    Obesity induces white adipose tissue (WAT) dysfunction characterized by unremitting inflammation and fibrosis, impaired adaptive thermogenesis and increased lipolysis. Prostaglandins (PGs) are powerful lipid mediators that influence the homeostasis of several organs and tissues. The aim of the current study was to explore the regulatory actions of PGs in human omental WAT collected from obese patients undergoing laparoscopic bariatric surgery. In addition to adipocyte hypertrophy, obese WAT showed remarkable inflammation and total and pericellular fibrosis. In this tissue, a unique molecular signature characterized by altered expression of genes involved in inflammation, fibrosis and WAT browning was identified by microarray analysis. Targeted LC-MS/MS lipidomic analysis identified increased PGE2 levels in obese fat in the context of a remarkable COX-2 induction and in the absence of changes in the expression of terminal prostaglandin E synthases (i.e. mPGES-1, mPGES-2 and cPGES). IPA analysis established PGE2 as a common top regulator of the fibrogenic/inflammatory process present in this tissue. Exogenous addition of PGE2 significantly reduced the expression of fibrogenic genes in human WAT explants and significantly down-regulated Col1α1, Col1α2 and αSMA in differentiated 3T3 adipocytes exposed to TGF-β. In addition, PGE2 inhibited the expression of inflammatory genes (i.e. IL-6 and MCP-1) in WAT explants as well as in adipocytes challenged with LPS. PGE2 anti-inflammatory actions were confirmed by microarray analysis of human pre-adipocytes incubated with this prostanoid. Moreover, PGE2 induced expression of brown markers (UCP1 and PRDM16) in WAT and adipocytes, but not in pre-adipocytes, suggesting that PGE2 might induce the trans-differentiation of adipocytes towards beige/brite cells. Finally, PGE2 inhibited isoproterenol-induced adipocyte lipolysis. Taken together, these findings identify PGE2 as a regulator of the complex network of interactions

  20. Prostaglandin E2 Exerts Multiple Regulatory Actions on Human Obese Adipose Tissue Remodeling, Inflammation, Adaptive Thermogenesis and Lipolysis.

    Directory of Open Access Journals (Sweden)

    Verónica García-Alonso

    Full Text Available Obesity induces white adipose tissue (WAT dysfunction characterized by unremitting inflammation and fibrosis, impaired adaptive thermogenesis and increased lipolysis. Prostaglandins (PGs are powerful lipid mediators that influence the homeostasis of several organs and tissues. The aim of the current study was to explore the regulatory actions of PGs in human omental WAT collected from obese patients undergoing laparoscopic bariatric surgery. In addition to adipocyte hypertrophy, obese WAT showed remarkable inflammation and total and pericellular fibrosis. In this tissue, a unique molecular signature characterized by altered expression of genes involved in inflammation, fibrosis and WAT browning was identified by microarray analysis. Targeted LC-MS/MS lipidomic analysis identified increased PGE2 levels in obese fat in the context of a remarkable COX-2 induction and in the absence of changes in the expression of terminal prostaglandin E synthases (i.e. mPGES-1, mPGES-2 and cPGES. IPA analysis established PGE2 as a common top regulator of the fibrogenic/inflammatory process present in this tissue. Exogenous addition of PGE2 significantly reduced the expression of fibrogenic genes in human WAT explants and significantly down-regulated Col1α1, Col1α2 and αSMA in differentiated 3T3 adipocytes exposed to TGF-β. In addition, PGE2 inhibited the expression of inflammatory genes (i.e. IL-6 and MCP-1 in WAT explants as well as in adipocytes challenged with LPS. PGE2 anti-inflammatory actions were confirmed by microarray analysis of human pre-adipocytes incubated with this prostanoid. Moreover, PGE2 induced expression of brown markers (UCP1 and PRDM16 in WAT and adipocytes, but not in pre-adipocytes, suggesting that PGE2 might induce the trans-differentiation of adipocytes towards beige/brite cells. Finally, PGE2 inhibited isoproterenol-induced adipocyte lipolysis. Taken together, these findings identify PGE2 as a regulator of the complex network of

  1. Cytosolic prostaglandin E2 synthase (cPGES) expression is decreased in discrete cortical regions in psychiatric disease.

    Science.gov (United States)

    Maida, Mary E; Hurley, Sean D; Daeschner, Jo Anna; Moore, Amy H; O'Banion, M Kerry

    2006-08-04

    The number of adults in the US affected by bipolar disorder, depression, or schizophrenia is approaching 15 million. Despite decades of research, etiologies of these illnesses remain elusive. Theories of aberrant brain morphology, neurotransmission, and signal conduction have provided the heuristic framework for a large body of literature, with attention focused upon hypotheses of monoamine signaling underlying psychiatric disease. More recently, attention has turned to potential contributions of other signaling pathways, including the arachidonic acid cascade and generation of prostaglandins (PG). To determine the potential involvement of the pathways leading to PGE2 synthesis in psychiatric disease, immunohistochemistry and immunoblotting were performed to measure regional expression of the cyclooxygenases (COX) and one of the terminal PGE2 synthases (PGES) in postmortem tissue provided by The Stanley Medical Research Institute. For normal, bipolar, depressed, and schizophrenic subjects, COX-1 and COX-2 protein levels did not differ across region and patient populations. In contrast, there was a significant effect of diagnosis on cytosolic PGES (cPGES) protein levels in the frontal cortex, with remarkable decreases observed in all psychiatric groups relative to normal tissue (P bipolar subjects. Evaluation of medicated vs. non-medicated subjects revealed a significant effect of medication on cPGES expression in the frontal cortex of bipolar, but not depressed or schizophrenic subjects. These novel findings further support hypotheses of abnormalities in fatty acid and phospholipid metabolism in regions associated with psychiatric disease.

  2. Flaxseed enriched diet-mediated reduction in ovarian cancer severity is correlated to the reduction of prostaglandin E(2) in laying hen ovaries.

    Science.gov (United States)

    Eilati, Erfan; Hales, Karen; Zhuge, Yan; Ansenberger Fricano, Kristine; Yu, Rui; van Breemen, Richard B; Hales, Dale Buchanan

    2013-09-01

    Prevention of ovarian cancer is the best approach for reducing the impact of this deadly disease. The laying hen is a robust model of spontaneous ovarian cancer that recapitulates the human disease. Dietary intervention with flaxseed, the richest vegetable source of omega-3 fatty acids (OM-3FAs) and phytoestrogen lignans, demonstrate the potential for effective prevention and amelioration of ovarian cancer by targeting inflammatory prostaglandin pathways. Prostaglandin E2 (PGE2) is the most pro-inflammatory ecoisanoid and one of the downstream products of two isoforms of cyclooxygenase (COX) enzymes: COX-1 and COX-2. Our objective was to investigate the effect of flaxseed supplementation for one year on ovarian cancer and correlate its effects to expression of COX enzymes and concentrations of prostaglandins. White Leghorn hens were fed 10% flaxseed-enriched or standard diet for one year. The severity of ovarian cancer was determined by gross pathology and histology. COX-1 and COX-2 localization and protein and mRNA expression and PGE2 and PGE3 concentrations in ovaries were measured by IHC, western blot, quantitative real-time PCR and LC-MS-MS, respectively. The results demonstrated a significant reduction in late stage ovarian tumors in the flaxseed-fed hens compared with the control diet-fed hens. In correlation with decreased ovarian cancer severity, concentrations of PGE2 and expression of COX-2 were diminished in ovaries of flaxseed-fed hens. PGE3 concentrations were below the level of detection. The results demonstrated that in normal ovaries, COX-1 was localized to the granulosa cell layer surrounding the follicles and ovarian surface epithelium (OSE) whereas COX-2 protein was localized to the granulosa cell layer in the follicle. Extensive COX-1 and COX-2 protein expression was found throughout the ovarian carcinoma. Our findings suggest that the flaxseed-mediated reduction in the severity of ovarian cancer in hens is correlated to the reduction in PGE2 in

  3. Dominant role of prostaglandin E2 EP4 receptor in furosemide-induced salt-losing tubulopathy: a model for hyperprostaglandin E syndrome/antenatal Bartter syndrome

    DEFF Research Database (Denmark)

    Nüsing, Rolf M; Treude, Antje; Weissenberger, Christian

    2005-01-01

    Increased formation of prostaglandin E2 (PGE2) is a key part of hyperprostaglandin E syndrome/antenatal Bartter syndrome (HPS/aBS), a renal disease characterized by NaCl wasting, water loss, and hyperreninism. Inhibition of PGE2 formation by cyclo-oxygenase inhibitors significantly lowers patient...... animals studied, furosemide stimulated a rise in diuresis and electrolyte excretion. However, this effect was blunted in EP1-/-, EP3-/-, and EP4-/- mice. Compared with WT mice, no difference was observed in EP2-/- and IP-/- mice. The furosemide-induced increase in plasma renin concentration...... was significantly decreased in EP4-/- mice and to a lesser degree also in IP-/- mice. Pharmacologic inhibition of EP4 receptors in furosemide-treated WT mice with the specific antagonist ONO-AE3-208 mimicked the changes in renin mRNA expression, plasma renin concentration, diuresis, and sodium excretion seen in EP4...

  4. Topical 0.1% Bromfenac Sodium for Intraoperative Miosis Prevention and Prostaglandin E2 Inhibition in Femtosecond Laser-Assisted Cataract Surgery.

    Science.gov (United States)

    Chen, Hui; Lin, Haotian; Chen, Wan; Zhang, Bo; Xiang, Wu; Li, Jing; Chen, Weirong

    2017-04-01

    The purpose of this study was to evaluate the effect of topical 0.1% bromfenac sodium, a nonsteroidal anti-inflammatory drug (NSAID), on intraoperative pupil dilation maintenance and prostaglandin E2 (PGE2) inhibition during femtosecond laser-assisted cataract surgery. Sixty patients (30 each in study and control groups) were included in this study. The patients received 0.1% bromfenac ophthalmic solution or control placebo twice a day for 3 days before surgery. Pupil size was measured at the initiation of femtosecond laser pretreatment and phacoemulsification. Aqueous humor was collected at the beginning of routine cataract surgery. PGE2 levels were measured with an enzyme-linked immunoassay. Laser flare photometry was measured preoperatively and at 1 day postoperatively. Compared with untreated patients, the change in pupil size and postoperative day 1 aqueous flare were significantly reduced throughout the operation in the patients treated with 0.1% bromfenac (P miosis, and reducing PGE2 levels.

  5. Mouse gastric tumor models with prostaglandin E2 pathway activation show similar gene expression profiles to intestinal-type human gastric cancer

    Directory of Open Access Journals (Sweden)

    Oshima Masanobu

    2009-12-01

    Full Text Available Abstract Background Gastric cancers are generally classified into better differentiated intestinal-type tumor and poorly differentiated diffuse-type one according to Lauren's histological categorization. Although induction of prostaglandin E2 pathway promotes gastric tumors in mice in cooperation with deregulated Wnt or BMP signalings, it has remained unresolved whether the gastric tumor mouse models recapitulate either of human gastric cancer type. This study assessed the similarity in expression profiling between gastric tumors of transgenic mice and various tissues of human cancers to find best-fit human tumors for the transgenic mice models. Results Global expression profiling initially found gastric tumors from COX-2/mPGES-1 (C2mE-related transgenic mice (K19-C2mE, K19-Wnt1/C2mE, and K19-Nog/C2mE resembled gastric cancers among the several tissues of human cancers including colon, breast, lung and gastric tumors. Next, classification of the C2mE-related transgenic mice by a gene signature to distinguish human intestinal- and diffuse-type tumors showed C2mE-related transgenic mice were more similar to intestinal-type compared with diffuse one. We finally revealed that induction of Wnt pathway cooperating with the prostaglandin E2 pathway in mice (K19-Wnt1/C2mE mice further reproduce features of human gastric intestinal-type tumors. Conclusion We demonstrated that C2mE-related transgenic mice show significant similarity to intestinal-type gastric cancer when analyzed by global expression profiling. These results suggest that the C2mE-related transgenic mice, especially K19-Wnt1/C2mE mice, serve as a best-fit model to study molecular mechanism underlying the tumorigenesis of human gastric intestinal-type cancers.

  6. Utilizing immunoaffinity chromatography (IAC) cross-reactivity in GC-MS/MS exemplified at the measurement of prostaglandin E1 in human plasma using prostaglandin E2-specific IAC columns.

    Science.gov (United States)

    Tsikas, Dimitrios; Suchy, Maria-Theresia; Tödter, Klaus; Heeren, Joerg; Scheja, Ludger

    2016-05-15

    Immunoaffinity chromatography (IAC) is an elegant and highly efficient method to isolate a particular compound from biological samples for measurement by mass spectrometry coupled to GC, CE, or LC. The utility of IAC for the quantitative determination of several prostaglandins including prostaglandin E2 (PGE2) by GC-MS/MS and LC-MS/MS has been demonstrated. The aim of the present work was to test whether the cross-reactivity of the antibody immobilized on an insoluble support can be utilized for the quantitative determination of biomolecules by stable-isotope dilution mass spectrometry. In this communication, we provide evidence that this is indeed possible for prostaglandin E1 (PGE1) in human plasma by GC-MS/MS using commercially available Sepharose 4-based IAC columns with immobilized mouse anti-PGE2 monoclonal antibody with a declared cross-reactivity of about 19% toward PGE1. Endogenous PGE1 and the internal standard [3,3',4,4'-(2)H4]-PGE1 (d4-PGE1) externally added to human plasma samples were extracted by IAC, converted to their pentafluorobenzyl ester-methoxime-trimethylsilyl ether derivatives and analyzed by GC-MS/MS in the electron-capture negative-ion chemical ionization mode. Quantification was performed by selected-reaction monitoring of the mass transition m/z 526→m/z 258 for PGE1 and m/z 530→m/z 262 for d4-PGE1. By this method we measured PGE1 concentrations in EDTA plasma samples (1mL) of six healthy volunteers in the range 10-25pg/mL (29-72pM). PGE1 plasma concentration showed a trend for positive correlation with plasma parameters such as low density lipoprotein (LDL)-cholesterol, total cholesterol and glucose. The method described here provides a novel tool to study the potential link of PGE1 formation to dyslipidemia, insulin resistance and related metabolic disorders. Copyright © 2015 Elsevier B.V. All rights reserved.

  7. Direct analysis of prostaglandin-E2 and -D2 produced in an inflammatory cell reaction and its application for activity screening and potency evaluation using turbulent flow chromatography liquid chromatography-high resolution mass spectrometry.

    Science.gov (United States)

    Shin, Jeong-Sook; Peng, Lei; Kang, Kyungsu; Choi, Yongsoo

    2016-09-09

    Direct analysis of prostaglandin-E2 (PGE2) and -D2 (PGD2) produced from a RAW264.7 cell-based reaction was performed by liquid chromatography high-resolution mass spectrometry (LC-HRMS), which was online coupled with turbulent flow chromatography (TFC). The capability of this method to accurately measure PG levels in cell reaction medium containing cytokines or proteins as a reaction byproduct was cross-validated by two conventional methods. Two methods, including an LC-HRMS method after liquid-liquid extraction (LLE) of the sample and a commercial PGE2 enzyme-linked immunosorbent assay (ELISA), showed PGE2 and/or PGD2 levels almost similar to those obtained by TFC LC-HRMS over the reaction time after LPS stimulation. After the cross-validation, significant analytical throughputs, allowing simultaneous screening and potency evaluation of 80 natural products including 60 phytochemicals and 20 natural product extracts for the inhibition of the PGD2 produced in the cell-based inflammatory reaction, were achieved using the TFC LC-HRMS method developed. Among the 60 phytochemicals screened, licochalcone A and formononetin inhibited PGD2 production the most with IC50 values of 126 and 151nM, respectively. For a reference activity, indomethacin and diclofenac were used, measuring IC50 values of 0.64 and 0.21nM, respectively. This method also found a butanol extract of Akebia quinata Decne (AQ) stem as a promising natural product for PGD2 inhibition. Direct and accurate analysis of PGs in the inflammatory cell reaction using the TFC LC-HRMS method developed enables the high-throughput screening and potency evaluation of as many as 320 samples in less than 48h without changing a TFC column. Copyright © 2016 Elsevier B.V. All rights reserved.

  8. Direct Melanoma Cell Contact Induces Stromal Cell Autocrine Prostaglandin E2-EP4 Receptor Signaling That Drives Tumor Growth, Angiogenesis, and Metastasis*

    Science.gov (United States)

    Inada, Masaki; Takita, Morichika; Yokoyama, Satoshi; Watanabe, Kenta; Tominari, Tsukasa; Matsumoto, Chiho; Hirata, Michiko; Maru, Yoshiro; Maruyama, Takayuki; Sugimoto, Yukihiko; Narumiya, Shuh; Uematsu, Satoshi; Akira, Shizuo; Murphy, Gillian; Nagase, Hideaki; Miyaura, Chisato

    2015-01-01

    The stromal cells associated with tumors such as melanoma are significant determinants of tumor growth and metastasis. Using membrane-bound prostaglandin E synthase 1 (mPges1−/−) mice, we show that prostaglandin E2 (PGE2) production by host tissues is critical for B16 melanoma growth, angiogenesis, and metastasis to both bone and soft tissues. Concomitant studies in vitro showed that PGE2 production by fibroblasts is regulated by direct interaction with B16 cells. Autocrine activity of PGE2 further regulates the production of angiogenic factors by fibroblasts, which are key to the vascularization of both primary and metastatic tumor growth. Similarly, cell-cell interactions between B16 cells and host osteoblasts modulate mPGES-1 activity and PGE2 production by the osteoblasts. PGE2, in turn, acts to stimulate receptor activator of NF-κB ligand expression, leading to osteoclast differentiation and bone erosion. Using eicosanoid receptor antagonists, we show that PGE2 acts on osteoblasts and fibroblasts in the tumor microenvironment through the EP4 receptor. Metastatic tumor growth and vascularization in soft tissues was abrogated by an EP4 receptor antagonist. EP4-null Ptger4−/− mice do not support B16 melanoma growth. In vitro, an EP4 receptor antagonist modulated PGE2 effects on fibroblast production of angiogenic factors. Our data show that B16 melanoma cells directly influence host stromal cells to generate PGE2 signals governing neoangiogenesis and metastatic growth in bone via osteoclast erosive activity as well as angiogenesis in soft tissue tumors. PMID:26475855

  9. Direct Melanoma Cell Contact Induces Stromal Cell Autocrine Prostaglandin E2-EP4 Receptor Signaling That Drives Tumor Growth, Angiogenesis, and Metastasis.

    Science.gov (United States)

    Inada, Masaki; Takita, Morichika; Yokoyama, Satoshi; Watanabe, Kenta; Tominari, Tsukasa; Matsumoto, Chiho; Hirata, Michiko; Maru, Yoshiro; Maruyama, Takayuki; Sugimoto, Yukihiko; Narumiya, Shuh; Uematsu, Satoshi; Akira, Shizuo; Murphy, Gillian; Nagase, Hideaki; Miyaura, Chisato

    2015-12-11

    The stromal cells associated with tumors such as melanoma are significant determinants of tumor growth and metastasis. Using membrane-bound prostaglandin E synthase 1 (mPges1(-/-)) mice, we show that prostaglandin E2 (PGE2) production by host tissues is critical for B16 melanoma growth, angiogenesis, and metastasis to both bone and soft tissues. Concomitant studies in vitro showed that PGE2 production by fibroblasts is regulated by direct interaction with B16 cells. Autocrine activity of PGE2 further regulates the production of angiogenic factors by fibroblasts, which are key to the vascularization of both primary and metastatic tumor growth. Similarly, cell-cell interactions between B16 cells and host osteoblasts modulate mPGES-1 activity and PGE2 production by the osteoblasts. PGE2, in turn, acts to stimulate receptor activator of NF-κB ligand expression, leading to osteoclast differentiation and bone erosion. Using eicosanoid receptor antagonists, we show that PGE2 acts on osteoblasts and fibroblasts in the tumor microenvironment through the EP4 receptor. Metastatic tumor growth and vascularization in soft tissues was abrogated by an EP4 receptor antagonist. EP4-null Ptger4(-/-) mice do not support B16 melanoma growth. In vitro, an EP4 receptor antagonist modulated PGE2 effects on fibroblast production of angiogenic factors. Our data show that B16 melanoma cells directly influence host stromal cells to generate PGE2 signals governing neoangiogenesis and metastatic growth in bone via osteoclast erosive activity as well as angiogenesis in soft tissue tumors. © 2015 by The American Society for Biochemistry and Molecular Biology, Inc.

  10. Effect of sodium hydrosulfide on mRNA expression of prostaglandin E2 receptors in response to mucosal acidification and distention-induced gastric acid secretion in rats

    Directory of Open Access Journals (Sweden)

    Seyyed Ali Mard

    2017-02-01

    Full Text Available Objective(s: Prostaglandins have been shown to mediate the gastro-protective effect of sodium hydrosulfide (NaHS but effect of NaHS on mRNA expression of prostaglandin E2 receptors (EP1, 3-4; EPs has not been investigated. Therefore, this study designed to evaluate the effect of NaHS on mRNA expression of EPs receptors in response to mucosal acidification and distention-induced gastric acid secretion in rats. Materials and Methods: Fasted rats were randomly assigned into 4 groups (n=6/group. They were control, and NaHS-treated groups. To evaluate the effect of NaHS on mucosal mRNA expression of EPs receptors, the gastric mucosa exposed to stimulated gastric acid output and mucosal acidification. The pylorus sphincter catheterized for instillation of isotonic neutral saline or acidic solution. Ninety min after beginning the experiments, animals sacrificed and the gastric mucosa collected to determine the pH, mucus secretion and to quantify the mRNA expression of EPs receptors by quantitative real-time PCR. Results: present results showed that a NaHS increased the mucus secretion, mRNA expression of EP3 and EP4 receptors in response to distention-induced expression; b The mRNA expression of EP1 receptors increased while EP4 mRNA receptors decreased in response to mucosal acidification in NaHS-pretreated rats; and c NaHS increased pH of gastric contents both in response to distention-induced gastric acid secretion and mucosal acidification. Conclusion: NaHS behaves in a different manner. It effectively only increased the pH of gastric contents to reinforce the gastric mucosa against a highly acidic solution but modulated both acid and mucus secretion when the rate of acid increase in the stomach was slower.

  11. Inhibition of microsomal prostaglandin E2 synthase-1 as a molecular basis for the anti-inflammatory actions of boswellic acids from frankincense.

    Science.gov (United States)

    Siemoneit, U; Koeberle, A; Rossi, A; Dehm, F; Verhoff, M; Reckel, S; Maier, T J; Jauch, J; Northoff, H; Bernhard, F; Doetsch, V; Sautebin, L; Werz, O

    2011-01-01

    Frankincense, the gum resin derived from Boswellia species, showed anti-inflammatory efficacy in animal models and in pilot clinical studies. Boswellic acids (BAs) are assumed to be responsible for these effects but their anti-inflammatory efficacy in vivo and their molecular modes of action are incompletely understood. A protein fishing approach using immobilized BA and surface plasmon resonance (SPR) spectroscopy were used to reveal microsomal prostaglandin E(2) synthase-1 (mPGES1) as a BA-interacting protein. Cell-free and cell-based assays were applied to confirm the functional interference of BAs with mPGES1. Carrageenan-induced mouse paw oedema and rat pleurisy models were utilized to demonstrate the efficacy of defined BAs in vivo. Human mPGES1 from A549 cells or in vitro-translated human enzyme selectively bound to BA affinity matrices and SPR spectroscopy confirmed these interactions. BAs reversibly suppressed the transformation of prostaglandin (PG)H(2) to PGE(2) mediated by mPGES1 (IC(50) = 3-10 µM). Also, in intact A549 cells, BAs selectively inhibited PGE(2) generation and, in human whole blood, β-BA reduced lipopolysaccharide-induced PGE(2) biosynthesis without affecting formation of the COX-derived metabolites 6-keto PGF(1α) and thromboxane B(2) . Intraperitoneal or oral administration of β-BA (1 mg·kg(-1) ) suppressed rat pleurisy, accompanied by impaired levels of PGE(2) and β-BA (1 mg·kg(-1) , given i.p.) also reduced mouse paw oedema, both induced by carrageenan. Suppression of PGE(2) formation by BAs via interference with mPGES1 contribute to the anti-inflammatory effectiveness of BAs and of frankincense, and may constitute a biochemical basis for their anti-inflammatory properties. © 2010 The Authors. British Journal of Pharmacology © 2010 The British Pharmacological Society.

  12. Prostaglandin E2 is critical for the development of niacin-deficiency-induced photosensitivity via ROS production

    Science.gov (United States)

    Sugita, Kazunari; Ikenouchi-Sugita, Atsuko; Nakayama, Yasuko; Yoshioka, Haruna; Nomura, Takashi; Sakabe, Jun-Ichi; Nakahigashi, Kyoko; Kuroda, Etsushi; Uematsu, Satoshi; Nakamura, Jun; Akira, Shizuo; Nakamura, Motonobu; Narumiya, Shuh; Miyachi, Yoshiki; Tokura, Yoshiki; Kabashima, Kenji

    2013-10-01

    Pellagra is a photosensitivity syndrome characterized by three ``D's'': diarrhea, dermatitis, and dementia as a result of niacin deficiency. However, the molecular mechanisms of photosensitivity dermatitis, the hallmark abnormality of this syndrome, remain unclear. We prepared niacin deficient mice in order to develop a murine model of pellagra. Niacin deficiency induced photosensitivity and severe diarrhea with weight loss. In addition, niacin deficient mice exhibited elevated expressions of COX-2 and PGE syntheses (Ptges) mRNA. Consistently, photosensitivity was alleviated by a COX inhibitor, deficiency of Ptges, or blockade of EP4 receptor signaling. Moreover, enhanced PGE2 production in niacin deficiency was mediated via ROS production in keratinocytes. In line with the above murine findings, human skin lesions of pellagra patients confirmed the enhanced expression of Ptges. Niacin deficiency-induced photosensitivity was mediated through EP4 signaling in response to increased PGE2 production via induction of ROS formation.

  13. Adipose-derived mesenchymal stem cells modulate CD14++CD16+expression on monocytes from sepsis patients in vitro via prostaglandin E2.

    Science.gov (United States)

    Qiu, Guanguan; Zheng, Guoping; Ge, Menghua; Huang, Lanfang; Tong, Haijiang; Chen, Ping; Lai, Dengming; Hu, Yaoqin; Cheng, Baoli; Shu, Qiang; Xu, Jianguo

    2017-04-26

    Mesenchymal stem cells (MSCs) have been shown to reduce sepsis-induced inflammation and improve survival in mouse models of sepsis. CD16 + monocytes are proinflammatory and abundant in inflammatory conditions such as sepsis. The primary objective in this exploratory study was to determine the effects of adipose-derived MSCs (ASCs) on three subsets of monocytes from sepsis patients in vitro and to delineate the underlying mechanism. This is a prospective cohort study of patients admitted to the medical intensive care unit (ICU) at an academic medical center. The levels of CD14 ++ CD16 + , CD14 + CD16 ++ , and CD14 ++ CD16 - monocytes from 23 patients in the early phase of severe sepsis or septic shock as well as 25 healthy volunteers were determined via flow cytometry after coculture with or without ASCs. To determine the molecular mechanisms, the effects of exogenous prostaglandin E2 (PGE2) and the cyclooxygenase-2 (COX-2) inhibitor NS-398 on monocyte phenotypes and cytokine expression were also examined. Basal levels of CD14 ++ CD16 + but not CD14 + CD16 ++ monocytes were significantly elevated in severe sepsis and septic shock. A positive linear relationship existed between the levels of CD14 ++ CD16 + monocytes and the Acute Physiology and Chronic Health Evaluation (APACHE) II score as well as Sequential Organ Failure Assessment (SOFA) score. Coculture of ASCs with monocytes from sepsis patients for 24 h significantly reduced CD14 ++ CD16 + expression while increasing the CD14 ++ CD16 - phenotype. The coculture also significantly elevated PGE2, COX-2, and prostaglandin E2 receptor (EP)4 levels generated from monocytes. Functionally, ASCs reduced the tumor necrosis factor (TNF)-α and increased the interleukin (IL)-10 secretion in monocytes of septic patients. Furthermore, the effects of ASCs on the CD14 ++ CD16 + phenotype and cytokine expression were mimicked by exogenous PGE2 and abolished by the COX-2 inhibitor NS-398. Additionally, ASCs also modified levels

  14. Exogenous arachidonic acid mediates permeability of human brain microvessel endothelial cells through prostaglandin E2 activation of EP3 and EP4 receptors.

    Science.gov (United States)

    Dalvi, Siddhartha; Nguyen, Hieu H; On, Ngoc; Mitchell, Ryan W; Aukema, Harold M; Miller, Donald W; Hatch, Grant M

    2015-12-01

    The blood-brain barrier, formed by microvessel endothelial cells, is the restrictive barrier between the brain parenchyma and the circulating blood. Arachidonic acid (ARA; 5,8,11,14-cis-eicosatetraenoic acid) is a conditionally essential polyunsaturated fatty acid [20:4(n-6)] and is a major constituent of brain lipids. The current study examined the transport processes for ARA in confluent monolayers of human brain microvascular endothelial cells (HBMEC). Addition of radioactive ARA to the apical compartment of HBMEC cultured on Transwell(®) inserts resulted in rapid incorporation of radioactivity into the basolateral medium. Knock down of fatty acid transport proteins did not alter ARA passage into the basolateral medium as a result of the rapid generation of prostaglandin E2 (PGE2 ), an eicosanoid known to facilitate opening of the blood-brain barrier. Permeability following ARA or PGE2 exposure was confirmed by an increased movement of fluorescein-labeled dextran from apical to basolateral medium. ARA-mediated permeability was attenuated by specific cyclooxygenase-2 inhibitors. EP3 and EP4 receptor antagonists attenuated the ARA-mediated permeability of HBMEC. The results indicate that ARA increases permeability of HBMEC monolayers likely via increased production of PGE2 which acts upon EP3 and EP4 receptors to mediate permeability. These observations may explain the rapid influx of ARA into the brain previously observed upon plasma infusion with ARA. The blood-brain barrier, formed by microvessel endothelial cells, is a restrictive barrier between the brain parenchyma and the circulating blood. Radiolabeled arachidonic acid (ARA) movement across, and monolayer permeability in the presence of ARA, was examined in confluent monolayers of primary human brain microvessel endothelial cells (HBMECs) cultured on Transwell(®) plates. Incubation of HBMECs with ARA resulted in a rapid increase in HBMEC monolayer permeability. The mechanism was mediated, in part

  15. Prostaglandin E2 Adds Bone to a Cancellous Bone Site with a Closed Growth Plate and Low Bone Turnover in Ovariectomized Rats

    Science.gov (United States)

    Ma, Y. F.; Ke, H. Z.; Jee, W. S. S.

    1994-01-01

    The objects of this study were to determine the responses of a cancellous bone site with a closed growth plate (the distal tibial metaphysis, DTM) to ovariectomy (OVX) and OVX plus a prostaglandin E2 (PGE2) treatment, and compare the site's response to previous findings reported for another site (the proximal tibial metaphysis, PTM). Thirty-five 3-month old female Sprague-Dawley rats were divided into five groups: basal, sham-OVX, and OVX+0, +1, or +6 mg PGE2/kg/d injected subcutaneously for 3 months and given double fluorescent labels before sacrifice. Cancellous bone histomorphometric analyses were performed on 20-micron-thick undecalcified DTM sections. Similar to the PTM, the DTM showed age-related decreases in bone formation and increases in bone resorption, but it differed in that at 3 months post-OVX; there was neither bone loss nor changes in formation endpoints. Giving 1 mg PGE2/kg/d to OVX rats prevented most age-related changes and maintained the bone formation histomorphometry near basal levels. Treating OVX rats with 6 mg PGE2/kg/d prevented age-related bone changes, added extra bone, and improved microanatomical structure by stimulating bone formation without altering bone resorption. Furthermore, after PGE2 administration, the DTM, a cancellous bone site with a closed growth plate, inereased bone formation more than did the cancellous bone in the PTM.

  16. Prostaglandin E2 induction of labor and cervical ripening for term isolated oligohydramnios in pregnant women with Bishop score ≤ 5.

    Science.gov (United States)

    Kansu-Celik, Hatice; Gun-Eryılmaz, Ozlem; Dogan, Nasuh Utku; Haktankaçmaz, Seval; Cinar, Mehmet; Yilmaz, Saynur Sarici; Gülerman, Cavidan

    2017-03-01

    We aimed to evaluate the efficacy and safety of dinoprostone for cervical ripening and labor induction in patients with term oligohydramnios and Bishop score ≤ 5. This was a prospective case-control study, which included 104 consecutive women with a Bishop score≤5. Participants were divided into two groups. Women with term isolated oligohydramnios and Bishop score≤5 underwent induction of labor with a vaginal insert containing 10-mg timed-release dinoprostone (prostaglandin E2; Group A, n=40). The control group, Group B, consisted of 64 cases of pregnancy with normal amniotic fluid volume (amniotic fluid index≥5 cm) and Bishop score≤5, and was matched for patient's age and parity. The primary outcome was time from induction to delivery; the secondary outcomes were the caesarean section (CS) rate, uterine hyperstimulation, rate of failed induction, and neonatal complications. The mean time interval from induction to delivery was not different between the two groups (p=0.849), but there was a statistically significant difference between the groups in terms of the CS rate (p=0.005). There were no differences between the groups in neonatal outcome or perinatal morbidity or mortality. Dinoprostone appears to be a safe alternative for induction of labor in pregnancies with oligohydramnios. Induction of labor with dinoprostone in term pregnancies with isolated oligohydramnios is associated with increased rate of CS but there is no higher risk of perinatal complications. Copyright © 2016. Published by Elsevier Taiwan LLC.

  17. Prostaglandin E2 Levels of Aqueous and Vitreous Humor in Ketorolac 0.4% and Nepafenac 0.1% Administered Healthy Rabbits.

    Science.gov (United States)

    Acar, Ugur; Acar, Damla Erginturk; Tanriverdi, Cafer; Acar, Mutlu; Ozdemir, Ozdemir; Erikci, Acelya; Ornek, Firdevs

    2017-06-01

    To compare the lowering effects of ketorolac 0.4% and nepafenac 0.1% on aqueous and vitreous humor prostaglandin E2 (PGE2) levels in rabbits. Ketorolac and nepafenac ophthalmic solutions were administered to the right eyes of 24 healthy rabbits after randomized division into two groups. The left eyes of these rabbits were considered as controls for the two groups. On the 4th day of the experiment, the samples were taken from the aqueous and vitreous humors of the rabbits bilaterally, and PGE2 levels were measured by an enzyme immune assay kit. Ketorolac and nepafenac achieved a statistically significant decrease (pvitreous humor (6.58 ± 4.62 and 9.83 ± 4.55 pg/mL, respectively). Both ketorolac and nepafenac inhibited PGE2 levels in both the aqueous and vitreous humors of rabbits. Although PGE2-lowering effects were similar in the aqueous humor, nepafenac seemed to be more potent than ketorolac in the vitreous humor.

  18. Effects of caffeine and paracetamol alone or in combination with acetylsalicylic acid on prostaglandin E(2) synthesis in rat microglial cells.

    Science.gov (United States)

    Fiebich, B L; Lieb, K; Hüll, M; Aicher, B; van Ryn, J; Pairet, M; Engelhardt, G

    2000-08-23

    Paracetamol has mild analgesic and antipyretic properties and is, along with acetylsalicylic acid, one of the most popular "over the counter" analgesic agents. However, the mechanism underlying its clinical effects is unknown. Another drug whose mechanism of action is unknown is caffeine, which is often used in combination with other analgesics, augmenting their effect. We investigated the inhibitory effect of paracetamol and caffeine on lipopolysaccharide (LPS)-induced cyclooxygenase (COX)- and prostaglandin (PG)E(2)-synthesis in primary rat microglial cells and compared it with the effect of acetylsalicylic acid, salicylic acid, and dipyrone. Furthermore, combinations of these drugs were used to investigate a possible synergistic inhibitory effect on PGE(2)-synthesis. Both paracetamol (IC(50)=7.45 microM) and caffeine (IC(50)=42.5 microM) dose-dependently inhibited microglial PGE(2) synthesis. In combination with acetylsalicylic acid (IC(50)=3.12 microM), both substances augmented the inhibitory effect of acetylsalicylic acid on LPS-induced PGE(2)-synthesis. Whereas paracetamol inhibited only COX enzyme activity, caffeine also inhibited COX-2 protein synthesis. These results are compatible with the view that the clinical activity of paracetamol and caffeine is due to inhibition of COX. Furthermore, these results may help explain the clinical experience of an adjuvant analgesic effect of caffeine and paracetamol when combined with acetylsalicylic acid.

  19. A randomized comparison of vaginal prostaglandin E2 with oxytocin plus amniotomy for induction of labour in women with intermediately ripe cervices.

    Science.gov (United States)

    Parazzini, F; Benedetto, C; Danti, L; Zanini, A; Facchinetti, F; Ettore, G; Franchi, M; Bertulessi, C; Caruso, A

    1998-10-01

    To compare the effects of oxytocin and amniotomy or vaginal prostaglandin E2 (PGE2) for induction of labour. We conducted a randomized clinical trial. Eligible for the trial were women with normal pregnancy, parity 0-3, with intact membranes, >40 weeks of gestation documented by ultrasound examination before 20 weeks gestation, observed in a network of 13 general and teaching hospitals in Italy. Inclusion criteria were cervical Bishop's score 5-7, less than six uterine contractions per hour, single pregnancy, cephalic presentation, no history of cesarean section and uterine surgery. Eligible women were randomly assigned by phone to oxytocin plus amniotomy (163 women) or vaginal PGE2 2 mg, two doses at 6-h intervals (157 women). Overall, 50 women (15.6%) delivered by cesarean section, 22 (13.5%) randomized to oxytocin, and 28 (17.8%) randomized to PGE2 (not significant). Twelve hours after randomization, induction had failed in 26 women of the 163 randomized to oxytocin plus amniotomy (21.6%) and 34 out of the 157 randomized to PGE2 (15.9%): the difference was not significant. Neonatal outcome was similar in the two groups. This study did not find marked differences in labour and neonatal outcome between women randomized to oxytocin plus amniotomy or vaginal PGE2. A shorter induction delivery interval in the group receiving amniotomy and oxytocin after PGE2 priming was observed.

  20. Effects of phenylbutazone, indomethacin, prostaglandin E2, butyrate, and glutamine on restitution of oxidant-injured right dorsal colon of horses in vitro.

    Science.gov (United States)

    Rötting, Anna K; Freeman, David E; Constable, Peter D; Eurell, Jo Ann C; Wallig, Matthew A

    2004-11-01

    To study the effects of phenylbutazone, indomethacin, prostaglandin E2 (PGE2), glutamine, and butyrate on restitution of oxidant-injured right dorsal colon of horses in vitro. Right dorsal colon from 9 adult horses euthanatized for reasons other than gastrointestinal tract disease. Mucosal segments from the right dorsal colon were injured via exposure to HOCl and incubated in Ussing chambers in solutions containing phenylbutazone, indomethacin, indomethacin and PGE2, glutamine, and butyrate. Transepithelial resistance and mucosal permeability to mannitol were measured, and all mucosal segments were examined histologically. The HOCl-injured mucosa had lower resistance and higher permeability to mannitol, compared with control tissue. Histologic changes were also evident. Resistance of HOCl-injured mucosa recovered partially during the incubation period, and glutamine improved recovery. Phenylbutazone and indomethacin increased resistance, but these increases were not significant. Butyrate and PGE2 had no effects, compared with nontreated HOCl-injured tissues. Mucosal permeability to mannitol was lower in glutamine-treated tissue, compared with nontreated tissue. Histologic changes reflected the resistance and permeability changes. According to our findings, phenylbutazone and indomethacin do not seem to interfere with restitution of oxidant-injured mucosa of equine colon in vitro, and glutamine could facilitate mucosal restitution.

  1. The effects of Leptin on gastric ulcer due to physical and psychological stress: Involvement of nitric oxide and prostaglandin E2

    Directory of Open Access Journals (Sweden)

    Soghra Fallahi

    2011-12-01

    Full Text Available The present study aimed to assess the effects of Leptin on physical and psychological stresses inducing gastric ulcer. The potential role of endogenous nitric oxide (NO and prostaglandin E2 (PGE2 in the effects of Leptin on the gastric ulcer in rats are also investigated. In this study, fifty-four male Wistar rats were equally divided into 9 groups and Leptin (10 µg/kg, s.c. was administered twice a day for 14 days in advance of physical and psychological stress. Also, NG- nitro-l-arginine-methyl ester (L-NAME, 10 mg/kg, an inhibitor of NO synthase and indomethtacin (5 mg/kg, in order to inhibit PG synthesis were applied before Leptin administration. Ulcer index, gastric acid secretion, NO metabolites and PGE2 of stomach tissue suspension were all measured. Results indicated that ulcer index and gastric acid secretion were significantly decreased (p<0.05 in Leptin in compare with those of single stress groups. Also, NO metabolites and PGE2 were increased (p<0.05 in Leptin groups than both L-NAME and Indomethacin+Leptin groups. Conclusively, data of this study emphasized the healing ability of Leptin on gastric ulcer induced by physical and psychological stresses involves the NO and PGE2 pathways.

  2. Effects of topical ketorolac tromethamine 0.45% on intraoperative miosis and prostaglandin E2 release during femtosecond laser-assisted cataract surgery.

    Science.gov (United States)

    Jun, Jong Hwa; Yoo, Young-Sik; Lim, Sung A; Joo, Choun-Ki

    2017-04-01

    To determine the effects of topical 0.45% ketorolac tromethamine on intraoperative miosis and prostaglandin E2 (PGE2) release during femtosecond laser-assisted cataract surgery. Seoul St. Mary's Hospital, Seoul, Korea. Prospective case series. The study comprised the following 3 groups: conventional cataract surgery without topical NSAIDs (conventional group); femtosecond laser-assisted cataract surgery with preoperative topical ketorolac tromethamine 0.45% (femtosecond NSAID group), and femtosecond laser-assisted cataract surgery without topical NSAIDs (femtosecond no-NSAID group). To measure the aqueous humor PGE2 concentration, a 100 μL aqueous humor sample was collected from the anterior chamber after femtosecond laser pretreatment. The PGE2 concentration was measured using an enzyme immunoassay. Topical ketorolac tromethamine 0.45% led to a significant reduction in intraoperative miosis in the femtosecond NSAID group compared with the femtosecond no-NSAID group (P  .05, conventional versus femtosecond NSAID). Preoperative topical ketorolac tromethamine 0.45% reduced miosis induced by femtosecond laser pretreatment and inhibited aqueous humor PGE2 elevation. Copyright © 2017 ASCRS and ESCRS. Published by Elsevier Inc. All rights reserved.

  3. Prostaglandin E2 Activates YAP and a Positive-Signaling Loop to Promote Colon Regeneration After Colitis but Also Carcinogenesis in Mice.

    Science.gov (United States)

    Kim, Han-Byul; Kim, Minchul; Park, Young-Soo; Park, Intae; Kim, Tackhoon; Yang, Sung-Yeun; Cho, Charles J; Hwang, DaeHee; Jung, Jin-Hak; Markowitz, Sanford D; Hwang, Sung Wook; Yang, Suk-Kyun; Lim, Dae-Sik; Myung, Seung-Jae

    2017-02-01

    Prostaglandin E2 (PGE2) is mediator of inflammation that regulates tissue regeneration, but its continual activation has been associated with carcinogenesis. Little is known about factors in the PGE2 signaling pathway that contribute to tumor formation. We investigated whether yes-associated protein 1 (YAP1), a transcriptional co-activator in the Hippo signaling pathway, mediates PGE2 function. DLD-1 and SW480 colon cancer cell lines were transfected with vectors expressing transgenes or small hairpin RNAs and incubated with recombinant PGE2, with or without pharmacologic inhibitors of signaling proteins, and analyzed by immunoblot, immunofluorescence, quantitative reverse-transcription polymerase chain reaction, transcriptional reporter, and proliferation assays. Dextran sodium sulfate (DSS) was given to induce colitis in C57/BL6 (control) mice, as well as in mice with disruption of the hydroxyprostaglandin dehydrogenase 15 gene (15-PGDH-knockout mice), Yap1 gene (YAP-knockout mice), and double-knockout mice. Some mice also were given indomethacin to block PGE2 synthesis. 15-PGDH knockout mice were crossed with mice with intestine-specific disruption of the salvador family WW domain containing 1 gene (Sav1), which encodes an activator of Hippo signaling. We performed immunohistochemical analyses of colon biopsy samples from 26 patients with colitis-associated cancer and 51 age-and sex-matched patients with colorectal cancer (without colitis). Incubation of colon cancer cell lines with PGE2 led to phosphorylation of cyclic adenosine monophosphate-responsive element binding protein 1 and increased levels of YAP1 messenger RNA, protein, and YAP1 transcriptional activity. This led to increased transcription of the prostaglandin-endoperoxide synthase 2 gene (PTGS2 or cyclooxygenase 2) and prostaglandin E-receptor 4 gene (PTGER4 or EP4). Incubation with PGE2 promoted proliferation of colon cancer cell lines, but not cells with knockdown of YAP1. Control mice developed

  4. The Anti-inflammatory Effect of Personalized Omega-3 Fatty Acid Dosing for Reducing Prostaglandin E2 in the Colonic Mucosa Is Attenuated in Obesity.

    Science.gov (United States)

    Djuric, Zora; Turgeon, D Kim; Sen, Ananda; Ren, Jianwei; Herman, Kirk; Ramaswamy, Devon; Zhao, Lili; Ruffin, Mack T; Normolle, Daniel P; Smith, William L; Brenner, Dean E

    2017-12-01

    This clinical trial developed a personalized dosing model for reducing prostaglandin E2 (PGE2) in colonic mucosa using ω-3 fatty acid supplementation. The model utilized serum eicosapentaenoic acid (EPA, ω-3):arachidonic acid (AA, ω-6) ratios as biomarkers of colonic mucosal PGE2 concentration. Normal human volunteers were given low and high ω-3 fatty acid test doses for 2 weeks. This established a slope and intercept of the line for dose versus serum EPA:AA ratio in each individual. The slope and intercept was utilized to calculate a personalized target dose that was given for 12 weeks. This target dose was calculated on the basis of a model, initially derived from lean rodents, showing a log-linear relationship between serum EPA:AA ratios and colonic mucosal PGE2 reduction. Bayesian methods allowed addition of human data to the rodent model as the trial progressed. The dosing model aimed to achieve a serum EPA:AA ratio that is associated with a 50% reduction in colonic PGE2 Mean colonic mucosal PGE2 concentrations were 6.55 ng/mg protein (SD, 5.78) before any supplementation and 3.59 ng/mg protein (SD, 3.29) after 12 weeks of target dosing. In secondary analyses, the decreases in PGE2 were significantly attenuated in overweight and obese participants. This occurred despite a higher target dose for the obese versus normal weight participants, as generated by the pharmacodynamic predictive model. Large decreases also were observed in 12-hydroxyicosatetraenoic acids, and PGE3 increased substantially. Future biomarker-driven dosing models for cancer prevention therefore should consider energy balance as well as overall eicosanoid homeostasis in normal tissue. Cancer Prev Res; 10(12); 729-37. ©2017 AACR. ©2017 American Association for Cancer Research.

  5. Piracy of prostaglandin E2/EP receptor-mediated signaling by Kaposi's sarcoma-associated herpes virus (HHV-8) for latency gene expression: strategy of a successful pathogen.

    Science.gov (United States)

    George Paul, Arun; Sharma-Walia, Neelam; Kerur, Nagaraj; White, Carl; Chandran, Bala

    2010-05-01

    Kaposi's sarcoma-associated herpes virus (KSHV) is implicated in the pathogenesis of KS, a chronic inflammation-associated malignancy. Cyclooxygenase-2 (COX-2) and its metabolite prostaglandin E2 (PGE2), two pivotal proinflammatory/oncogeneic molecules, are proposed to play roles in the expression of major KSHV latency-associated nuclear antigen-1 (LANA-1). Microsomal PGE2 synthase, PGE2, and its receptors (EP1, EP2, EP3, and EP4) were detected in KS lesions with the distinct staining of EP2/EP4 in KS lesions. In latently infected endothelial TIVE-LTC cells, EP receptor antagonists downregulated LANA-1 expression as well as Ca(2+), p-Src, p-PI3K, p-PKCzeta/lambda, and p-NF-kappaB, which are also some of the signal molecules proposed to be important in KS pathogenesis. Exogenous PGE2 and EP receptor agonists induced the LANA-1 promoter in 293 cells, and YY1, Sp1, Oct-1, Oct-6, C/EBP, and c-Jun transcription factors seem to be involved in this induction. PGE2/EP receptor-induced LANA-1 promoter activity was downregulated significantly by the inhibition of Ca(2+), p-Src, p-PI3K, p-PKCzeta/lambda, and p-NF-kappaB. These findings implicate the inflammatory PGE2/EP receptors and the associated signal molecules in herpes virus latency and uncover a novel paradigm that shows the evolution of KSHV genome plasticity to use inflammatory response for its survival advantage of maintaining latent gene expression. These data also suggest that potential use of anti-COX-2 and anti-EP receptor therapy may not only ameliorate the chronic inflammation associated with KS but could also lead to elimination of the KSHV latent infection and the associated KS lesions. (c)2010 AACR.

  6. Angiotensin II-dependent hypertension requires cyclooxygenase 1-derived prostaglandin E2 and EP1 receptor signaling in the subfornical organ of the brain.

    Science.gov (United States)

    Cao, Xian; Peterson, Jeffrey R; Wang, Gang; Anrather, Josef; Young, Colin N; Guruju, Mallikarjuna R; Burmeister, Melissa A; Iadecola, Costantino; Davisson, Robin L

    2012-04-01

    Cyclooxygenase (COX)-derived prostanoids have long been implicated in blood pressure (BP) regulation. Recently prostaglandin E(2) (PGE(2)) and its receptor EP(1) (EP(1)R) have emerged as key players in angiotensin II (Ang II)-dependent hypertension (HTN) and related end-organ damage. However, the enzymatic source of PGE(2,) that is, COX-1 or COX-2, and its site(s) of action are not known. The subfornical organ (SFO) is a key forebrain region that mediates systemic Ang II-dependent HTN via reactive oxygen species (ROS). We tested the hypothesis that cross-talk between PGE(2)/EP(1)R and ROS signaling in the SFO is required for Ang II HTN. Radiotelemetric assessment of blood pressure revealed that HTN induced by infusion of systemic "slow-pressor" doses of Ang II was abolished in mice with null mutations in EP(1)R or COX-1 but not COX-2. Slow-pressor Ang II-evoked HTN and ROS formation in the SFO were prevented when the EP(1)R antagonist SC-51089 was infused directly into brains of wild-type mice, and Ang-II-induced ROS production was blunted in cells dissociated from SFO of EP(1)R(-/-) and COX-1(-/-) but not COX-2(-/-) mice. In addition, slow-pressor Ang II infusion caused a ≈3-fold increase in PGE(2) levels in the SFO but not in other brain regions. Finally, genetic reconstitution of EP(1)R selectively in the SFO of EP(1)R-null mice was sufficient to rescue slow-pressor Ang II-elicited HTN and ROS formation in the SFO of this model. Thus, COX 1-derived PGE(2) signaling through EP(1)R in the SFO is required for the ROS-mediated HTN induced by systemic infusion of Ang II and suggests that EP(1)R in the SFO may provide a novel target for antihypertensive therapy.

  7. Prostaglandin E2 Inhibits Histamine-Evoked Ca2+ Release in Human Aortic Smooth Muscle Cells through Hyperactive cAMP Signaling Junctions and Protein Kinase A.

    Science.gov (United States)

    Taylor, Emily J A; Pantazaka, Evangelia; Shelley, Kathryn L; Taylor, Colin W

    2017-11-01

    In human aortic smooth muscle cells, prostaglandin E2 (PGE2) stimulates adenylyl cyclase (AC) and attenuates the increase in intracellular free Ca2+ concentration evoked by activation of histamine H1 receptors. The mechanisms are not resolved. We show that cAMP mediates inhibition of histamine-evoked Ca2+ signals by PGE2 Exchange proteins activated by cAMP were not required, but the effects were attenuated by inhibition of cAMP-dependent protein kinase (PKA). PGE2 had no effect on the Ca2+ signals evoked by protease-activated receptors, heterologously expressed muscarinic M3 receptors, or by direct activation of inositol 1,4,5-trisphosphate (IP3) receptors by photolysis of caged IP3 The rate of Ca2+ removal from the cytosol was unaffected by PGE2, but PGE2 attenuated histamine-evoked IP3 accumulation. Substantial inhibition of AC had no effect on the concentration-dependent inhibition of Ca2+ signals by PGE2 or butaprost (to activate EP2 receptors selectively), but it modestly attenuated responses to EP4 receptors, activation of which generated less cAMP than EP2 receptors. We conclude that inhibition of histamine-evoked Ca2+ signals by PGE2 occurs through "hyperactive signaling junctions," wherein cAMP is locally delivered to PKA at supersaturating concentrations to cause uncoupling of H1 receptors from phospholipase C. This sequence allows digital signaling from PGE2 receptors, through cAMP and PKA, to histamine-evoked Ca2+ signals. Copyright © 2017 by The Author(s).

  8. Inhibition of lysyl oxidase by prostaglandin E2 via EP2/EP4 receptors in human amnion fibroblasts: Implications for parturition.

    Science.gov (United States)

    Liu, Chao; Zhu, Ping; Wang, Wangsheng; Li, Wenjiao; Shu, Qun; Chen, Zi-Jiang; Myatt, Leslie; Sun, Kang

    2016-03-15

    The underlying mechanism leading to rupture of the membranes at parturition is not fully understood. Lysyl oxidase (LOX) cross-links collagen fibrils thereby increasing the tensile strength of the membranes. Thus, understanding the regulation of LOX expression may be of crucial importance for elucidation of the process of rupture of the fetal membranes. Prostaglandin E2 (PGE2), mainly produced in the amnion, plays crucial roles during human parturition. However it is not known whether PGE2 regulates LOX expression in the fetal membranes. Using primary human amnion fibroblasts, we showed that addition of PGE2 decreased LOX mRNA and protein levels, which were blocked by inhibition of EP2/EP4 receptors and the receptor-coupled cAMP/PKA pathway. EP2/EP4 receptor agonists and stimulators of the cAMP/PKA pathway consistently decreased LOX expression. Furthermore, PGE2 induced cyclo-oxygenase-2 (COX-2) expression, a key enzyme in PGE2 production, via an EP2 and EP4 receptor-coupled cAMP/PKA pathway. Small interfering RNA-mediated knock-down of COX-2 expression significantly increased the basal expression of LOX. In addition, an increase in COX-2 and a reciprocal decrease in LOX abundance occurred in amnion tissue following labor at term. In conclusion, we have revealed a feed-forward loop of induction of COX-2 and reduction in LOX expression by PGE2 acting via an EP2/EP4 receptor-coupled cAMP/PKA pathway in human amnion fibroblasts toward the end of gestation, which may play a significant role in the rupture of fetal membranes. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

  9. Expression of Prostaglandin E2 Enzymes in the Synovium of Arthralgia Patients at Risk of Developing Rheumatoid Arthritis and in Early Arthritis Patients.

    Directory of Open Access Journals (Sweden)

    Maria J H de Hair

    Full Text Available Arthralgia may precede the development of synovial inflammation in autoantibody-positive individuals at risk of developing rheumatoid arthritis (RA. A major pathway involved in pain is the prostaglandin (PG E2 pathway. We investigated this pathway in the synovium of individuals with RA-specific autoantibodies and in early arthritis patients.Nineteen autoantibody-positive individuals (IgM-rheumatoid factor and/or anti-cyclic citrullinated peptide antibodies with arthralgia (n=15 and/or a positive family history of RA (n=8, who had been prospectively followed for at least 2 years, were included. In addition, we included early arthritis patients (disease-modifying antirheumatic drug naïve who after 2 years follow up fulfilled classification criteria for RA (n=63, spondyloarthritis (SpA; n=14, or had unclassified arthritis (UA; n=27. In all subjects we assessed pain and performed synovial biopsy sampling by mini-arthroscopy at baseline. Tissue sections were examined by immunohistochemistry to detect and quantify PGE2 pathway enzymes expression levels (mPGES-1; COX-1 and -2; 15-PGDH.In both study groups synovial expression of PGE2 enzymes was not clearly related to pain sensation. Expression levels at baseline were not associated with the development of arthritis after follow up (6 out of 19 autoantibody-positive individuals. However, in early SpA patients the expression levels of mPGES-1 and COX-1 were significantly increased compared to RA and UA patients.Pain in autoantibody-positive individuals without synovial inflammation who are at risk of developing RA and in early arthritis patients may be regulated by pathways other than the PGE2 pathway or originate at sites other than the synovium. In contrast, in SpA, the PGE2 pathway may be inherently linked to the pathophysiology/etiology of the disease.

  10. Evaluation of flunixin meglumine pour-on administration on prostaglandin E2concentration in inflammatory exudate after induction of inflammation in cattle.

    Science.gov (United States)

    Thiry, Julien; Fournier, René; Roy, Olivier; Catala, Mathias

    2017-10-01

    The effect of flunixin transdermal pour-on solution (Finadyne® Transdermal; MSD Animal Health) on prostaglandin E 2 (PGE 2 ) synthesis in bovine inflammatory exudate was evaluated in a tissue cage model of acute inflammation. Twelve calves were randomly allocated to two-treatment groups over two sequences. Three weeks prior to the first period, sterile hollow perforated polyethylene balls were surgically embedded in the subcutis at four distinct sites in each animal. On the first day of each period, an aseptic inflammation was induced by injecting 0.5mL of a 2% carrageenan solution into the lumen of each tissue cage. Treatment with either flunixin transdermal or negative control (NaCl) immediately followed. 0.5mL of exudate was collected prior to challenge, and at 2, 4, 8, 12, 24, 36 and 48h after challenge. Exudate PGE 2 concentrations were analyzed using ultra-high pressure liquid chromatography coupled with tandem mass spectrometry method. Mean PGE 2 concentrations were consistently lower in calves treated with flunixin transdermal than those measured in calves treated with negative control, indicating an inhibitory activity on cyclooxygenase. Inhibition was the highest at 8h after treatment, and differences with the negative control were significant at +8, 24, 36 and 48h. The flunixin transdermal formulation was effective in reducing PGE 2 concentrations in bovine exudate following an induced inflammation. Its anti-inflammatory action started in the first hours after treatment and lasted up to 48h. Copyright © 2017 Elsevier Ltd. All rights reserved.

  11. Effect of three sources of long-chain fatty acids on the plasma fatty acid profile, plasma prostaglandin E2 concentrations, and pruritus symptoms in hemodialysis patients.

    Science.gov (United States)

    Peck, L W; Monsen, E R; Ahmad, S

    1996-08-01

    Patients with chronic renal failure exhibit plasma fatty acid patterns indicative of essential fatty acid deficiency. The plasma fatty acid profile of 25 hemodialysis patients with a history of pruritus symptoms indicated lower 20:3n-9 (eicosatrienoic acid), 20:4n-6 (arachidonic acid), and 20:5n-3 (eicosapentaenoic acid) concentrations; a higher 18:1n-9 (oleic acid) concentration; and above-normal ranges of prostaglandin E2 (PGE2) compared with 22 subjects chosen from a normal population. No significant difference in 22:6n-3 (docosahexaenoic acid) was shown between the hemodialysis patients and the normal subjects. The dietary intake of 20:5n-3 was higher and that of 18:1n-9 lower in the patients compared with the normal population group. In this 8-wk double-blind study the hemodialysis patients were randomly assigned to receive daily supplements of 6 g ethyl ester of either fish oil, olive oil, or safflower oil. At the end of 8 wk of treatment the fish oil group (FO group) had a greater decrease in 18:1n-9 (P P > 0.05) compared with the other two groups. The increases in 20:5n-3 and 22:6n-3 in the FO group indicate compliance with fish oil supplementation. Results indicate that hemodialysis patients have abnormal fatty acid profiles and increased PGE2 values. Fish oil intervention changes the fatty acid profile and may improve the symptoms of pruritus.

  12. Esomeprazole and 325 mg/d Aspirin Reduce Tissue Concentrations of Prostaglandin E2 in Patients with Barrett’s Esophagus

    Science.gov (United States)

    Falk, Gary W.; Buttar, Navtej S.; Foster, Nathan R.; Ziegler, Katie L. Allen; DeMars, Catherine J.; Romero, Yvonne; Marcon, Norman E.; Schnell, Thomas; Corley, Douglas A.; Sharma, Prateek; Cruz-Correa, Marcia R.; Hur, Chin; Fleischer, David E.; Chak, Amitabh; DeVault, Kenneth R.; Weinberg, David S.; Della’Zanna, Gary; Richmond, Ellen; Smyrk, Thomas C.; Mandrekar, Sumithra J.; Limburg, Paul J.

    2012-01-01

    Background & Aims Proton pump inhibitors (PPIs) and nonsteroidal anti-inflammatory drugs might prevent esophageal adenocarcinoma in patients with Barrett’s esophagus (BE), but there are limited data from clinical trials to support this concept. We conducted a randomized, double-blind, placebo-controlled phase II trial to assess the effects of the combination of aspirin (3 different doses) and esomeprazole on tissue concentrations of prostaglandin E2 (PGE2) in patients with BE with no dysplasia or low-grade dysplasia. Methods Participants were recruited through the multi-center Cancer Prevention Network and randomly assigned to groups that were given esomeprazole (40 mg, twice daily) in combination with an aspirin placebo (once daily) (Arm A; n=42), with 81 mg aspirin (once daily) (Arm B; n=63), or with 325 mg aspirin (once daily) (Arm C; n=63) for 28 days. We collected esophageal biopsies before and after the intervention period, to determine the absolute change in mean concentrations of PGE2 (the primary endpoint). Results Based on data from 114 patients, baseline characteristics were similar among groups. The absolute mean tissue concentrations of PGE2 was reduced by 67.6±229.68 pg/mL in Arm A, was reduced by 123.9±284.0 pg/mL in Arm B (P=.10 vs Arm A), and was reduced by 174.9 ±263.62 pg/mL in Arm C (P=.02 vs Arm A). Conclusions In combination with esomeprazole, short-term administration of higher doses of aspirin, but not lower doses or no aspirin, significantly reduced tissue concentrations of PGE2 patients with BE with either no dysplasia or low-grade dysplasia. These data support further evaluation of higher doses of aspirin and esomeprazole to prevent esophageal adenocarcinoma in these patients. PMID:22796132

  13. Successful induction of sclerostin in human-derived fibroblasts by 4 transcription factors and its regulation by parathyroid hormone, hypoxia, and prostaglandin E2.

    Science.gov (United States)

    Fujiwara, Makoto; Kubota, Takuo; Wang, Wei; Ohata, Yasuhisa; Miura, Kohji; Kitaoka, Taichi; Okuzaki, Daisuke; Namba, Noriyuki; Michigami, Toshimi; Kitabatake, Yasuji; Ozono, Keiichi

    2016-04-01

    Sclerostin, coded by SOST, is a secretory protein that is specifically expressed in osteocytes and suppresses osteogenesis by inhibiting WNT signaling. The regulatory mechanism underlying SOST expression remains unclear mainly due to the absence of an adequate human cell model. Thus, we herein attempted to establish a cell model of human dermal fibroblasts in order to investigate the functions of sclerostin. We selected 20 candidate transcription factors (TFs) that induce SOST expression by analyzing gene expression patterns in the human sarcoma cell line, SaOS-2, between differentiation and maintenance cultures using microarrays. An effective set of TFs to induce SOST expression was sought by their viral transduction into fibroblasts, and a combination of four TFs: ATF3, KLF4, PAX4, and SP7, was identified as the most effective inducer of SOST expression. Quantitative PCR demonstrated that the expression levels of SOST in fibroblasts treated with the 4 TFs were 199- and 1439-fold higher than those of the control after 1-week and 4-week cultures, respectively. The level of sclerostin in the conditioned medium, as determined by ELISA, was 21.2pmol/l 4weeks after the transduction of the 4 TFs. Interestingly, the production of Dickkopf1 (DKK1), another secreted inhibitor of WNT signaling, was also increased by transduction of these 4 TFs. Parathyroid hormone (PTH) significantly suppressed the induced SOST by 38% and sclerostin by 82% that of the vehicle. Hypoxia increased the induced SOST by 62% that of normoxia. Furthermore, prostaglandin E2 (PGE2) increased SOST expression levels to 16-fold those of the vehicle. In conclusion, the efficient induction of SOST expression and sclerostin production was achieved in human dermal fibroblasts by the transduction of ATF3, KLF4, PAX4, and SP7, and the induced SOST and sclerostin were regulated by PTH, hypoxia, and PGE2. This model may contribute to elucidating the regulatory mechanisms underlying SOST expression and advancing

  14. Screening and identification of dietary oils and unsaturated fatty acids in inhibiting inflammatory prostaglandin E2 signaling in fat stromal cells

    Directory of Open Access Journals (Sweden)

    Ruan Diana

    2012-08-01

    Full Text Available Abstract Background The molecular mechanisms of dietary oils (such as fish oil and unsaturated fatty acids, which are widely used by the public for anti-inflammation and vascular protection, have not been settled yet. In this study, prostaglandin E2 (PGE2-mediated calcium signaling was used to screen dietary oils and eight unsaturated fatty acids for identification of their anti-inflammatory mechanisms. Isolated fat/stromal cells expressing endogenous PGE2 receptors and an HEK293 cell line specifically expressing the recombinant human PGE2 receptor subtype-1 (EP1 were cultured and used in live cell calcium signaling assays. The different dietary oils and unsaturated fatty acids were used to affect cell signaling under the specific stimulation of a pathological amount of inflammatory PGE2. Results It was identified that fish oil best inhibited the PGE2 signaling in the primary cultured stromal cells. Second, docosahexaenoic acid (DHA, found in abundance in fish oil, was identified as a key factor of inhibition of PGE2 signaling. Eicosapentaenoic acid (EPA, another major fatty acid found in fish oil and tested in this study was found to have small effect on EP1 signaling. The study suggested one of the four PGE2 subtype receptors, EP1 as the key target for the fish oil and DHA target. These findings were further confirmed by using the recombinant EP1 expressed in HEK293 cells as a target. Conclusion This study demonstrated the new mechanism behind the positive effects of dietary fish oils in inhibiting inflammation originates from the rich concentration of DHA, which can directly inhibit the inflammatory EP1-mediated PGE2 receptor signaling, and that the inflammatory response stimulated by PGE2 in the fat stromal cells, which directly related to metabolic diseases, could be down regulated by fish oil and DHA. These findings also provided direct evidence to support the use of dietary oils and unsaturated fatty acids for protection against heart

  15. Angiotensin-II-dependent Hypertension Requires Cyclooxygenase 1-derived Prostaglandin E2 and EP1 Receptor Signaling in the Subfornical Organ of the Brain

    Science.gov (United States)

    Cao, Xian; Peterson, Jeffrey R.; Wang, Gang; Anrather, Josef; Young, Colin N.; Guruju, Mallikarjuna R.; Burmeister, Melissa A.; Iadecola, Costantino; Davisson, Robin L.

    2012-01-01

    Cyclooxygenase (COX)-derived prostanoids have long been implicated in blood pressure (BP) regulation. Recently prostaglandin E2 (PGE2) and its receptor EP1R have emerged as key players in angiotensin II (Ang-II)-dependent hypertension (HTN) and related end-organ damage. However, the enzymatic source of PGE2, ie COX-1 or COX-2, and its site(s) of action are not known. The subfornical organ (SFO) is a key forebrain region that mediates systemic Ang-II-dependent HTN via reactive oxygen species (ROS). We tested the hypothesis that cross-talk between PGE2/EP1R and ROS signaling in the SFO is required for Ang-II HTN. Radiotelemetric assessment of BP revealed that HTN induced by infusion of systemic “slow-pressor” doses of Ang-II was abolished in mice with null mutations in EP1R or COX-1 but not COX-2. Slow-pressor Ang-II-evoked HTN and ROS formation in the SFO were prevented when the EP1R antagonist SC-51089 was infused directly into brains of wild-type mice, and Ang-II-induced ROS production was blunted in cells dissociated from SFO of EP1R−/− and COX-1−/− but not COX-2−/− mice. In addition, slow-pressor Ang-II infusion caused a ~3-fold increase in PGE2 levels in the SFO but not in other brain regions. Finally, genetic reconstitution of EP1R selectively in the SFO of EP1R-null mice was sufficient to rescue slow-pressor AngII-elicited HTN and ROS formation in the SFO of this model. Thus, COX-1-derived PGE2 signaling through EP1R in the SFO is required for the ROS-mediated HTN induced by systemic infusion of Ang-II, and suggests that EP1R in the SFO may provide a novel target for antihypertensive therapy. PMID:22371360

  16. Prostaglandin E2 inhibits p53 in human breast adipose stromal cells: a novel mechanism for the regulation of aromatase in obesity and breast cancer.

    Science.gov (United States)

    Wang, Xuyi; Docanto, Maria M; Sasano, Hironobu; Lo, Camden; Simpson, Evan R; Brown, Kristy A

    2015-02-15

    Obesity is a risk factor for postmenopausal breast cancer and the majority of these cancers are estrogen dependent. Aromatase converts androgens into estrogens and its increased expression in breast adipose stromal cells (ASC) is a major driver of estrogen receptor-positive breast cancer. In particular, obesity-associated and tumor-derived factors, such as prostaglandin E2 (PGE2), have been shown to drive the expression of aromatase by stimulating the activity of the proximal promoter II (PII). The tumor-suppressor p53 is a key regulator of cell-cycle arrest and apoptosis and is frequently mutated in breast cancer. Mutations in p53 are rare in tumor-associated ASCs. Therefore, it was hypothesized that p53 is regulated by PGE2 and involved in the PGE2-mediated regulation of aromatase. Results demonstrate that PGE2 causes a significant decrease in p53 transcript and nuclear protein expression, as well as phosphorylation at Ser15 in primary human breast ASCs. Stabilization of p53 with RITA leads to a significant decrease in the PGE2-stimulated aromatase mRNA expression and activity, and PII activity. Interaction of p53 with PII was demonstrated and this interaction is decreased in the presence of PGE2. Moreover, mutation of the identified p53 response element leads to an increase in the basal activity of the promoter. Immunofluorescence on clinical samples demonstrates that p53 is decreased in tumor-associated ASCs compared with ASCs from normal breast tissue, and that there is a positive association between perinuclear (inactive) p53 and aromatase expression in these cells. Furthermore, aromatase expression is increased in breast ASCs from Li-Fraumeni patients (germline TP53 mutations) compared with non-Li-Fraumeni breast tissue. Overall, our results demonstrate that p53 is a negative regulator of aromatase in the breast and its inhibition by PGE2 provides a novel mechanism for aromatase regulation in obesity and breast cancer. ©2015 American Association for Cancer

  17. Lipopolysaccharide induces inflammation and facilitates lung metastasis in a breast cancer model via the prostaglandin E2-EP2 pathway.

    Science.gov (United States)

    Li, Shancheng; Xu, Xiaoya; Jiang, Man; Bi, Yuli; Xu, Jiying; Han, Mingyong

    2015-06-01

    Inflammation is a potent promoter of tumor metastasis. The aim of the present study was to explore the function of systemic inflammation in the formation of lung metastasis of breast cancer cells in a mouse model. BALB/c mice were injected intraperitoneally with lipopolysaccharide (LPS) in order to establish an inflammatory animal model and 4T1 murine breast cancer cells were injected through the tail vein to induce lung metastasis. The levels of proinflammatory cytokines were evaluated by ELISA. Metastases on the surface of the lungs were counted and histologically analyzed by hematoxylin and eosin staining. Angiogenesis in the lungs was examined by CD31 immunofluorescence. Mouse pulmonary endothelial cells (MPVECs) were isolated and used to assay endothelial tube formation and determine the protein expression levels of vascular endothelial growth factor (VEGF) in vitro. Serum levels of VEGF and prostaglandin E2 (PGE2), the number and size of metastatic lesions, and the expression levels of cyclooxygenase‑2 were significantly greater in the lungs of LPS‑treated mice, as compared with those in control mice threated with phosphate‑buffered saline. Blood vessel density was also markedly increased in the LPS‑treated mice. These increases were reversed by treatment with celecoxib. In vitro, the protein expression levels of VEGF produced by the PGE2‑treated cells were significantly increased in a concentration‑dependent manner. In addition, the production of VEGF was increased in response to treatment with the PGE2 receptor (EP2) agonist ONO‑AE1‑259‑01; however, this increase was abrogated by treatment with AH6809, an EP2 receptor antagonist. Treatment with PGE2 or VEGF alone promoted the tube formation of MPVECs and this effect was reversed by treatment with celecoxib. These results demonstrated that PGE2 may regulate the release of VEGF by MPVECs through the EP2 receptor pathway and thereby promoted pulmonary angiogenesis and breast cancer

  18. Effect of 16.16 dimethyl prostaglandin E2, N-acetyl-cysteine and the proton pump inhibitor BY 831-78 on hydrogen peroxide-induced mucosal damage in the rat stomach.

    Science.gov (United States)

    Schürer-Maly, C C; Haussner, V; Halter, F

    1990-01-01

    Reactive oxygen species are noxious to gastrointestinal mucosa and contribute to a variety of gastrointestinal diseases. We examined whether 16.16 dimethyl prostaglandin E2 (PG) is protective against the oxidizing action of 6% H2O2 causing gross hemorrhagic lesions in rat gastric mucosa. Male Wistar rats were treated with PG, 0.005-5 micrograms/kg, either intragastrically (i.g.) or subcutaneously, 30 min prior to i.g. administration of 6% H2O2, 0.5 ml/100 g. Further animals received 25 mg of the mucus dissolvent N-acetyl-cystein (NAC) following oral PG treatment or 30 mumol/kg of the H+K(+)-ATPase inhibitor BY 831-78 (BY), 4 h before onset of the experiments. Volume, pH and beta-N-acetyl-glucosaminidase and lactate dehydrogenase as parameters of cell damage were determined in the gastric juice. i.g. PG treatment achieved 60 and 55% reduction of the mucosal lesions in doses between 5 and 0.05 micrograms/kg, respectively. i.p. PG administration was effective in all doses tested. Gastric juice volume was only slightly and enzymes were not significantly affected by PG treatment. NAC did not diminish PG efficacy or aggravate mucosal lesions. Gastric acid suppression did not increase PG-induced protection but was strongly protective by itself, reducing damage by 75%. Low-dose PG treatment achieves an effective protection against oxidative damage in gastric mucosa, which is not the result of dilution or enhanced mucus production.

  19. E2F1 enhances glycolysis through suppressing Sirt6 transcription in cancer cells.

    Science.gov (United States)

    Wu, Minghui; Seto, Edward; Zhang, Jingsong

    2015-05-10

    The fast proliferation of cancer cells requires reprogramming of its energy metabolism with aerobic glycolysis as a major energy source. Sirt6, a class III histone deacetylase, has been shown to down regulate glycolysis by inhibiting the expression of several key glycolytic genes. Based on the published study on the metabolic phenotype of E2F1 -/- mice and SIRT6 -/- mice, we hypothesize that E2F1 enhances glycolysis and inhibits the expression of Sirt6. Indeed, over-expressing of E2F1, but not its DNA binding deficient mutant, significantly enhanced glucose uptake and lactate production in bladder and prostate cancer cell lines. E2F1 over-expression also suppressed Sirt6 expression and function. Moreover, E2F1 directly bound to Sirt6 promoter and suppressed Sirt6 promoter activity under both normoxic and hypoxic culture conditions. E2F1 siRNA blocked the up-regulation of E2F1 under hypoxia, increased Sirt6 expression and decreased glycolysis compared to those of scrambled siRNA transected cells. Furthermore, HDAC1 deacetylated E2F1 and diminished its transcription suppression of Sirt6 promoter. Treatment with the HDAC inhibitor, trichostatin A (TSA), suppressed Sirt6 promoter activity with increased binding of acetylated E2F1 to Sirt6 promoter. Mutating the E2F1 binding site on the proximal Sirt6 promoter abolished the suppression of Sirt6 transcription by TSA. These data indicate a novel oncogenic role of E2F1, i.e. enhancing glycolysis by suppressing Sirt6 transcription.

  20. The role of prostaglandins E2 and F2 alpha on canine arterial in vitro lipid biosynthesis from /sup 14/C-acetate

    Energy Technology Data Exchange (ETDEWEB)

    Soulsby, M.E.; Perlmutter, B.H.

    1981-01-01

    This study was designed to investigate the influence of prostaglandin on in vitro incorporation of 14C acetate into canine aortic lipid. Aortae were excised from pentobarbital-anesthetized dogs, stripped of their adventitial layer and incubated four hours in the presence of labeled substrate alone or labeled substrate plus prostaglandin. The tissue was subsequently homogenized and the lipid phase extracted. Thin layer chromatography was used to separate lipid subfractions. Incorporated 14C was measured by liquid scintillation. PGE2 (0.05-0.10 microgram/ml) significantly decreased (p less than 0.01) incorporation of 14C acetate into phospholipid. Other lipid subfractions were not affected. PGF2 alpha (0.01-0.05 microgram/ml) significantly increased (p less than 0.01) incorporation of 14C acetate into phospholipid, triglyceride and FFA. Other subfractions were not affected. Studies conducted on intimal and medial layers separately failed to alter the extent to which 14C was incorporated into these tissue layers. Tissue ''blanks'' performed following destruction of enzymatic activity failed to demonstrate any significant background uptake of 14C. Therefore, in vitro effect of PGE2 is to decrease aortic wall lipid synthesis from acetate, while the effect of PGF2 alpha is to increase aortic lipid synthesis from acetate.

  1. Microsomal prostaglandin E synthase type 2 (mPGES2) is a glutathione-dependent heme protein, and dithiothreitol dissociates the bound heme to produce active prostaglandin E2 synthase in vitro.

    Science.gov (United States)

    Takusagawa, Fusao

    2013-04-05

    An x-ray study indicated that microsomal prostaglandin E synthase type 2 (mPGES2) is a heme-bound protein and catalyzes prostaglandin (PG) H2 degradation, but not PGE2 formation (Yamada, T., and Takusagawa, F. (2007) Biochemistry 46, 8414-8424). In response to the x-ray study, Watanabe et al. claimed that mPGES2 is a heme-free protein and that both the heme-free and heme-bound proteins have PGE2 synthesis activity in the presence of dithiothreitol (Watanabe, K., Ito, S., and Yamamoto, S. (2008) Biochem. Biophys. Res. Commun. 367, 782-786). To resolve the contradictory results, the heme-binding scheme of mPGES2 was further characterized in vivo and in vitro by absorption and fluorescence spectroscopies. A substantial amount of heme-bound mPGES2 was detected in cell extracts. The heme content in mPGES2 was increased along with an increase in Fe(3+) in the culture medium. Heme-free mPGES2 was converted to the heme-bound form by mixing it with pig liver extract, indicating that mPGES2 is capable of forming a complex with heme in mammalian cells. Heme binds to mPGES2 only in the presence of glutathione. The newly determined heme dissociation constant (2.9 nM) supports strongly that mPGES2 is a heme-bound protein in vivo. The bound heme was not dissociated by oxidation by H2O2 or reduction by glutathione or 2-mercaptoethanol. However, reduction by dithiothreitol (an artificial reducing compound) induced the bound heme to dissociate from mPGES2 and released heme-free mPGES2, which exhibited PGE2 synthesis activity in vitro. Imidazole bound to mPGES2 by stacking on the bound heme and inhibited heme oxidation by H2O2 and reduction by dithiothreitol.

  2. NRIP enhances HPV gene expression via interaction with either GR or E2

    Energy Technology Data Exchange (ETDEWEB)

    Chang, Szu-Wei; Lu, Pei-Yu; Guo, Jih-Huong [Graduate Institute of Microbiology, College of Medicine, National Taiwan University, Taipei 100, Taiwan (China); Tsai, Tzung-Chieh [Department of Microbiology and Immunology, National Chiayi University, Chiayi 600-04, Taiwan (China); Tsao, Yeou-Ping [Department of Ophthalmology, Mackay Memorial Hospital, Taipei 104, Taiwan (China); Chen, Show-Li, E-mail: showlic@ha.mc.ntu.edu.tw [Graduate Institute of Microbiology, College of Medicine, National Taiwan University, Taipei 100, Taiwan (China)

    2012-02-05

    We previously identified a gene, nuclear receptor-interaction protein (NRIP), which functions as a transcription cofactor in glucocorticoid receptor (GR) and human papillomavirus E2 (HPV E2)-driven gene expression. Here, we comprehensively evaluated the role of NRIP in HPV-16 gene expression. NRIP acts as a transcription cofactor to enhance GR-regulated HPV-16 gene expression in the presence of hormone. NRIP also can form complex with E2 that caused NRIP-induced HPV gene expression via E2-binding sites in a hormone-independent manner. Furthermore, NRIP can associate with GR and E2 to form tri-protein complex to activate HPV gene expression via GRE, not the E2-binding site, in a hormone-dependent manner. These results indicate that NRIP and GR are viral E2-binding proteins and that NRIP regulates HPV gene expression via GRE and/or E2 binding site in the HPV promoter in a hormone-dependent or independent manner, respectively.

  3. Levels of serum interleukin (IL)-6 and gingival crevicular fluid of IL-1beta and prostaglandin E(2) among non-smoking subjects with gingivitis and type 2 diabetes.

    Science.gov (United States)

    Andriankaja, O M; Barros, S P; Moss, K; Panagakos, F S; DeVizio, W; Beck, J; Offenbacher, S

    2009-02-01

    The goal of this study was to assess whether non-smoking patients with type 2 diabetes present with increased levels of local and systemic proinflammatory mediators and, if so, whether such an increase is associated with enhanced clinical gingival inflammation compared to non-smoking patients without diabetes. We used a cross-sectional database consisting of 725 self-reported lifelong non-smokers aged 53 to 74 years. Gingival crevicular fluid (GCF) levels of interleukin (IL)-1beta and prostaglandin E(2) (PGE(2)) and serum levels of IL-6 were measured using enzyme-linked immunosorbent assay. No participant had probing depth >3 mm. Participants with bleeding on probing (BOP) in or=10% of sites were defined as having biofilm-gingival interface (BGI) gingivitis. Approximately 53% (n = 385) and 11% (n = 80) of the sample had BGI gingivitis and type 2 diabetes, respectively. The mean age-adjusted level of GCF IL-1beta was significantly elevated in the diabetic group compared to the non-diabetic group (P = 0.048), but serum IL-6 (P = 0.14) and GCF PGE(2) were not (P = 0.98). The mean GCF IL-1beta and PGE(2) levels were significantly elevated in subjects with BGI gingivitis (136.2 +/- 112.9 ng/ml and 277.2 +/- 187.2 ng/ml, respectively) compared to subjects with gingival health (95.9 +/- 82.9 ng/ml and 205.7 +/- 149.6 ng/ml, respectively), regardless of diabetic status (P gingivitis compared to subjects with gingival health only among subjects with diabetes (2.9 +/- 3.2 pg/ml versus 1.5 +/- 1.4 pg/ml; P = 0.008). With the exception of serum IL-6 in subjects without diabetes, an increase in the levels of proinflammatory mediators was associated with increased odds of having BGI gingivitis. The associations were stronger in the diabetic group. Type 2 diabetes may increase the host inflammatory response to oral biofilm, which, in turn, may exacerbate preconditions associated with gingivitis in susceptible individuals. Furthermore, systemic inflammation, as demonstrated by the

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

    Science.gov (United States)

    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.

  5. A randomised controlled trial of an oral solution of prostaglandin E2 and oral oxytocin used immediately after low amniotomy for induction of labour in the presence of a favourable cervix.

    Science.gov (United States)

    Mathews, D D; Hossain, H; Bhargava, S; D'Souza, F

    1976-01-01

    A randomised controlled trial was carried out in 50 primigravidae and 50 multigravidae to compare the effectiveness in induction of labour after low amniotomy of prostaglandin E2, given as an oral solution, and oxytocin, given as buccal tablets. The results showed that in dosages recommended by the manufacturers, both oxytocic preparations were almost equally effective. With oral oxytocin, once labour had been established and dosage was left to the discretion of the staff, there appeared to be a potentially dangerous tendency to continue giving large doses despite adequate uterine contractions. The authors comment that this was probably the reason why oxytocin-treated multigravidae having normal deliveries within 24 hours had labours significantly shorter on average than those of other successfully induced patients.

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

    Science.gov (United States)

    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.

  7. Prostaglandin E2 promotes M2 polarization of macrophages via a cAMP/CREB signaling pathway and deactivates granulocytes in teleost fish.

    Science.gov (United States)

    Montero, Jana; Gómez-Abellán, Victoria; Arizcun, Marta; Mulero, Victoriano; Sepulcre, María P

    2016-08-01

    The profile of prostaglandin (PG) production is determined by the differential expression of the enzymes involved in their production and degradation. Although the production of PGE2 by fish leukocytes has been relatively well studied in several fish species, knowledge of how its production is regulated, its biological activities and the signaling pathways activated by this PG is scant or even contradictory. In this work we show that in the teleost fish gilthead seabream (Sparus aurata L.) macrophages regulate PGE2 release mainly by inducing the expression of the genes encoding the enzymes responsible for its synthesis, while acidophilic granulocytes (AGs) not only induce these genes quickly after activation but also inhibit the expression of the genes encoding the enzymes responsible for PGE2 degradation at later time points. In addition, treatment of macrophages with PGE2 promoted their M2 polarization, which is characterized by high expression levels of interleukin-10, mannose-receptor c-type 1 and arginase 2 genes. In sharp contrast, PGE2 promoted the deactivation of AGs, since it decreased the production of reactive oxygen species and the expression of genes encoding pro-inflammatory cytokines. These differences are the result of the alternative signaling pathways used by PGE2 in macrophages and AGs, a cAMP/CREB signaling pathway operating in macrophages, but not in AGs, downstream of PGE2. Our data identify for the first time a role for professional phagocyte-derived-PGE2 in the resolution of inflammation in fish and highlight key differences in the PGE2 signaling pathway in macrophages and granulocytes. Copyright © 2016 Elsevier Ltd. All rights reserved.

  8. Prostaglandins in Cancer Cell Adhesion, Migration, and Invasion

    Directory of Open Access Journals (Sweden)

    David G. Menter

    2012-01-01

    Full Text Available Prostaglandins exert a profound influence over the adhesive, migratory, and invasive behavior of cells during the development and progression of cancer. Cyclooxygenase-2 (COX-2 and microsomal prostaglandin E2 synthase-1 (mPGES-1 are upregulated in inflammation and cancer. This results in the production of prostaglandin E2 (PGE2, which binds to and activates G-protein-coupled prostaglandin E1-4 receptors (EP1-4. Selectively targeting the COX-2/mPGES-1/PGE2/EP1-4 axis of the prostaglandin pathway can reduce the adhesion, migration, invasion, and angiogenesis. Once stimulated by prostaglandins, cadherin adhesive connections between epithelial or endothelial cells are lost. This enables cells to invade through the underlying basement membrane and extracellular matrix (ECM. Interactions with the ECM are mediated by cell surface integrins by “outside-in signaling” through Src and focal adhesion kinase (FAK and/or “inside-out signaling” through talins and kindlins. Combining the use of COX-2/mPGES-1/PGE2/EP1-4 axis-targeted molecules with those targeting cell surface adhesion receptors or their downstream signaling molecules may enhance cancer therapy.

  9. Efecto antiinflamatorio de apitoxina de Apis mellifera sobre prostaglandina E2 del fluido crevicular gingival de pacientes con y sin enfermedad periodontal, sometidos a apiterapia: ensayo preliminar Anti-inflammatory effect of apitoxin and Apis mellifera on prostaglandin E2 in gingival crevicular fluid of patients with and without periodontal disease, submitted to apitherapy: preliminary test

    Directory of Open Access Journals (Sweden)

    W Faúndez Poblete

    2011-08-01

    Full Text Available Introducción: La apitoxina que es producida por la Apis mellifera posee efecto antiinflamatorio sobre una serie de marcadores biológicos. La prostaglandina E2 forma parte de ellos, estando presente en el fluido gingival crevicular (FGC. La prostaglandina E2 es evidenciada en la enfermedad periodontal. Objetivo: En este estudio se evaluó el efecto antiinflamatorio de la apitoxina sobre la concentración de prostaglandina E2 del FGC de un paciente sin enfermedad periodontal (SEP y otro con enfermedad periodontal (CEP. Materiales y Método: Se seleccionó un paciente SEP y otro CEP, que sometidos a apiterapia durante 28 días, se registraron 5 muestras por paciente de FGC, siendo almacenadas, centrifugadas y refrigeradas para su conservación. Posteriormente se midió la concentración de prostaglandina E2 crevicular mediante inmunodifusión radial simple en placas petri con concentración de anticuerpo anti prostaglandina E2 de 1:1000. Selladas a 4°C, se esperó 72 horas para permitir su difusión, tiñéndose con Azul brillante de Coomasie, determinándose la concentración de cada placa. Resultados: Paciente SEP inmediatamente antes de apiterapia presentó una concentración de 0.9636 ± 0.0055 (µg/µL, finalizando con una concentración de 0.9196±0.0733 (µg/µL al completar 28 días de tratamiento. El paciente CEP antes de recibir apiterapia presento una concentración de 1.1866 ± 0.0867 (µg/µL, finalizando con una concentración de 0.9858 ± 0.0074 (µg/µL al completar 28 días de tratamiento. Discusión: Los hallazgos de este estudio demuestran una disminución de la concentración de PGE2 del FGC tanto para el paciente CEP y SEP sometidos a apiterapia durante 28 días, siendo esta disminución 3.7 veces mayor en el paciente CEP.Introduction: Apitoxin, which is produced by Apis mellifera, has anti-inflammatory effect on a number of biomarkers. Prostaglandin E2 is one of them, being present in gingival crevicular fluid (GCF

  10. beta-oxidation modulates metabolic competition between eicosapentaenoic acid and arachidonic acid regulating prostaglandin E(2) synthesis in rat hepatocytes-Kupffer cells

    DEFF Research Database (Denmark)

    Du, Zhen-Yu; Ma, Tao; Winterthun, Synnøve

    2010-01-01

    and eicosapentaenoic acid (EPA) for PGE(2) synthesis in a rat hepatocyte-Kupffer cell (HPC/KC) co-culture system when the cellular oxidation capacity was enhanced by exogenous l-carnitine. We demonstrate that in the absence of l-carnitine, 1) beta-oxidation rates of EPA and AA were comparable in HPCs and in KCs; 2) AA...... and not EPA was preferentially incorporated into glycerolipids; and 3) addition of EPA significantly decreased AA-dependent PGE(2) synthesis in HPCs and cyclooxygenase-2 (COX-2) expression in co-cultured HPCs/KCs. However, enhancing the cellular oxidation capacity by the addition of l-carnitine 1...... inhibition of AA-dependent PGE(2) synthesis and COX-2 expression by EPA. Taken together, the results strongly suggest that l-carnitine affects competition between AA and EPA in PG synthesis in liver cells by enhancing oxidation of EPA in HPCs. This implies that the beneficial effects of n-3 PUFA, especially...

  11. Prostaglandin E2 potentiates mesenchymal stem cell-induced IL-10+IFN-γ+CD4+ regulatory T cells to control transplant arteriosclerosis.

    Science.gov (United States)

    Hsu, Wan-Tseng; Lin, Cheng-Hsin; Chiang, Bor-Luen; Jui, Hsiang-Yiang; Wu, Kenneth Kun-Yu; Lee, Chii-Ming

    2013-03-01

    Mesenchymal stem cells (MSCs) are known for their immunomodulatory functions. We previously demonstrated that bone marrow-derived MSCs effectively control transplant arteriosclerosis (TA) by enhancing IL-10(+) and IFN-γ(+) cells. The objective of this study is to elucidate the mechanism by which MSCs induce IL-10(+)IFN-γ(+)CD4(+) regulatory T type 1 (T(R)1)-like cells. In an MLR system using porcine PBMCs, MSC-induced IL-10(+)IFN-γ(+)CD4(+) cells, which confer resistance to allogeneic proliferation in an IL-10-dependent manner, resemble T(R)1-like cells. Both cyclooxygenase-derived PGE(2) and IDO help to induce T(R)1-like cells by MSCs. MSCs constitutively secrete PGE(2), which is augmented in allogeneic reactions. However, T(R)1-like cells were deficient in PGE(2) and 4-fold less potent than were MSCs in suppressing MLR. PGE(2) mimetic supplements can enhance the immunosuppressive potency of T(R)1-like cells. In a porcine model of allogeneic femoral arterial transplantation, MSC-induced T(R)1-like cells combined with PGE(2), but not either alone, significantly reduced TA at the end of 6 wk (percentage of luminal area stenosis: T(R)1-like cells + PGE(2): 11 ± 10%; PGE(2) alone: 93 ± 8.7%; T(R)1-like cells alone: 88 ± 2.4% versus untreated 94 ± 0.9%, p < 0.001). These findings indicate that PGE(2) helps MSC-induced IL-10(+)IFN-γ(+)CD4(+) T(R)1-like cells inhibit TA. PGE(2) combined with MSC-induced T(R)1-like cells represents a new approach for achieving immune tolerance.

  12. Prostaglandins and its analogues : An approach for treatment of anoestrus and to enhance breeding efficiency

    Directory of Open Access Journals (Sweden)

    G B Dudhatra

    2012-12-01

    Full Text Available Cloprostenol is a synthetic prostaglandin F analogue. It is a FP (Prostaglandin F receptor agonist, which shows 2á powerful luteolytic effects. It also stimulates the contraction of uterine and bronchial smooth muscle and produces vasoconstriction in some vessels. Anoestrous may be due to some conditions like abnormal pregnancy, early pregnancy, pyometra, endometritis, retention of placenta, maceration and mummification. So, get rid of this conditions cloprostenol is widely used. It has been now in vogue to administer PGF or its analogue in early 2á postpartum cows and buffaloes in order to hasten early resumption of cyclic ovarian activity and thereby to increase the reproductive efficiency. To improve reproductive efficiency, it is necessary to inseminate cows early in the breeding season so that, thereby achieving a more compact calving season. Breeding efficiency is increased by means of synchronization of estrus, conception rate and pregnancy rate. Estrus synchronization can be achieved by lysis of corpus luteum by administration of prostaglandin (PGF or its synthetic analogue on 5-17 2á days of the estrus cycle. The cows will return to estrus within 3-5 days. The effective therapeutic doses for cloprostenol are 500 μg in cattle and 175 μg in pigs. However, for R-cloprostenol, the recommended doses are: 150 μg in cattle and 75 μg in pigs. In both cases, it is administered by the intramuscular route. [Vet. World 2012; 5(6.000: 378-384

  13. Prostaglandins and prostaglandin receptor antagonism in migraine

    DEFF Research Database (Denmark)

    Antonova, Maria

    2013-01-01

    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....... 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...

  14. Bioproduction of prostaglandins in a transgenic liverwort, Marchantia polymorpha.

    Science.gov (United States)

    Takemura, Miho; Kanamoto, Hirosuke; Nagaya, Shingo; Ohyama, Kanji

    2013-10-01

    Prostaglandins are biologically active substances used in a wide range of medical treatments. Prostaglandins have been supplied mainly by chemical synthesis; nevertheless, the high cost of prostaglandin production remains a factor. To lower the cost of prostaglandin production, we attempted to produce prostaglandins using a liverwort, Marchantia polymorpha L., which accumulates arachidonic acid, which is known as a substrate of prostaglandins. Here we report the first bioproduction of prostaglandins in plant species by introducing a cyclooxygenase gene from a red alga, Gracilaria vermiculophylla into the liverwort. The transgenic liverworts accumulated prostaglandin F2α, prostaglandin E2 and prostaglandin D2 which were not detected in the wild-type liverwort. Moreover, we succeeded in drastically increasing the bioproduction of prostaglandins using an in vitro reaction system with the extracts of transgenic liverworts.

  15. Comparison of the effects of IV administration of meloxicam, carprofen, and flunixin meglumine on prostaglandin E(2) concentration in aqueous humor of dogs with aqueocentesis-induced anterior uveitis.

    Science.gov (United States)

    Gilmour, Margi A; Payton, Mark E

    2012-05-01

    To compare the effects of meloxicam, carprofen, and flunixin meglumine administered IV on the concentration of prostaglandin E(2) (PGE(2)) in the aqueous humor of dogs with aqueocentesis-induced anterior uveitis. 15 adult dogs with ophthalmically normal eyes. Each dog was assigned to 1 of 4 treatment groups. Treatment groups were saline (0.9% NaCl) solution (1 mL, IV), meloxicam (0.2 mg/kg, IV), carprofen (4.4 mg/kg, IV), and flunixin meglumine (0.5 mg/kg, IV). Each dog was anesthetized, treatment was administered, and aqueocentesis was performed on each eye at 30 and 60 minutes after treatment. Aqueous humor samples were frozen at -80°C until assayed for PGE(2) concentration with an enzyme immunoassay kit. For all 4 treatment groups, PGE(2) concentration was significantly higher in samples obtained 60 minutes after treatment, compared with that in samples obtained 30 minutes after treatment, which indicated aqueocentesis-induced PGE(2) synthesis. For aqueous humor samples obtained 60 minutes after treatment, PGE(2) concentration did not differ significantly among groups treated with saline solution, meloxicam, and carprofen; however, the PGE(2) concentration for the group treated with flunixin meglumine was significantly lower than that for each of the other 3 treatment groups. Flunixin meglumine was more effective than meloxicam or carprofen for minimizing the PGE(2) concentration in the aqueous humor of dogs with experimentally induced uveitis. Flunixin meglumine may be an appropriate pre-medication for use prior to intraocular surgery in dogs.

  16. DNA Bending is Induced in an Enhancer by the DNA-Binding Domain of the Bovine Papillomavirus E2 Protein

    Science.gov (United States)

    Moskaluk, Christopher; Bastia, Deepak

    1988-03-01

    The E2 gene of bovine papillomavirus type 1 has been shown to encode a DNA-binding protein and to trans-activate the viral enhancer. We have localized the DNA-binding domain of the E2 protein to the carboxyl-terminal 126 amino acids of the E2 open reading frame. The DNA-binding domain has been expressed in Escherichia coli and partially purified. Gel retardation and DNase I ``footprinting'' on the bovine papillomavirus type 1 enhancer identify the sequence motif ACCN6GGT (in which N = any nucleotide) as the E2 binding site. Using electrophoretic methods we have shown that the DNA-binding domain changes conformation of the enhancer by inducing significant DNA bending.

  17. HMGA2 induces pituitary tumorigenesis by enhancing E2F1 activity

    DEFF Research Database (Denmark)

    Fedele, Monica; Visone, Rosa; De Martino, Ivana

    2006-01-01

    show that HMGA2 interacts with pRB and induces E2F1 activity in mouse pituitary adenomas by displacing HDAC1 from the pRB/E2F1 complex-a process that results in E2F1 acetylation. We found that loss of E2F1 function (obtained by mating HMGA2 and E2F1(-/-) mice) suppressed pituitary tumorigenesis in HMGA......HMGA2 gene amplification and overexpression in human prolactinomas and the development of pituitary adenomas in HMGA2 transgenic mice showed that HMGA2 plays a crucial role in pituitary tumorigenesis. We have explored the pRB/E2F1 pathway to investigate the mechanism by which HMGA2 acts. Here we...

  18. α-Melanocyte stimulating hormone (MSH) and prostaglandin E2 (PGE2) drive melanosome transfer by promoting filopodia delivery and shedding spheroid granules: Evidences from atomic force microscopy observation.

    Science.gov (United States)

    Ma, Hui-Jun; Ma, Hui-Yong; Yang, Yang; Li, Peng-Cheng; Zi, Shao-Xia; Jia, Chi-Yu; Chen, Rong

    2014-12-01

    Skin pigmentation is accomplished by production of melanin in melanosome and by transfer of these organelles from melanocytes (MCs) to surrounding keratinocytes (KCs). However, the detailed mechanism is still unknown. We aimed to investigate the morphological structure changes on human epidermal MCs and KCs, which were either mono-cultured or co-cultured, with or without the treatment of both α-Melanocyte-stimulating hormone (α-MSH) and prostaglandin E2 (PGE2), by atomic force microscopy (AFM) and to provide more direct proofs for process of melanosome transfer. Human epidermal MCs and KCs were isolated and co-cultured with 1:10 ratio in a defined Keratinocyte-serum free medium (K-SFM). After exposure with 100 nM α-MSH or 20 μM PGE2 for 3 days, cells were fixed with 0.5% glutaraldehyde and AFM images of scanning observation were captured by contacting and tapping model under normal atmospheric pressure and temperature. It showed that human epidermal MCs in culture had secondary or tertiary branches. Except for globular granules structure on the surface of dendrites, some filopodia were protruded on the tips and lateral sides of the dendrites. The administration of α-MSH and PGE2 made not only the dendrites thinner and longer, but also the globular granules more intensive and denser. Many spheroid granules were shed from branches of dendrite and most of them adhered with dense filopodia. Compared with untreated group, the number of filopodia per cell, diameter of filopodia, and shedding spheroid granules per field all increased following α-MSH and PGE2 exposure (Pspheroid granules per field all increased after the administration of α-MSH and PGE2 (Pspheroid granules, filopodia delivery and KC phagocytosis are major mode of melanosome transfer between MCs and KCs. PGE2, as well as α-MSH, drives melanosome transfer by promoting filopodia delivery and numbers of shedding spheroid granules in MCs, but no direct morphological effects on KCs. These findings open a

  19. 16, 16 Dimethyl prostaglandin E2 prevents the development of fulminant hepatitis and blocks the induction of monocyte/macrophage procoagulant activity after murine hepatitis virus strain 3 infection.

    Science.gov (United States)

    Abecassis, M; Falk, J A; Makowka, L; Dindzans, V J; Falk, R E; Levy, G A

    1987-01-01

    16, 16 Dimethyl prostaglandin E2 (dmPGE2), a known cytoprotective agent, was examined for its ability to alter the course of fulminant hepatitis in an experimental model of fulminant viral hepatitis, murine hepatitis murine hepatitis type 3 (MHV-3). Fully susceptible BALB/cJ mice, infected with 100 50% lethal doses (LD50) of MHV-3 developed histologic and biochemical evidence of fulminant hepatitis, as evidenced by massive hepatic necrosis with hypoglycemia, metabolic acidosis, and a markedly elevated serum alanine aminotransferase (ALT) (mean, 1,402 +/- 619 IU/liter). In contrast, animals treated with dmPGE2 either before or after infection (up to 48 h) demonstrated a marked reduction in both histologic and biochemical evidence of liver damage as characterized by normal blood glucose, total CO2, and ALT determinations (mean ALT, 63 +/- 40 IU/liter). Treatment of infected mice with PGF2 alpha demonstrated no cytoprotective effects. High titers of infectious virus were recovered from the livers of both dmPGE2-treated and -untreated animals throughout the course of infection. In a parallel in vitro study, dmPGE2 (10(-4)-10(-8) M) demonstrated a similar cytoprotective effect on monolayers of isolated cultured hepatocytes from fully susceptible BALB/cJ mice infected at a multiplicity of infection of 0.1, 1.0, and 10.0. In addition, splenic macrophages recovered from infected and untreated BALB/cJ mice demonstrated a marked augmentation in procoagulant activity (PCA) from a basal 10 +/- 5 mU/10(6) splenic macrophages to a maximum of 615 +/- 102 mU/10(6) splenic macrophages, whereas no increase in macrophage PCA was detected in infected animals treated with dmPGE2. These results suggest that dmPGE2, without detectably altering viral replication or infectivity in vivo, confers a marked cytoprotective effect on hepatocytes both in vivo and in vitro, and prevents the induction of macrophage PCA in vivo in fully susceptible BALB/cJ mice after murine hepatitis virus type 3

  20. Effect of Aspirin and ibuprofen either alone or in combination on gastric mucosa and bleeding time and on serum prostaglandin E2 and thromboxane A2 levels in the anaesthetized rats in vivo.

    Science.gov (United States)

    Bastaki, Salim M A; Padol, Ireneusz T; Amir, Naheed; Hunt, Richard H

    2018-01-01

    There is much evidence that a combination of ibuprofen (IBU) and Aspirin (ASA) can antagonize the irreversible inhibition of platelet function. This study was designed to investigate the degree of gastric damage, bleeding time (BT) and fluctuations in the serum levels of prostaglandin E2 (PGE2) and thromboxane A2 (TXA2) after oral administration of ASA (200 mg/kg) and IBU (50 mg/kg) either alone or in combination in rats in vivo. The stomach was assessed for any damage either after 6 h, 18 h or 6 days and carboxymethylcellulose (1% CMC) served as a vehicle and control. ELISA was used to measure TXA2 and PGE2 in serum. Bleeding time was assessed using tail blood. The results show that ASA and IBU either alone or in combination can cause gastric ulceration in 25-100% of the rats at 6 and 18 h. In contrast, gastric ulceration was seen in 50% of rats with a combination of ASA given before IBU only after 6 days of oral administration. BT was unaffected either by ASA or IBU when administered alone except after 18 h for IBU. In contrast, BT was significantly reduced when IBU was administered before ASA after 18 h and 6 days (P < 0.001). Serum PGE2 levels decreased significantly after ASA administered either alone or in combination with IBU for 6 h, 18 h and 6 days (P < 0.05). Serum TXA2 levels were significantly reduced after 6 h, 18 h and 6 days following ASA and IBU administration except for IBU alone which caused a significant increase in serum TXA2 6 days after its administration (P < 0.01). It can be concluded that ASA and IBU administered either alone or in combination can cause gastric ulcers in the rat stomach after 6 h and 18 h, but less severe after 6 days. IBU either alone or in combination with ASA reduced BT only after 18 h and 6 days of administration. Together, the results show that gastric ulceration correlated well with the inhibition of serum PGE2 and TXA2 levels.

  1. Role of Ca2+-activated K+ channels and Na+-K+-ATPase in prostaglandin E1- and E2-induced inhibition of the adrenergic response in human vas deferens

    OpenAIRE

    Medina Bessó, Pascual; Segarra Irles, Gloria Vicenta; Mauricio Aviñó, María Dolores; Vila Salinas, José María; Chuan Nuez, Pascual; Lluch López, Salvador

    2011-01-01

    Abstract We studied the role of K+ channels and Na+,K+-ATPase in the presynaptic inhibitory effects of prostaglandin E1 (PGE1) and PGE2 on the adrenergic responses of human vas deferens. Furthermore, we determined the effects of increasing extracellular K+ concentrations ([K+]o) and inhibition of Na+,K+-ATPase on neurogenic and norepinephrine -induced contractile responses. Ring segments of the epididymal part of the vas deferens were taken from 45 elective vasectomies and mounted ...

  2. Food deprivation alters thermoregulatory responses to lipopolysaccharide by enhancing cryogenic inflammatory signaling via prostaglandin D2.

    Science.gov (United States)

    Krall, Catherine M; Yao, Xiujuan; Hass, Martha A; Feleder, Carlos; Steiner, Alexandre A

    2010-06-01

    We tested the hypothesis that food deprivation alters body temperature (T(b)) responses to bacterial LPS by enhancing inflammatory signaling that decreases T(b) (cryogenic signaling) rather than by suppressing inflammatory signaling that increases T(b) (febrigenic signaling). Free-feeding or food-deprived (24 h) rats received LPS at doses (500 and 2,500 microg/kg iv) that are high enough to activate both febrigenic and cryogenic signaling. At these doses, LPS caused fever in rats at an ambient temperature of 30 degrees C, but produced hypothermia at an ambient temperature of 22 degrees C. Whereas food deprivation had little effect on LPS fever, it enhanced LPS hypothermia, an effect that was particularly pronounced in rats injected with the higher LPS dose. Enhancement of hypothermia was not due to thermogenic incapacity, since food-deprived rats were fully capable of raising T(b) in response to the thermogenic drug CL316,243 (1 mg/kg iv). Neither was enhancement of hypothermia associated with altered plasma levels of cytokines (TNF-alpha, IL-1beta, and IL-6) or with reduced levels of an anti-inflammatory hormone (corticosterone). The levels of PGD(2) and PGE(2) during LPS hypothermia were augmented by food deprivation, although the ratio between them remained unchanged. Food deprivation, however, selectively enhanced the responsiveness of rats to the cryogenic action of PGD(2) (100 ng icv) without altering the responsiveness to febrigenic PGE(2) (100 ng icv). These findings support our hypothesis and indicate that cryogenic signaling via PGD(2) underlies enhancement of LPS hypothermia by food deprivation.

  3. Enhanced prostaglandin E2 production by monocytes in atopic dermatitis (AD) is not accompanied by enhanced production of IL-6, IL-10 or IL-12

    NARCIS (Netherlands)

    Snijders, A.; van der Pouw Kraan, T. C.; Engel, M.; Wormmeester, J.; Widjaja, P.; Zonneveld, I. M.; Bos, J. D.; Kapsenberg, M. L.

    1998-01-01

    AD is associated with a bias of the T helper cells to show increased IL-4 and reduced interferon-gamma (IFN-gamma) production. The production of IFN-gamma and IL-4 and the development of Th cells into either high IFN-gamma or high IL-4 producers is strongly influenced by factors produced by

  4. H2O2 increases production of constrictor prostaglandins in smooth muscle leading to enhanced arteriolar tone in Type 2 diabetic mice.

    Science.gov (United States)

    Erdei, Nóra; Bagi, Zsolt; Edes, István; Kaley, Gabor; Koller, Akos

    2007-01-01

    Our previous study showed that arteriolar tone is enhanced in Type 2 diabetes mellitus (T2-DM) due to an increased level of constrictor prostaglandins. We hypothesized that, in mice with T2-DM, hydrogen peroxide (H(2)O(2)) is involved in the increased synthesis of constrictor prostaglandins, hence enhanced basal tone in skeletal muscle arterioles. Isolated, pressurized gracilis muscle arterioles ( approximately 100 microm in diameter) of mice with T2-DM (C57BL/KsJ-db(-)/db(-)) exhibited greater basal tone to increases in intraluminal pressure (20-120 mmHg) than that of control vessels (at 80 mmHg, control: 25 +/- 5%; db/db: 34 +/- 4%, P < 0.05), which was reduced back to control level by catalase (db/db: 24 +/- 4%). Correspondingly, in carotid arteries of db/db mice, the level of dichlorofluorescein-detectable and catalase-sensitive H(2)O(2) was significantly greater. In control arterioles, exogenous H(2)O(2) (0.1-100 micromol/l) elicited dilations (maximum, 58 +/- 10%), whereas in arterioles of db/db mice H(2)O(2) caused constrictions (-28 +/- 8%), which were converted to dilations (maximum, 16 +/- 5%) by the thromboxane A(2)/prostaglandin H(2) (TP) receptor antagonist SQ-29548. In addition, arteriolar constrictions in response to the TP receptor agonist U-46619 were not different between the two groups of vessels. Endothelium denudation did not significantly affect basal tone and H(2)O(2)-induced arteriolar responses in either control or db/db mice. Also, in arterioles of db/db mice, but not in controls, 3-nitrotyrosine staining was detected in the endothelial layer of vessels. Thus we propose that, in mice with T2-DM, arteriolar production of H(2)O(2) is enhanced, which leads to increased synthesis of the constrictor prostaglandins thromboxane A(2)/prostaglandin H(2) in the smooth muscle cells, which enhance basal arteriolar tone. These alterations may contribute to disturbed regulation of skeletal muscle blood flow in Type 2 diabetes mellitus.

  5. Enhancing trabecular outflow by disrupting the actin cytoskeleton, increasing uveoscleral outflow with prostaglandins, and understanding the pathophysiology of presbyopia

    Science.gov (United States)

    Kaufman, Paul L.

    2008-01-01

    Several major areas of work by the author and his international collaborators are reviewed. 1) The ciliary muscle in the nonhuman primate eye was disinserted at the scleral spur. Pilocarpine was then ineffective in increasing outflow facility, indicating that ciliary muscle contraction mediated the IOP-lowering effect of muscarinic cholinergics. 2) Compounds such as cytochalasins, H-7 and latrunculin A/B, which alter the actin cytoskeleton, cellular contractility and cellular adhesions in cultured trabecular meshwork cells, relaxed trabecular pathway cells and consequently the meshwork itself so as to decrease IOP and enhance trabecular outflow facility in nonhuman primates. Gene transfer approaches utilizing C3 and caldesmon over-expression by viral vectors to target specific steps in the cellular contractility/cytoskeleton/cell adhesion cascades characteristically altered trabecular meshwork cell morphology and increased outflow facility in organ-cultured anterior segments. 3) Prostaglandin F2α analogues enhanced matrix metalloproteinase production by ciliary muscle cells and scleral fibroblasts, leading to remodeling of the extracellular matrix of the ciliary muscle and sclera and consequently to increased uveoslceral outflow and decreased IOP in primates. 4) The rhesus monkey was an excellent model for human presbyopia, losing the accommodative response to cholinergic stimulation in the same timeframe relative to lifespan. No changes were found in ciliary muscle enzymes involved in acetylcholine biosynthesis or degradation or in muscarinic receptor numbers or affinity. Contractility of isolated ciliary muscle did not diminish with age, but posterior ciliary muscle attachments stiffened, suggesting a possible role in restricting muscle and consequently lens movement during accommodation. A model to reproducibly stimulate accommodation through central stimulation of the Edinger-Westphal nucleus was developed. Goniovideography and ultrasound biomicroscopic

  6. Association of Human Papillomavirus 16 E2 with Rad50-Interacting Protein 1 Enhances Viral DNA Replication.

    Science.gov (United States)

    Campos-León, Karen; Wijendra, Kalpanee; Siddiqa, Abida; Pentland, Ieisha; Feeney, Katherine M; Knapman, Alison; Davies, Rachel; Androphy, Elliot J; Parish, Joanna L

    2017-03-01

    Rad50-interacting protein 1 (Rint1) associates with the DNA damage response protein Rad50 during the transition from the S phase to the G2/M phase and functions in radiation-induced G2 checkpoint control. It has also been demonstrated that Rint1 is essential in vesicle trafficking from the Golgi apparatus to the endoplasmic reticulum (ER) through an interaction with Zeste-White 10 (ZW10). We have isolated a novel interaction between Rint1 and the human papillomavirus 16 (HPV16) transcription and replication factor E2. E2 binds to Rint1 within its ZW10 interaction domain, and we show that in the absence of E2, Rint1 is localized to the ER and associates with ZW10. E2 expression results in a disruption of the Rint1-ZW10 interaction and an accumulation of nuclear Rint1, coincident with a significant reduction in vesicle movement from the ER to the Golgi apparatus. Interestingly, nuclear Rint1 and members of the Mre11/Rad50/Nbs1 (MRN) complex were found in distinct E2 nuclear foci, which peaked during mid-S phase, indicating that the recruitment of Rint1 to E2 foci within the nucleus may also result in the recruitment of this DNA damage-sensing protein complex. We show that exogenous Rint1 expression enhances E2-dependent virus replication. Conversely, the overexpression of a truncated Rint1 protein that retains the E2 binding domain but not the Rad50 binding domain acts as a dominant negative inhibitor of E2-dependent HPV replication. Put together, these experiments demonstrate that the interaction between Rint1 and E2 has an important function in HPV replication.IMPORTANCE HPV infections are an important driver of many epithelial cancers, including those within the anogenital and oropharyngeal tracts. The HPV life cycle is tightly regulated and intimately linked to the differentiation of the epithelial cells that it infects. HPV replication factories formed in the nucleus are locations where viral DNA is copied to support virus persistence and amplification of

  7. An Asp49 Phospholipase A2 from Snake Venom Induces Cyclooxygenase-2 Expression and Prostaglandin E2 Production via Activation of NF-κB, p38MAPK, and PKC in Macrophages

    Directory of Open Access Journals (Sweden)

    Vanessa Moreira

    2014-01-01

    Full Text Available Phospholipases A2 (PLA2 are key enzymes for production of lipid mediators. We previously demonstrated that a snake venom sPLA2 named MT-III leads to prostaglandin (PGE2 biosynthesis in macrophages by inducing the expression of cyclooxygenase-2 (COX-2. Herein, we explored the molecular mechanisms and signaling pathways leading to these MT-III-induced effects. Results demonstrated that MT-III induced activation of the transcription factor NF-κB in isolated macrophages. By using NF-κB selective inhibitors, the involvement of this factor in MT-III-induced COX-2 expression and PGE2 production was demonstrated. Moreover, MT-III-induced COX-2 protein expression and PGE2 release were attenuated by pretreatment of macrophages with SB202190, and Ly294002, and H-7-dihydro compounds, indicating the involvement of p38MAPK, PI3K, and PKC pathways, respectively. Consistent with this, MT-III triggered early phosphorylation of p38MAPK, PI3K, and PKC. Furthermore, SB202190, H-7-dihydro, but not Ly294002 treatment, abrogated activation of NF-κB induced by MT-III. Altogether, these results show for the first time that the induction of COX-2 protein expression and PGE2 release, which occur via NF-κB activation induced by the sPLA2-MT-III in macrophages, are modulated by p38MAPK and PKC, but not by PI3K signaling proteins.

  8. Efecto antiinflamatorio de apitoxina de Apis mellifera sobre prostaglandina E2 del fluido crevicular gingival de pacientes con y sin enfermedad periodontal, sometidos a apiterapia: ensayo preliminar Anti-inflammatory effect of apitoxin and Apis mellifera on prostaglandin E2 in gingival crevicular fluid of patients with and without periodontal disease, submitted to apitherapy: preliminary test

    OpenAIRE

    Faúndez Poblete,W; CG Narváez Carrasco; Burgos Arias, A.

    2011-01-01

    Introducción: La apitoxina que es producida por la Apis mellifera posee efecto antiinflamatorio sobre una serie de marcadores biológicos. La prostaglandina E2 forma parte de ellos, estando presente en el fluido gingival crevicular (FGC). La prostaglandina E2 es evidenciada en la enfermedad periodontal. Objetivo: En este estudio se evaluó el efecto antiinflamatorio de la apitoxina sobre la concentración de prostaglandina E2 del FGC de un paciente sin enfermedad periodontal (SEP) y otro con enf...

  9. [Influence of dicinone and taurine on the effects of prostaglandins].

    Science.gov (United States)

    Bunin, A Ia; Ermakova, V N; Shvarts, G Ia; Mashkovskiĭ, M D

    1980-01-01

    In rabbit experiments, the local administration of prostaglandins E2 and F2 alpha provoked an increase in intraocular pressure because of hyperproduction of intraocular liquid and increased permeability of the histoophthalmic barrier. Local administration of dicinon and taurin elicited a protective action and prevented the hypertensive effect of prostaglandins. Dicinon and taurin did not produce any influence on spasmogenic and hemodynamic effects of prostaglandins on isolated preparations of smooth muscle organs. Therefore, the protective effect of the drugs in the prostaglandin-induced hypertension of the eye is not related to the antiprostaglandin properties shown by these drugs.

  10. Prostaglandins in teleost ovulation: A review of the roles with a view to comparison with prostaglandins in mammalian ovulation.

    Science.gov (United States)

    Takahashi, Takayuki; Hagiwara, Akane; Ogiwara, Katsueki

    2018-02-05

    Prostaglandins are well known to be central regulators of vertebrate ovulation. Studies addressing the role of prostaglandins in mammalian ovulation have established that they are involved in the processes of oocyte maturation and cumulus oocyte complex expansion. In contrast, despite the first indication of the role of prostaglandins in teleost ovulation appearing 40 years ago, the mechanistic background of their role has long been unknown. However, studies conducted on medaka over the past decade have provided valuable information. Emerging evidence indicates an indispensable role of prostaglandin E2 and its receptor subtype Ptger4b in the process of follicle rupture. In this review, we summarize studies addressing the role of prostaglandins in teleost ovulation and describe recent advances. To help understand differences from and similarities to ovulation in mammalian species, the findings on the roles of prostaglandins in mammalian ovulation are discussed in parallel. Copyright © 2017 Elsevier B.V. All rights reserved.

  11. An inverted repeat motif stabilizes binding of E2F and enhances transcription of the dihydrofolate reductase gene

    DEFF Research Database (Denmark)

    Wade, M; Blake, M C; Jambou, R C

    1995-01-01

    and viral genes. This element, 5'-TTTCGCGCCAAA-3', is comprised of two overlapping, oppositely oriented sites which match the consensus E2F site (5'-TTT(C/G)(C/G)CGC-3'). Recent work has shown that E2F binding activity is composed of at least six related cellular polypeptides which are capable of forming...

  12. Ionophores stimulate prostaglandin and thromboxane biosynthesis*

    Science.gov (United States)

    Knapp, Howard R.; Oelz, Oswald; Roberts, L. Jackson; Sweetman, Brian J.; Oates, John A.; Reed, Peter W.

    1977-01-01

    The role of calcium in triggering prostaglandin and thromboxane synthesis was studied in several systems with ionophores of different ion specificities. Divalent cationophore A23187 stimulates prostaglandin and thromboxane production by washed human platelets in a concentration-dependent manner (0.3-9 μM). A23187 also induces an antimycin A-insensitive burst in oxygen utilization which is partially blocked by 5 mM aspirin or 10 μM indomethacin. Under our conditions, A23187 (up to 10 μM) does not appear to damage platelet membranes since it does not cause appreciable loss of lactate dehydrogenase or β-glucuronidase. Mono- and divalent cationophore X537A also stimulates platelet thromboxane B2 production and oxygen utilization, but monovalent cationophores nigericin, monensin A, A204, and valinomycin have no effect. The synthesis of prostaglandins E2, D2, and F2α by rat renal medulla mince is stimulated by 1 and 5 μM A23187 without changes in tissue ATP content, lactate output, or K+ efflux. X537A, monensin A, and nigericin (all 5 μM) stimulate both prostaglandin output and K+ efflux from renal medulla, while 5 μM valinomycin or A204 has no effect on either. None of the ionophores stimulates renomedullary prostaglandin production if calcium is omitted from the incubation medium. A23187 also stimulates prostaglandin production by human lymphoma cells, rat stomach and trachea preparations, and guinea pig polymorphonuclear leukocytes. These observations suggest a major role for Ca2+ in stimulating prostaglandin and thromboxane biosynthesis, and also indicate that prostaglandin and/or thromboxane release may partially mediate some of the previously described effects of ionophores on cells and tissues. PMID:270668

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

    Science.gov (United States)

    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.

  14. Nuclear factor E2-related factor 2 knockdown enhances glucose uptake and alters glucose metabolism in AML12 hepatocytes.

    Science.gov (United States)

    Yuan, Xiaoyang; Huang, Huijing; Huang, Yi; Wang, Jinli; Yan, Jinhua; Ding, Ling; Zhang, Cuntai; Zhang, Le

    2017-05-01

    Nuclear factor E2-related factor 2 (Nrf2) is a transcription factor known to induce the expression of a variety of antioxidant and detoxification genes. Recently, increasing evidence has revealed roles for Nrf2 in glucose, lipid, and energy metabolism; however, the exact functions of Nrf2 in hepatocyte biology are largely unclear. In the current study, the transient knockdown of Nrf2 via siRNA transfection enhanced the glucose uptake of fasting AML12 hepatocytes to 325.3 ± 11.1% ( P glucose metabolism were then examined in AML12 cells under both high-glucose (33 mmol/L) and low-glucose (4.5 mmol/L) conditions. NK lowered the gene and protein expression of the anti-oxidases heme oxygenase-1 and NAD(P)H: quinone oxidoreductase 1 and increased p-eukaryotic initiation factor-2α S51 , p-nuclear factor-κB p65 S276 , and its downstream proinflammatory factors, including interleukin-1 beta, tumor necrosis factor-α, matrix metalloproteinase 2, and matrix metalloproteinase 9, at the protein level. NK also altered the protein expression of fibroblast growth factor 21, glucose transporter type 4, insulin-like growth factor 1, forkhead box protein O1, p-AKT S473 , and p-GSK3α/β Y279/Y216 , which are involved in glucose uptake, glycogenesis, and gluconeogenesis in AML12 cells. Our results provide a comprehensive understanding of the central role of Nrf2 in the regulation of glucose metabolism in AML12 hepatocytes, in addition to its classical roles in the regulation of redox signaling, endoplasmic reticulum stress and proinflammatory responses, and support the potential of Nrf2 as a therapeutic target for the prevention and treatment of obesity and other associated metabolic syndromes. Impact statement Increasing evidence supports the complexity of Nrf2 functions beyond the antioxidant and detoxification response. Previous in vivo studies employing either Nrf2-knockout or Nrf2-activated mice have achieved a similar endpoint: protection against an obese and

  15. Inhibition of Nitric Oxide and Prostaglandin E2 Expression by ...

    African Journals Online (AJOL)

    HP

    ZL, Wu CJ. Inhibition of lipopolysaccharide (LPS)- induced inflammatory responses by Sargassum hemiphyllum sulfated polysaccharide extract in. RAW 264.7 macrophage cells. J Agric Food Chem. 2011; 59: 2062–2068. 19. Baldwin AS (Jr). The NF-κB and IκB proteins: new discoveries and insights. Annu Rev Immunol.

  16. Prostaglandin E2 to diagnose between reversible and irreversible pulpitis.

    Science.gov (United States)

    Petrini, M; Ferrante, M; Ciavarelli, L; Brunetti, L; Vacca, M; Spoto, G

    2012-01-01

    The aim of this work is to verify a correlation between the grade of inflammation and the concentration of PGE2 in human dental pulp. A total of 25 human dental pulps were examined by histological analysis and radioimmunologic dosage of PGE2. The pulps used in this experiment were from healthy and symptomatic teeth; the first ones were collected from teeth destined to be extracted for orthodontic reasons. An increase was observed of PGE2 in reversible pulpitis compared with healthy pulps and with the irreversible pulpitis and the clear decrease of these when NSAIDs are taken. This study demonstrates that PGE2 level is correlated to histological analysis thus allowing to distinguish symptomatic teeth in reversible and irreversible pulpitis.

  17. Prostaglandin E 2 is raised in kwashiorkor | Iputo | South African ...

    African Journals Online (AJOL)

    Plasma PGEZ and plasma proteins were measured in children admitted with oedematous kwashiorkor, and compared with PGEZ in children with cerebral palsy. Results. Plasma PGEZ was higher in children with kwashiorkor than in control children (7.25 ± 3.5 v. 3.51 ± 1.59, P < 0.01). Within the kwashiorkor study group ...

  18. E2/ER β Enhances Calcineurin Protein Degradation and PI3K/Akt/MDM2 Signal Transduction to Inhibit ISO-Induced Myocardial Cell Apoptosis

    Directory of Open Access Journals (Sweden)

    Kuan-Ho Lin

    2017-04-01

    Full Text Available Secretion of multifunctional estrogen and its receptor has been widely considered as the reason for markedly higher frequency of heart disease in men than in women. 17β-Estradiol (E2, for instance, has been reported to prevent development of cardiac apoptosis via activation of estrogen receptors (ERs. In addition, protein phosphatase such as protein phosphatase 1 (PP1 and calcineurin (PP2B are also involved in cardiac hypertrophy and cell apoptosis signaling. However, the mechanism by which E2/ERβ suppresses apoptosis is not fully understood, and the role of protein phosphatase in E2/ERβ action also needs further investigation. In this study, we observed that E2/ERβ inhibited isoproterenol (ISO-induced myocardial cell apoptosis, cytochrome c release and downstream apoptotic markers. Moreover, we found that E2/ERβ blocks ISO-induced apoptosis in H9c2 cells through the enhancement of calcineurin protein degradation through PI3K/Akt/MDM2 signaling pathway. Our results suggest that supplementation with estrogen and/or overexpression of estrogen receptor β gene may prove to be effective means to treat stress-induced myocardial damage.

  19. The role of prostaglandins in livestock production | Okon | Global ...

    African Journals Online (AJOL)

    Prostaglandins belong to the family of lipid. Soluble unsaturated hydroxyl acid containing twenty carbon (c) atoms and based on the prostanoic acid skeleton. There are two main types of Prostaglandins (PGs), the E and F series each having 3 members E1, E2, E3 and F1σ, F2σ, F3σ. The other PGs are known as secondary ...

  20. Prostaglandin E 2 (PgE 2 ) Inhibition By Crude Extracts Of Selected ...

    African Journals Online (AJOL)

    This study was undertaken to assess anti-inflammatory activity of crude extracts of Cassine transvaalensis Burtt-Davy, Clerodendrum uncinatum Schinz and Commiphora glandulosa Schinz using COX inhibition assay. Water extract of C. transvaalensis root bark (125mg/ml) exhibited a (90%) PGE2 inhibition in ...

  1. [Therapeutic abortions in the second trimestre of pregnancy with prostaglandine gel (author's transl)].

    Science.gov (United States)

    Heinzl, S

    1978-03-01

    Results of 141 therapeutic abortions in the second trimestre of pregnancy with Prostaglandine E2 gel or Prostaglandine F2 alpha gel are reported. Some required oxytocin augmentation. There were 102 legal abortions. Five cases had medical indications, 97 cases had psychosocial indications. There were 39 cases of missed abortion or intra-uterine fetal death. Prostaglandine gel was developed in 1973 by Lippert. The Prostaglandine gel was administered by catheter into the extra-amniotic space. Of all 141 cases 136 (96.5%) aborted within 36 hours. The mean administration-abortion interval was 10 h 5 min-3 h 45 min in the group with Prostaglandine E2 gel and 10 h 4 min +/- 6 h 3 min in the group with Prostaglandine E2 gel augmented with Oxytocin. In the group with Prostaglandine F2 alpha gel the mean interval was 9 h 52 min +/- 6 h 50 min and in the group with Prostaglandine F2 alpha gel augmented with oxytocin the mean interval was 16 h 17 min +/- 8 h 19 min. The mean dosage of Prostaglandine corresponded to the mean administration abortion interval time. 1/3 of the cases had side effects. The method and it's result are compared with other series.

  2. An in vitro investigation of the actions of reproductive hormones on the cervix of the ewe in the follicular stage: the effects of 17β-estradiol, oxytocin, FSH, and arachidonic acid on the cervical pathway for the synthesis of prostaglandin E2.

    Science.gov (United States)

    Falchi, L; Scaramuzzi, R J

    2015-04-01

    During the periovulatory period, the cervix of the ewe relaxes and this mechanism is thought to be mediated by oxytocin and prostaglandin E2 (PGE2) in response to increased concentrations of 17β-estradiol and perhaps FSH. The aim of the study was to determine the in vitro effects of 17β-estradiol, FSH, oxytocin, and arachidonic acid (AA) on the synthesis of PGE2 and on the expression of oxytocin receptor (OTR), cytoplasmic phospholipase A2 (cPLA2), and cyclooxygenase 2 (COX-2) in explants of cervical tissue collected from ewes in the periovulatory phase of the estrous cycle. Cervical minces from ewes in the follicular phase of the estrous cycle were cultured in supplemented Eagle's Minimum Essential Medium for 48 hours with 17β-estradiol, FSH, oxytocin, or AA. After incubation, the tissue was stored at -80 °C and the media at -20 °C. Western immunoblotting was used to determine relative levels of OTR, cPLA2, and COX-2 in cervical tissue, and the media was analyzed by RIA, to determine the concentration of PGE2. The addition of 17β-estradiol increased the concentration of PGE2 in the media (P = 0.001), the levels of COX-2 (P = 0.02) and OTR (P = 0.006) but not those of cPLA2 (P = 0.15). The addition of FSH increased the levels of COX-2 (P = 0.01) but, it had no effect on the concentration of PGE2 (P = 0.08) or on the levels of OTR (P = 0.07) and cPLA2 (P = 0.15). Oxytocin did not increase the levels of COX-2 (P = 0.38) but increased those of OTR (P = 0.001) and cPLA2 (P = 0.01) but not on the concentration of PGE2 in the media. Arachidonic acid increased the levels of cPLA2 (P = 0.01) and those of COX-2 (P = 0.02) but not the concentration of PGE2 in the media. Our findings suggest that the PGE2-mediated mechanisms of cervical relaxation in the ewe during the follicular phase are stimulated by FSH, 17β-estradiol, oxytocin, and AA. They all appear to act by inducing receptors and enzymes along the synthetic pathway for PGE2

  3. Cysteinyl leukotriene E4activates human group 2 innate lymphoid cells and enhances the effect of prostaglandin D2and epithelial cytokines.

    Science.gov (United States)

    Salimi, Maryam; Stöger, Linda; Liu, Wei; Go, Simei; Pavord, Ian; Klenerman, Paul; Ogg, Graham; Xue, Luzheng

    2017-10-01

    Group 2 innate lymphoid cells (ILC2s) are a potential innate source of type 2 cytokines in the pathogenesis of allergic conditions. Epithelial cytokines (IL-33, IL-25, and thymic stromal lymphopoietin [TSLP]) and mast cell mediators (prostaglandin D 2 [PGD 2 ]) are critical activators of ILC2s. Cysteinyl leukotrienes (cysLTs), including leukotriene (LT) C 4 , LTD 4 , and LTE 4 , are metabolites of arachidonic acid and mediate inflammatory responses. Their role in human ILC2s is still poorly understood. We sought to determine the role of cysLTs and their relationship with other ILC2 stimulators in the activation of human ILC2s. For ex vivo studies, fresh blood from patients with atopic dermatitis and healthy control subjects was analyzed with flow cytometry. For in vitro studies, ILC2s were isolated and cultured. The effects of cysLTs, PGD 2 , IL-33, IL-25, TSLP, and IL-2 alone or in combination on ILC2s were defined by using chemotaxis, apoptosis, ELISA, Luminex, quantitative RT-PCR, and flow cytometric assays. The effect of endogenous cysLTs was assessed by using human mast cell supernatants. Human ILC2s expressed the LT receptor CysLT 1 , levels of which were increased in atopic subjects. CysLTs, particularly LTE 4 , induced migration, reduced apoptosis, and promoted cytokine production in human ILC2s in vitro. LTE 4 enhanced the effect of PGD 2 , IL-25, IL-33, and TSLP, resulting in increased production of type 2 and other proinflammatory cytokines. The effect of LTE 4 was inhibited by montelukast, a CysLT 1 antagonist. Interestingly, addition of IL-2 to LTE 4 and epithelial cytokines significantly amplified ILC2 activation and upregulated expression of the receptors for IL-33 and IL-25. CysLTs, particularly LTE 4 , are important contributors to the triggering of human ILC2s in inflammatory responses, particularly when combined with other ILC2 activators. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

  4. Microneedles enhance topical delivery of 15-deoxy-Δ(12,14)-prostaglandin J2 and reduce nociception in temporomandibular joint of rats.

    Science.gov (United States)

    Macedo, Cristina G; Jain, Amit K; Franz-Montan, Michelle; Napimoga, Marcelo H; Clemente-Napimoga, Juliana T; Gill, Harvinder Singh

    2017-07-01

    The pain arising from temporomandibular disorders is often treated with opioids and agents that inhibit the immune response and are associated with substantial adverse effects and long-term risks. Thus, the development of new therapies that are safer and more effective is of great interest to patients and clinicians. 15-deoxy-Δ(12,14)-prostaglandin J2 (15d-PGJ2) is naturally produced in the human body and has anti-inflammatory properties. We have previously shown in a rat temporomandibular joint (TMJ) model that injection of 15d-PGJ2 into the rat TMJ can provide antinociceptive relief against a subsequent noxious challenge from formalin injection into the same TMJ. However, intra-TMJ injections are painful. Thus, to make the treatment patient friendly, this study aimed to evaluate whether the antinociceptive property of 15d-PGJ2 cream can be enhanced with microneedles (MNs). We found that topical application of 15d-PGJ2 cream for 15min directly on the rat TMJ skin did not induce any significant antinociceptive effect. However, if MNs were inserted in the skin for 5min, removed, and then 15d-PGJ2 cream was applied, a significant reduction in formalin-induced nociceptive behavior was observed. This reduction in nociception was comparable to an intra-TMJ injection of 15d-PGJ2. A concentration-dependent effect of 15d-PGJ2 was observed, with higher concentrations of 15d-PGJ2 in the cream showing a more durable effect up to 8h. 15d-PGJ2 cream associated with MNs also significantly reduced the release of tumor necrosis factor-α and interleukin-1 beta, which are pro-inflammatory cytokines. Our findings suggest that 15d-PGJ2 cream associated with MNs provides antinociceptive and anti-inflammatory effect, and can offer a potential patient-friendly therapeutic option for pain control related to inflammatory disorders of the TMJ. Copyright © 2017 Elsevier B.V. All rights reserved.

  5. Metabolism of prostaglandin E and of glutathione conjugate of prostaglandin A (GSH-prostaglandin A) by prostaglandin 9-ketoreductase from rabbit kidney

    DEFF Research Database (Denmark)

    Toft, B.S.; Hansen, Harald S.

    1979-01-01

    Rabbit kidney prostaglandin 9-ketoreductase was found to metabolize the glutathione conjugate of prostaglandin A (GSH-prostaglandin A). Apparent K (GSH-prostaglandin A) 13 µM and apparent K (prostaglandin E) 200 µM. The cytosolic preparation was subjected to gelfiltration and isoelectric focusing...

  6. Renin-sodium profile and renal prostaglandins in the pathogenesis ...

    African Journals Online (AJOL)

    Changes in plasma renin activity (PRA), urinary aldosterone values and prostaglandin E2, (PGE2,) and F2a (PGF2a) excretion were simultaneously assessed. Renin profiles, obtained by the plotting of PRA against the urinary excretion of sodium, showed a 62% prevalence of low-renin hypertension, the remaining 38% of ...

  7. Effect of meloxicam and meloxicam with misoprostol on serum prostaglandins and gastrointestinal permeability in healthy beagle dogs

    OpenAIRE

    Roškar Tina; Nemec Svete Alenka; Jerin A.; Butinar J.; Kobal Silvestra

    2011-01-01

    The aim of the present study was to investigate the effect of meloxicam and meloxicam with misoprostol on prostaglandin E2 (PGE2) and prostaglandin I2 (PGI2) serum concentration, as well as on gastrointestinal permeability. NSAIDs, such as meloxicam, have gastrointestinal side effects, which are due to prostaglandins depletion and topical damage. Seven adult beagle dogs were included in the study. Three different 20 days long treatments were carried out (pl...

  8. Expression of microsomal prostaglandin E synthase-1 in intestinal type gastric adenocarcinoma and in gastric cancer cell lines

    NARCIS (Netherlands)

    van Rees, Bastiaan P.; Sivula, Anna; Thorén, Staffan; Yokozaki, Hiroshi; Jakobsson, Per-Johan; Offerhaus, G. Johan A.; Ristimäki, Ari

    2003-01-01

    Gastrointestinal carcinomas synthesize elevated levels of prostaglandin E(2) (PGE(2)), which has been mechanistically linked to carcinogenesis. Recently, microsomal prostaglandin E synthase-1 (mPGES-1) was cloned, which seems to be inducible and linked to cyclooxygenase-2 (Cox-2) in the biosynthesis

  9. Development of an enhanced bovine viral diarrhea virus subunit vaccine based on E2 glycoprotein fused to a single chain antibody which targets to antigen-presenting cells

    Directory of Open Access Journals (Sweden)

    Andrea Pecora

    2015-03-01

    Full Text Available Bovine viral diarrhea virus (BVDV is an important cause of economic losses worldwide. E2 is an immunodominant protein and a promising candidate to develop subunit vaccines. To improve its immunogenicity, a truncated E2 (tE2 was fused to a single chain antibody named APCH, which targets to antigen-presenting cells. APCH-tE2 and tE2 proteins were expressed in the baculovirus system and their immunogenicity was firstly compared in guinea pigs. APCH-tE2 vaccine was the best one to evoke a humoral response, and for this reason, it was selected for a cattle vaccination experiment. All the bovines immunized with 1.5 µg of APCH-tE2 developed high levels of neutralizing antibodies against BVDV up to a year post-immunization, demonstrating its significant potential as a subunit vaccine. This novel vaccine is undergoing scale-up and was transferred to the private sector. Nowadays, it is being evaluated for registration as the first Argentinean subunit vaccine for cattle.

  10. Development of an enhanced bovine viral diarrhea virus subunit vaccine based on E2 glycoprotein fused to a single chain antibody which targets to antigen-presenting cells.

    Science.gov (United States)

    Pecora, Andrea; Malacari, Darío A; Pérez Aguirreburualde, María S; Bellido, Demian; Escribano, José M; Dus Santos, María J; Wigdorovitz, Andrés

    2015-01-01

    Bovine viral diarrhea virus (BVDV) is an important cause of economic losses worldwide. E2 is an immunodominant protein and a promising candidate to develop subunit vaccines. To improve its immunogenicity, a truncated E2 (tE2) was fused to a single chain antibody named APCH, which targets to antigen-presenting cells. APCH-tE2 and tE2 proteins were expressed in the baculovirus system and their immunogenicity was firstly compared in guinea pigs. APCH-tE2 vaccine was the best one to evoke a humoral response, and for this reason, it was selected for a cattle vaccination experiment. All the bovines immunized with 1.5 μg of APCH-tE2 developed high levels of neutralizing antibodies against BVDV up to a year post-immunization, demonstrating its significant potential as a subunit vaccine. This novel vaccine is undergoing scale-up and was transferred to the private sector. Nowadays, it is being evaluated for registration as the first Argentinean subunit vaccine for cattle. Copyright © 2014 Asociación Argentina de Microbiología. Publicado por Elsevier España, S.L.U. All rights reserved.

  11. A multi-centre audit on the use of vaginal prostaglandin for the induction of labour.

    Science.gov (United States)

    Selo-Ojeme, D; Lawal, O; Nayar, B

    2008-07-01

    To induce labour, the National Institute for Health and Clinical Excellence (NICE) guideline recommend a maximum total dose of 6 mg of prostaglandin E(2) tablet or 4 mg of prostaglandin E(2) gel for women with an unfavourable cervix (3 mg gel for all other women). To determine clinicians' compliance with these recommendations, the data of 1,424 women, who were induced at 10 obstetric units in England, were reviewed. A higher-than-recommended total dose was administered in 11% of the sample. Women who received prostaglandin tablets had a 2.5-fold greater likelihood to receive higher-than-recommended maximum total dose (OR: 2.6, 95% CI: 1.8-3.7; p audit, 1 in 9 women, who underwent induction of labour, received higher than the recommended maximum total dose of vaginal prostaglandin.

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

    Energy Technology Data Exchange (ETDEWEB)

    Kim, Sojin; Jin, Zhenhua; Lee, Goeun [Department of Physiology, School of Medicine, Kyung Hee University, Seoul 130-701 (Korea, Republic of); Park, Yong Seek; Park, Cheung-Seog [Department of Microbiology, School of Medicine, Kyung Hee University, Seoul 130-701 (Korea, Republic of); Jin, Young-Ho, E-mail: jinyh@khu.ac.kr [Department of Physiology, School of Medicine, Kyung Hee University, Seoul 130-701 (Korea, Republic of)

    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

  13. Plasma levels and urinary excretion of prostaglandins in patients with rheumatoid arthritis.

    Science.gov (United States)

    Laitinen, O; Seppalä, E; Nissilä, M; Vapaatalo, H

    1983-12-01

    No significant differences were found in plasma concentrations and urinary excretion of prostaglandin E2 (PGE2), 6-keto-prostaglandin-F1 alpha (6-keto-PGF1 alpha) and thromboxane B2 (TxB2), between rheumatoid arthritis patients and controls. However, urinary excretion of PGEe and 6-keto-PGF1 alpha tended to be greater and plasma levels of TxB2 lower in rheumatoid arthritis. Plasma concentrations and urinary excretion showed no marked circadian variation, although night or morning values were slightly lower. Plasma and urine prostaglandins do not correlate with clinical symptomatology in rheumatoid arthritis.

  14. Roles of mPGES-1, an inducible prostaglandin E synthase, in enhancement of LPS-induced lymphangiogenesis in a mouse peritonitis model.

    Science.gov (United States)

    Matsuda, Hiromi; Hosono, Kanako; Tsuru, Seri; Kurashige, Chie; Sekiguchi, Kazuki; Akira, Shizuo; Uematsu, Satoshi; Okamoto, Hirotsugu; Majima, Masataka

    2015-12-01

    Lymphangiogenesis is frequently observed during inflammation, and this inflammation-induced lymphangiogenesis (IL) is a phenomenon actively involved in the pathophysiology of inflammation. We explored the roles of an inducible prostaglandin E synthase, mPGES-1, in IL elicited by lipopolysaccharide (LPS). Peritonitis was induced in mice by intraperitoneal injection of LPS (E. coli 0111-B4; 25μg/mouse every 2days), and IL was evaluated by LYVE-1 immunostaining of whole-mount diaphragm tissues. Compared to vehicle-treated wild-type (WT) mice, lymphatics in the diaphragms of mice injected with LPS were widened and the number of LYVE-1-positive ladder-structured lymphatics increased temporally. This increase in lymphangiogenesis was accompanied by increased expression of vascular endothelial growth factor (VEGF)-C/D in the diaphragms. In mice treated with celecoxib, a cyclooxygenase-2 inhibitor, IL was suppressed with reduced expression of VEGF-C/D. This was also observed in mPGES-1 knockout mice (KO). Immunoreactive COX-2 and mPGES-1 were detected in both CD11b-positive and CD3ε-positivecells in the diaphragm. When FITC-dextran was injected into the peritoneal cavities, the amount of residual FITC-dextran was reduced significantly in WT mice injected with LPS, and this reduction was significantly decreased in mPGES-1 KO mice. The present results suggest that mPGES-1 plays a significant role in lymphangiogenesis during inflammation, and represents a novel target for controlling IL. Copyright © 2015 Elsevier Inc. All rights reserved.

  15. Measuring spatial equity and access to maternal health services using enhanced two step floating catchment area method (E2SFCA) - a case study of the Indian Sundarbans.

    Science.gov (United States)

    Vadrevu, Lalitha; Kanjilal, Barun

    2016-06-07

    Inaccessibility due to terrain and lack of transport leaves mothers travelling for long hours before reaching a facility to deliver a child. In the present article we analyzed the issue of spatial inaccessibility and inequity of maternal health services in the Indian Sundarbans where complex topography and repeated climatic adversities make access to health services very difficult. We based the article on the health-GIS study conducted in the Patharpratima Block of the Sundarbans in the year 2012. The region has 87 villages that are inhabited, of which 54 villages are in the deltaic (river locked) region and 33 villages are located in the non-deltaic region of the block. We mapped all public and private maternal health facilities and road and water transport network. For measuring inaccessibility, we use the enhanced two-step floating catchment area method (E2SFCA). For assessing inequity in spatial access, we developed an area-based socioeconomic score and constructed a concentration curve to depict inequity. We used ARC GIS 10.3.1 and Stata 11 software for our analysis. The maternal health facilities are primarily located in the non-deltaic region of the block. On an average it takes 33.81 min to reach the closest maternal health facility. Fifty-two villages out of eighty seven villages have access scores less than the score calculated using Indian Primary Health Standards. Ten villages cannot access any maternal health facility; twenty-six villages have access scores of less than one doctor for 1000 pregnant women; fifty-six villages have access scores less than the block average of 3.54. The access scores are lower among villages in the deltaic region compared to the non-deltaic region. The concentration curve is below the line of equality showing that access scores were lower among villages that were socio-economically disadvantaged. Maternal health facilities are not equitably accessible to the populations that are disadvantaged and living in the remote

  16. Enhanced robustness in acetone-butanol-ethanol fermentation with engineered Clostridium beijerinckii overexpressing adhE2 and ctfAB.

    Science.gov (United States)

    Lu, Congcong; Yu, Le; Varghese, Saju; Yu, Mingrui; Yang, Shang-Tian

    2017-11-01

    Clostridium beijerinckii CC101 was engineered to overexpress aldehyde/alcohol dehydrogenase (adhE2) and CoA-transferase (ctfAB). Solvent production and acid assimilation were compared between the parental and engineered strains expressing only adhE2 (CC101-SV4) and expressing adhE2, ald and ctfAB (CC101-SV6). CC101-SV4 showed an early butanol production from glucose but stopped pre-maturely at a low butanol concentration of ∼6g/L. Compared to CC101, CC101-SV6 produced more butanol (∼12g/L) from glucose and was able to re-assimilate more acids, which prevented "acid crash" and increased butanol production, under all conditions studied. CC101-SV6 also showed better ability in using glucose and xylose present in sugarcane bagasse hydrolysate, and produced 9.4g/L solvents (acetone, butanol and ethanol) compared to only 2.6g/L by CC101, confirming its robustness and better tolerance to hydrolysate inhibitors. The engineered strain of C. beijerinckii overexpressing adhE2 and ctfAB should have good potential for producing butanol from lignocellulosic biomass hydrolysates. Copyright © 2017 Elsevier Ltd. All rights reserved.

  17. Menstrual regulation with prostaglandin analogues.

    Science.gov (United States)

    Hagenfeldt, K; Bygdeman, M

    1981-01-01

    The development of generally applicable, simple non-surgical methods for menstrual regulation has been desired for a long time. Such an approach to fertility control depends on the availability of a suitable therapeutic agent that should be effective, reliable, simple to administer and free from disturbing side effects. The classical prostaglandins have shown the capability but are unsuitable mainly due to high incidence of side effects. Most of these drawbacks seem to be overcome when prostaglandin analogues are used; however, vaginal administration caused appreciable pain in 10-30% of women, and so severely limits self-administration of these analogues.

  18. Alum and squalene-oil-in-water emulsion enhance the titer and avidity of anti-Aβ antibodies induced by multimeric protein antigen (1-11)E2, preserving the Igg1-skewed isotype distribution.

    Science.gov (United States)

    Mantile, Francesca; Trovato, Maria; Santoni, Andrea; Barba, Pasquale; Ottonello, Simone; De Berardinis, Piergiuseppe; Prisco, Antonella

    2014-01-01

    The development of active immunotherapy for Alzheimer's disease (AD) requires the identification of immunogens that can ensure a high titer antibody response toward Aβ, while minimizing the risks of adverse reactions. Multimeric protein (1-11)E2 induces a robust and persistent antibody response to Aβ in mice, when formulated in Freund's adjuvant. The goal of this translational study was to evaluate the immunogenicity of (1-11)E2 formulated in alum (Alhydrogel 2%), or in a squalene oil-in-water emulsion (AddaVax), or without adjuvant. A IgG1-skewed isotype distribution was observed for the anti-Aβ antibodies generated in mice immunized with either the non-adjuvanted or the adjuvanted vaccine, indicating that (1-11)E2 induces a Th2-like response in all tested conditions. Both Alhydrogel 2% and AddaVax enhanced the titer and avidity of the anti-Aβ response elicited by (1-11)E2. We conclude that (1-11)E2 is a promising candidate for anti-Aβ immunization protocols that include alum or squalene-oil-in-water emulsion, or no adjuvant.

  19. Alum and squalene-oil-in-water emulsion enhance the titer and avidity of anti-Aβ antibodies induced by multimeric protein antigen (1-11E2, preserving the Igg1-skewed isotype distribution.

    Directory of Open Access Journals (Sweden)

    Francesca Mantile

    Full Text Available The development of active immunotherapy for Alzheimer's disease (AD requires the identification of immunogens that can ensure a high titer antibody response toward Aβ, while minimizing the risks of adverse reactions. Multimeric protein (1-11E2 induces a robust and persistent antibody response to Aβ in mice, when formulated in Freund's adjuvant. The goal of this translational study was to evaluate the immunogenicity of (1-11E2 formulated in alum (Alhydrogel 2%, or in a squalene oil-in-water emulsion (AddaVax, or without adjuvant. A IgG1-skewed isotype distribution was observed for the anti-Aβ antibodies generated in mice immunized with either the non-adjuvanted or the adjuvanted vaccine, indicating that (1-11E2 induces a Th2-like response in all tested conditions. Both Alhydrogel 2% and AddaVax enhanced the titer and avidity of the anti-Aβ response elicited by (1-11E2. We conclude that (1-11E2 is a promising candidate for anti-Aβ immunization protocols that include alum or squalene-oil-in-water emulsion, or no adjuvant.

  20. Search for prostaglandin A1 in onion.

    Science.gov (United States)

    Attrep, K A; Mariani, J M; Attrep, M

    1973-08-01

    Thus far there have been no reports that prostaglandins have been isolated from plant materials. Numerous plant materials were screened using this layer chromatographic technique to determine if such materials could contain prostaglandins. Following this initial screening, onions were selected for further study. A fatty acid fraction separated from yellow onion was subjected to thin layer chromatographic techniques, UV and IR spectrophotometric analyses. This silicic acid-chromatographed fraction corresponded to the prostaglandin A1 fraction. Preliminary identification strongly suggested that this component of onions appeared to be a prostaglandin (PGA1) or a prostaglandin-like compound.

  1. Hyperthyroidism advances luteolysis in the pregnant rat through changes in prostaglandin balance.

    Science.gov (United States)

    Navas, Paola B; Motta, Alicia B; Hapon, María B; Jahn, Graciela A

    2011-10-01

    To investigate the underlying mechanisms implicated in the premature luteolysis induced by hyperthyroidism in pregnant rats. Experimental basic study. Research institute. Groups of 6-8 adult female Wistar rats were injected SC daily with T(4) (0.25 mg/kg) or vehicle, starting 8 days before mating, and killed by decapitation on days 19 (G19), 20 (G20), and 21 (G21) of pregnancy. Corpora lutea and truncal blood of control and hyperthyroid rats were obtained. Circulating and intraluteal hormones were determined by using RIA and luteal messenger RNA (mRNA) expression of enzymes and factors involved in P synthesis and metabolism by reverse transcriptase-polymerase chain reaction. 20α-Hydroxysteroid dehydrogenase (20αHSD) mRNA and protein expression was also determined by quantitative reverse transcriptase-polymerase chain reaction and Western blot. Hyperthyroidism advanced luteolysis and 20αHSD expression induction by one day without changes in enzymes involved in P synthesis, decreased circulating E(2) and luteal estrogen receptor beta, and increased luteal prostaglandin F(2α) on G19 and G20 and prostaglandin E(2) on G19, while decreasing it on G20. Thus, decreased estrogenic influence and high prostaglandin F(2α)/prostaglandin E(2) ratio favors premature induction of 20αHSD on hyperthyroid rats. Hyperthyroidism affects luteolysis in pregnant rats through alterations in luteal prostaglandin balance and decreased luteotrophic factors favoring the luteolytic action of prostaglandin F(2α) that induces premature 20αHSD expression that in turn advances circulating P fall and delivery. Copyright © 2011 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.

  2. Influence of some prostaglandins on DNA synthesis and DNA excision repair in mouse spleen cells in vitro

    Energy Technology Data Exchange (ETDEWEB)

    Egg, D.; Altmann, H.; Guenther R.; Klein W.; Kocsis, F.

    1978-03-01

    In vitro experiments were performed on mouse spleen cells to establish possible influences of some naturally occurring prostaglandins on DNA synthesis and DNA excision repair. The prostaglandins A1, B1, E1, E2, and F2 alpha were tested in concentrations of lopg, 5 ng and 2.5 microgram per ml cell suspension. DNA synthesis was significantly increased by PgF2 alpha in all the three concentrations tested, while the other tested prostaglandins were essentially ineffective. DNA excision repair was significantly inhibited by PgE1 and PgE2 at 5 ng/ml and at 2.5 microgram/ml but increased by PgF2 alpha in the two lower concentrations. The rejoining of DNA-strand breaks after gamma-irradiation was slightly reduced by PgE1, PgE2 and PgF2 alpha at 2.5 microgram/ml.

  3. Prostaglandin Hsynthase immunoreactivity in human gut. An immunohistochemical study

    DEFF Research Database (Denmark)

    Mikkelsen, Hanne Birte; Rumessen, Jüri Johannes; Qvortrup, Klaus

    1991-01-01

    Anatomy, prostaglandin H-synthase, smooth muscle cells, intestine, muscularis externa, immunohistochemistry......Anatomy, prostaglandin H-synthase, smooth muscle cells, intestine, muscularis externa, immunohistochemistry...

  4. The Papillomavirus E2 proteins

    Energy Technology Data Exchange (ETDEWEB)

    McBride, Alison A., E-mail: amcbride@nih.gov

    2013-10-15

    The papillomavirus E2 proteins are pivotal to the viral life cycle and have well characterized functions in transcriptional regulation, initiation of DNA replication and partitioning the viral genome. The E2 proteins also function in vegetative DNA replication, post-transcriptional processes and possibly packaging. This review describes structural and functional aspects of the E2 proteins and their binding sites on the viral genome. It is intended to be a reference guide to this viral protein. - Highlights: • Overview of E2 protein functions. • Structural domains of the papillomavirus E2 proteins. • Analysis of E2 binding sites in different genera of papillomaviruses. • Compilation of E2 associated proteins. • Comparison of key mutations in distinct E2 functions.

  5. Prostaglandins as PPARγ Modulators in Adipogenesis

    Directory of Open Access Journals (Sweden)

    Ko Fujimori

    2012-01-01

    Full Text Available Adipocytes and fat cells play critical roles in the regulation of energy homeostasis. Adipogenesis (adipocyte differentiation is regulated via a complex process including coordinated changes in hormone sensitivity and gene expression. PPARγ is a ligand-dependent transcription factor and important in adipogenesis, as it enhances the expression of numerous adipogenic and lipogenic genes in adipocytes. Prostaglandins (PGs, which are lipid mediators, are associated with the regulation of PPARγ function in adipocytes. Prostacyclin promotes the differentiation of adipocyte-precursor cells to adipose cells via activation of the expression of C/EBPβ and δ. These proteins are important transcription factors in the activation of the early phase of adipogenesis, and they activate the expression of PPARγ, which event precedes the maturation of adipocytes. PGE2 and PGF2α strongly suppress the early phase of adipocyte differentiation by enhancing their own production via receptor-mediated elevation of the expression of cycloxygenase-2, and they also suppress the function of PPARγ. In contrast, PGD2 and its non-enzymatic metabolite, Δ12-PGJ2, activate the middle-late phase of adipocyte differentiation through both DP2 receptors and PPARγ. This paper focuses on potential roles of PGs as PPARγ modulators in adipogenesis and regulators of obesity.

  6. Loss of Prostaglandin E2-induced Extra Cortical Bone after its Withdrawal in Rats

    Science.gov (United States)

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

    1992-01-01

    The object of this study was to determine the fate of PGE2-induced new cortical bone mass after withdrawal of PGE2 administration. Seven-month-old male Sprague-Dawley rats were given subcutaneous injections of 1, 3 and 6 mg PGE2/kg/day for 60 days and then withdrawn for 60 and 120 days (on/off treatment). Histomorphometric analyses were performed on double-fluorescent-labeled undecalcified tibial shaft sections (proximal to the tibiofibular junction). In a previous report we showed that after 60, 120 and 180 days of daily PGE2 (on)treatment, a new steady state was achieved marked by increased total bone area (+ 16%, +25% and + 34% with 1, 3 and 6 mg PGE2/kg/day) when compared to age-matched controls. The continuous PGE2 treatment stimulated periosteal and endocortical lamellar bone formation, activated endocortical woven trabecular bone formation and intracortical bone resorption. These responses increased cortical bone mass since the bone formation exceeded bone resorption. The current study showed that after withdrawal of PGE2 for 60 and 120 days, the extra endocortical bone, which was induced by the first 60-days treatment, was resorbed, but the new subperiosteal bone persisted resulting in a tibial shaft with larger cross sectional and marrow areas. Despite that, there was still the same amount of bone mass in these shafts as in age-related controls. A new steady state was achieved after 60 days of withdrawal, in which the bone mass and bone formation activity approximated that of age-related controls. It was concluded that maintaining the extra PGE2-induced cortical bone mass depends on continuous daily administration of PGE2.

  7. Partial Loss of Anabolic Effect of Prostaglandin E2 on Bone After Its Withdrawal in Rats

    Science.gov (United States)

    Ke, H. Z.; Li, X. J.; Jee, Webster S. S.

    1991-01-01

    The object of this study was to determine the fate of PGE(sub 2)-induced new bone mass after withdrawal of PGE(sub 2) administration. Seven-month-old male Sprague-Dawley rats were given subcutaneous injections of 1, 3, and 6 mg PGE(sub 2)/kg/d for 60 days and then withdrawn for 60 and 120 days. Histomorphometric analyses were performed on double fluorescent labeled undecalcified proximal tibial bone specimens. After 60 days of PGE(sub 2) treatment, a new steady state of increased trabecular bone area (+67% and +81% with 3 and 6 mg PGE(sub 2)/kg/d) from woven bone and stimulated lamellar bone formation, elevated bone turnover, and shortened remodeling periods were achieved compared to age-matched controls. In contrast, after 60 and 120 days withdrawal of PGE(sub 2), a new steady state characterized by less trabecular bone area (+40% to +60% of controls with 3 and 6 mg/kg/d doses), normal lamellar bone formation, no woven bone formation from controls, and eroded surface greater than those seen in controls and previously in 60-day PGE(sub 2) treated rats. The decrease in new bone mass after withdrawal of PGE(sub 2) was due to a further elevation of bone resorption above that induced by the PGE(sub 2) treatment and a reduction in PGE(sub 2) stimulated bone formation activities. Although there is more trabecular bone than in controls after 120 days' withdrawal of PGE(sub 2), we postulate that the skeletal adaptation to mechanical usage will eventually reduce the bone mass to control levels. Thus, it is conservative to conclude that the anabolic effect of PGE(sub 2) was dependent upon continuous daily administration of PGE(sub 2) in these older rats.

  8. Neonatal respiratory control : inspiration, inflammation and the prostaglandin E2 pathway

    OpenAIRE

    Siljehav, Veronica

    2014-01-01

    Immature or deficient autonomic control is a common problem in infants born at a premature age, and is of central importance in apneas. The pre- and perinatal development of the brainstem neural circuits that control autonomic functions is vital for survival after birth and for the regulation of breathing movements. Children with immature brainstem respiratory control have periods of irregular breathing with potential detrimental apneas that are increased during sleep and in...

  9. Effects of nicotine on differentiation, prostaglandin E2, and nitric oxide production in cementoblasts

    Directory of Open Access Journals (Sweden)

    Yi-Juai Chen

    2015-12-01

    Conclusion: Our results suggest that nicotine could inhibit cementoblast growth and differentiation. In addition, nicotine could also induce the inflammatory effects by the augmentation of PGE2 secretion and iNOS/NO expression.

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

    Czech Academy of Sciences Publication Activity Database

    Hu, XQ.; Cifarelli, V.; Sun, SS.; Kuda, Ondřej; Abumrad, N. A.; Su, X.

    2016-01-01

    Roč. 57, č. 4 (2016), s. 663-673 ISSN 0022-2275 R&D Projects: GA MŠk(CZ) LH14040 Institutional support: RVO:67985823 Keywords : adipose tissue * cyclooxygenase * eicosanoids * extracellular signal-regulated kinase * fatty acid * inflammation * lipase Subject RIV: FB - Endocrinology, Diabetology, Metabolism, Nutrition Impact factor: 4.810, year: 2016

  11. in vivo inhibition of prostaglandin e2 production by crude aqueous ...

    African Journals Online (AJOL)

    extent, its anti-inflammatory activity, viz., suppression of pain (analgesia), reversal of vasodilatation, de- creased capillary permeability and inhibition of migra- tion of inflammatory cells. CONCLUSION. Carrageenin-induced increase in plasma PGE2 concen- tration was reduced by the extract, indomethacin and nimesulide.

  12. The papillomavirus E2 proteins.

    Science.gov (United States)

    McBride, Alison A

    2013-10-01

    The papillomavirus E2 proteins are pivotal to the viral life cycle and have well characterized functions in transcriptional regulation, initiation of DNA replication and partitioning the viral genome. The E2 proteins also function in vegetative DNA replication, post-transcriptional processes and possibly packaging. This review describes structural and functional aspects of the E2 proteins and their binding sites on the viral genome. It is intended to be a reference guide to this viral protein. Published by Elsevier Inc.

  13. Hypoxia activates the cyclooxygenase-2-prostaglandin E synthase axis.

    Science.gov (United States)

    Lee, James J; Natsuizaka, Mitsuteru; Ohashi, Shinya; Wong, Gabrielle S; Takaoka, Munenori; Michaylira, Carmen Z; Budo, Daniela; Tobias, John W; Kanai, Michiyuki; Shirakawa, Yasuhiro; Naomoto, Yoshio; Klein-Szanto, Andres J P; Haase, Volker H; Nakagawa, Hiroshi

    2010-03-01

    Hypoxia-inducible factors (HIFs), in particular HIF-1alpha, have been implicated in tumor biology. However, HIF target genes in the esophageal tumor microenvironment remain elusive. Gene expression profiling was performed upon hypoxia-exposed non-transformed immortalized human esophageal epithelial cells, EPC2-hTERT, and comparing with a gene signature of esophageal squamous cell carcinoma (ESCC). In addition to known HIF-1alpha target genes such as carbonic anhydrase 9, insulin-like growth factor binding protein-3 (IGFBP3) and cyclooxygenase (COX)-2, prostaglandin E synthase (PTGES) was identified as a novel target gene among the commonly upregulated genes in ESCC as well as the cells exposed to hypoxia. The PTGES induction was augmented upon stabilization of HIF-1alpha by hypoxia or cobalt chloride under normoxic conditions and suppressed by dominant-negative HIF-1alpha. Whereas PTGES messenger RNA (mRNA) was negatively regulated by normoxia, PTGES protein remained stable upon reoxygenation. Prostaglandin E(2) (PGE(2)) biosynthesis was documented in transformed human esophageal cells by ectopic expression of PTGES as well as RNA interference directed against PTGES. Moreover, hypoxia stimulated PGE(2) production in a HIF-1alpha-dependent manner. In ESCC, PTGES was overexpressed frequently at the mRNA and protein levels. Finally, COX-2 and PTGES were colocalized in primary tumors along with HIF-1alpha and IGFBP3. Activation of the COX-2-PTGES axis in primary tumors was further corroborated by concomitant upregulation of interleukin-1beta and downregulation of hydroxylprostaglandin dehydrogenase. Thus, PTGES is a novel HIF-1alpha target gene, involved in prostaglandin E biosynthesis in the esophageal tumor hypoxic microenvironment, and this has implications in diverse tumors types, especially of squamous origin.

  14. Peripheral haemodynamic effects of inhibition of prostaglandin synthesis in congestive heart failure and interactions with captopril.

    Science.gov (United States)

    Townend, J. N.; Doran, J.; Lote, C. J.; Davies, M. K.

    1995-01-01

    OBJECTIVES--To investigate the role of prostaglandins in maintaining circulatory homoeostasis in chronic heart failure and the hypothesis that an increase in vasodilatory prostaglandin synthesis may contribute to the actions of angiotensin converting enzyme inhibitors in heart failure. DESIGN--Randomised, double blind, placebo controlled studies. Cardiac output and renal and limb blood flow were measured after oral indomethacin 50 mg or placebo followed by "open" intravenous infusion of prostaglandin E2 (study A). In a second study the same measurements were made after oral indomethacin 50 mg or placebo was given 30 min before "open" captopril (study B). METHODS--Blood pressure was measured using a mercury sphygmomanometer. Cardiac output was determined by Doppler interrogation of blood flow in the ascending aorta and echocardiographic measurement of aortic root diameter. Renal blood flow was calculated from the effective renal plasma flow measured by p-aminohippurate clearance and the haematocrit, and glomerular filtration rate by endogenous creatinine clearance. Limb blood flow was measured by venous occlusion plethysmography using mercury in silastic strain gauges. The concentration of plasma prostaglandin E2 was measured by radioimmunoassay. SETTING--University department of cardiovascular medicine. PATIENTS--12 patients with chronic stable heart failure before starting treatment with angiotensin converting enzyme inhibitors. RESULTS--Indomethacin resulted in adverse effects on cardiac output, systemic vascular resistance, renal blood flow, glomerular filtration, urinary sodium excretion, and calf vascular resistance. Changes were reversed with infusion of prostaglandin E2. Pretreatment with indomethacin resulted in the attenuation of the acute increase in cardiac output and decrease in systemic vascular resistance that occurred with captopril. Similarly, an increase in renal blood flow with captopril was attenuated by indomethacin. CONCLUSIONS--The acute

  15. Cyclo-oxygenase-2 mediated prostaglandin release regulates blood flow in connective tissue during mechanical loading in humans

    DEFF Research Database (Denmark)

    Langberg, H; Boushel, Robert Christopher; Skovgaard, D

    2003-01-01

    prior to the experiment) or COX unspecific (n = 8, indomethacin 100 mg (12 and 1 h pre-experiment) and acetyl salicylic acid 500 mg day-1 for 3 days pre-experiment). Prostaglandin E2 (PGE2) concentration was determined by microdialysis and blood flow by 133Xe washout. In C, interstitial PGE2 rose from...

  16. Isolation from Cannabis sativa L. of cannflavin--a novel inhibitor of prostaglandin production.

    Science.gov (United States)

    Barrett, M L; Gordon, D; Evans, F J

    1985-06-01

    The isolation from Cannabis sativa L. of an inhibitor of prostaglandin (PG) E2 production by cultured rheumatoid synovial cells is described. This agent, for which the name Cannflavin has been coined, is distinct from cannabinoids on the basis of isolation procedure, preliminary structural analysis and biological properties. The activity of Cannflavin has been compared with several established anti-inflammatory drugs and the major cannabinoids.

  17. Experimental ileitis alters prostaglandin biosynthesis in mesenteric lymphatic and blood vessels.

    Science.gov (United States)

    Rehal, Sonia; von der Weid, Pierre-Yves

    2015-01-01

    Prostaglandins are important mediators responsible for many changes that occur during the inflammatory response. Specifically, in inflammatory bowel disease (IBD), prostaglandins are key players in maintenance of blood flow and mucosal defense. In blood vessels, prostaglandins modulate and inhibit transmigration. In lymphatic vessels, on the other hand, prostaglandin E2 (PGE2) and prostacyclin (PGI2) have been shown to potently inhibit lymphatic contractility. Inhibition of lymphatic contractility could impair proper tissue fluid drainage during inflammation, consequently leading to the submucosal oedema observed in IBD. Alterations in production of PGE2 and PGI2 during inflammation could have severe implications on lymphatic and vascular functions within the small intestine. Using the 2,4,6-trinitrobenzenesulfonic acid (TNBS)-induced ileitis guinea pig and rat models, we assessed by quantitative PCR changes in mRNA transcript of enzymes and receptors involved in the production and actions of prostaglandins in mesenteric lymphatic and blood vessels as well as in the affected ileum. Furthermore, we also assessed lymphatic tissue levels of PGE2 and PGI2 during inflammation. We observed significant changes in lymphatic mRNA expression of COX-1, COX-2, MPGES-1, PGIS, EP4 and IP and increases in PGE2 and PGI2 in tissues of TNBS-treated animals. Changes in mRNA in blood vessels from TNBS-treated animals included differences in COX-1, COX-2, MPGES-1, PGIS, EP1, EP2 and IP expression. Prostaglandin metabolites are differentially regulated in both lymphatic and blood vessels during intestinal inflammation. Copyright © 2014 Elsevier Inc. All rights reserved.

  18. Mechanism of inhibition of herpes simplex virus replication by delta 7-prostaglandin A1 and delta 12-prostaglandin J2.

    Science.gov (United States)

    Yamamoto, N; Fukushima, M; Tsurumi, T; Maeno, K; Nishiyama, Y

    1987-08-14

    We studied the effect of prostaglandins (PGs) A1, delta 7-A1, A2, D2, E1, E2, F2 alpha, J2 and delta 12-J2 on the replication of herpes simplex virus type 2 (HSV-2). Of nine PGs we tested, delta 7-PGA1 was found to have the most potent inhibitory effect; 50% inhibitory dose (ID50) was 0.35 microgram/ml in the plaque reduction assays and HSV-2 induced protein synthesis was strongly suppressed at 0.5 microgram/ml whereas at this dose, the protein synthesis of uninfected cells was not inhibited. Dot blot hybridization analysis revealed that delta 7-PGA1 and delta 12-PGJ2 inhibited the primary transcription of HSV-2. Thus we suggest that those PGs are primarily active at the level of mRNA synthesis.

  19. High dietary niacin may increase prostaglandin formation but does not increase tumor formation in ApcMin/+ mice

    OpenAIRE

    Kwong, Alan M; Tippin, Brigette L.; Materi, Alicia M.; Buslon, Virgilio S; French, Samuel W; Lin, Henry J.

    2011-01-01

    High doses of niacin (nicotinic acid) used to treat dyslipidemias cause flushing, due to high levels of prostaglandin D2 (PGD2). GPR109A, a G-protein coupled receptor, triggers the flushing in the skin. In addition to boosting PGD2, niacin binding to GPR109A activates the entire prostanoid cascade. We found that GPR109A occurs throughout the gastrointestinal tract. Mice that alternated between a 1% niacin diet and a control diet had higher urinary prostaglandin E2 (PGE2) metabolite levels whe...

  20. Lubiprostone Increases Small Intestinal Smooth Muscle Contractions Through a Prostaglandin E Receptor 1 (EP1)-mediated Pathway.

    Science.gov (United States)

    Chan, Walter W; Mashimo, Hiroshi

    2013-07-01

    Lubiprostone, a chloride channel type 2 (ClC-2) activator, was thought to treat constipation by enhancing intestinal secretion. It has been associated with increased intestinal transit and delayed gastric emptying. Structurally similar to prostones with up to 54% prostaglandin E2 activity on prostaglandin E receptor 1 (EP1), lubiprostone may also exert EP1-mediated procontractile effect on intestinal smooth muscles. We investigated lubiprostone's effects on intestinal smooth muscle contractions and pyloric sphincter tone. Isolated murine small intestinal (longitudinal and circular) and pyloric tissues were mounted in organ baths with modified Krebs solution for isometric recording. Basal muscle tension and response to electrical field stimulation (EFS; 2 ms pulses/10 V/6 Hz/30 sec train) were measured with lubiprostone (10(-10)-10(-5) M) ± EP1 antagonist. Significance was established using Student t test and P Lubiprostone had no effect on the basal tension or EFS-induced contractions of longitudinal muscles. With circular muscles, lubiprostone caused a dose-dependent increase in EFS-induced contractions (2.11 ± 0.88 to 4.43 ± 1.38 N/g, P = 0.020) that was inhibited by pretreatment with EP1 antagonist (1.69 ± 0.70 vs. 4.43 ± 1.38 N/g, P = 0.030). Lubiprostone had no effect on circular muscle basal tension, but it induced a dose-dependent increase in pyloric basal tone (1.07 ± 0.01 to 1.97 ± 0.86 fold increase, P lubiprostone caused a dose-dependent and EP1-mediated increase in contractility of circular but not longitudinal small intestinal smooth muscles, and in basal tone of the pylorus. These findings suggest another mechanism for lubiprostone's observed clinical effects on gastrointestinal motility.

  1. Prostaglandin F2 alpha stimulates phosphatidylinositol 4,5-bisphosphate hydrolysis and mobilizes intracellular Ca2+ in bovine luteal cells

    Energy Technology Data Exchange (ETDEWEB)

    Davis, J.S.; Weakland, L.L.; Weiland, D.A.; Farese, R.V.; West, L.A.

    1987-06-01

    The present studies were conducted to determine whether prostaglandin F2 alpha (PGF2 alpha) stimulates the production of ''second messengers'' derived from inositol phospholipid hydrolysis and increases intracellular free Ca2+ ((Ca2+)i) in isolated bovine luteal cells. PGF2 alpha provoked rapid (10 sec) and sustained (up to 60 min) increases in the levels of inositol mono-, bis-, and trisphosphates (InsP, InsP2, and InsP3, respectively). InsP3 was formed more rapidly than InsP2 or InsP after PGF2 alpha treatment. In addition, PGF2 alpha increased inositol phospholipid turnover, as evidenced by increased /sup 32/PO/sub 4/ incorporation into phosphatidic acid and phosphatidylinositol. LiCl (1-20 mM) enhanced inositol phosphate accumulation in response to PGF2 alpha. Maximal increases in InsP3 occurred at 1 microM PGF2 alpha, with half-maximal stimulation occurring at 36 nM. The acute effects of PGF2 alpha on InsP3 levels were independent of reductions in extracellular calcium. Prostaglandins E1 and E2 also stimulated increases in inositol phosphate levels, albeit to a lesser extent. PGF2 alpha also induced rapid and concentration-dependent increases in (Ca2+)i as measured by quin-2 fluorescence. The PGF2 alpha-induced increases in (Ca2+)i were maximal within 30 sec (approximately 2- to 3-fold), and (Ca2+)i remained elevated for 8-10 min. The PGF2 alpha-induced increases in (Ca2+)i were also independent of extracellular calcium. These findings demonstrate that the action of PGF2 alpha is coupled to the phospholipase C-InsP3 and diacylglycerol second messenger system in the corpus luteum.

  2. If e2m (x

    Indian Academy of Sciences (India)

    (x+y) = 0 should be. If e2m(x+ y) dx dy = 0. R. Acknowledgements. Resonance gratefully acknowledges the help received from the following individuals: Jayant Rao, V Pati, C R Pranesachar and B J Venkatachala. India. Third World Countries.

  3. a randomised controlled trial oftwo prostaglandin regitnens

    African Journals Online (AJOL)

    visualised and stabilised with a swab holder. Three syringes each containing 0,5 mg PGE, gel were used in immediate succession to instil the prostaglandin through the cervix. The other group received intra-amniotic. PGF,cx_ Aspiration of 2 ml of amniotic fluid trans- abdominally to confirm correct position of the needle.

  4. THE ROLE OF PROSTAGLANDINS IN LIVESTOCK PRODUCTION

    African Journals Online (AJOL)

    2015-05-05

    May 5, 2015 ... important regulators of female productive functions (ovulation, uterine receptivity, Implantation and parturition) and associated with ... reproductive processes, hence, this paper seeks to review the role of Prostaglandins which is exploited in livestock .... ovarian oxytocin form part of the physiological stimulus.

  5. Expression of prostaglandin synthases (pgds and pges) during zebrafish gonadal differentiation

    DEFF Research Database (Denmark)

    Jørgensen, Anne; Nielsen, John E; Nielsen, Betina Frydenlund

    2010-01-01

    The present study aimed at elucidating whether the expression pattern of the membrane bound form of prostaglandin E2 synthase (pges) and especially the lipocalin-type prostaglandin D2 synthase (pgds) indicates involvement in gonadal sex differentiation in zebrafish as has previously been found....... In this study, a sexually dimorphic expression of pgds was found in gonads of adult zebrafish with expression in testis but not in ovaries. To determine whether the sex-specific expression pattern of pgds was present in gonads of juvenile zebrafish and therefore could be an early marker of sex in zebrafish, we...... microdissected gonads from four randomly selected individual zebrafish for every second day in the period 2-20 days post hatch (dph) and 0-1 dph. The temporal expression of pgds and pges was investigated in the microdissected gonads, however, no differential expression that could indicate sex-specific difference...

  6. Role of renal prostaglandins in the modulation of cisplatinum nephrotoxicity

    Energy Technology Data Exchange (ETDEWEB)

    Noordewier, B.; Danielson, P.W.; Noordewier, E.R.; Bredehoeft, S.J.

    1986-03-01

    Indomethacin (I) inhibition of renal prostaglandin (PG) synthesis potentiates the nephorotoxic effects of cis-dichlorodiamine platinum (Cis-Pt). The purpose of this study was to determine if this potentiation was unique to I or was shared by other inhibitors of PG synthesis. Male Fischer 344 rats were fed a purified diet replete (Repl) or deplete (Depl) in sodium. After 5 days on this diet, the rats were given saline or cis-Pt (10 mg/kg, iv) with or without tolmetin (Tol) (2 x 10 mg/kg, ip then iv). Toxicity was assessed 2 days after the injections. Cis-Pt given alone increased BUN and plasma creatinine (Cr) in both Depl (BUN = 43 mg/dl, Cr = 1.3 mg/dl) and Repl (BUN = 45, Cr = 1.3) groups. Tol produced a moderate increase in cis-Pt toxicity in Repl rats (BUN = 62, Cr = 1.5) and a marked increase in Depl rats (BUN = 138, Cr = 2.6). These biochemical changes were accompanied by concurrent changes in renal histology. Rats given cis-Pt alone had focal areas of toxicity marked by evidence of necrosis and vacuolation. Tol enhancement of toxicity was characterized by an increased extent of damage with the appearance of tubular protein and some mineralization. The effects of Tol mimic those of I indicating a role for renal prostaglandins in the renal toxicity of Cis-Pt.

  7. A study to compare circulating flunixin, meloxicam and gabapentin concentrations with prostaglandin E₂ levels in calves undergoing dehorning.

    Science.gov (United States)

    Fraccaro, E; Coetzee, J F; Odore, R; Edwards-Callaway, L N; Kukanich, B; Badino, P; Bertolotti, L; Glynn, H; Dockweiler, J; Allen, K; Bergamasco, L

    2013-08-01

    The purpose of this study was to investigate the pharmacokinetics of intravenous flunixin (2.2 mg/kg b.w.), oral meloxicam (1mg/kg b.w.), oral gabapentin (15 mg/kg b.w.) alone or co-administrated with meloxicam as well as the effects of these compounds on prostaglandin E2 (PGE2) synthesis in calves subjected to surgical dehorning. Plasma samples collected up to 24h after drug administration were analyzed by liquid chromatography/mass spectrometry, whereas blood PGE2 levels were measured by immunoenzymatic assay. In plasma, the terminal half-live of flunixin, meloxicam and gabapentin were 6.0 h (range, 3.4-11.0 h), 16.7h (range, 13.7-21.3h) and 15.3h (range, 11-32.9h), respectively. The co-administration of single doses of gabapentin and meloxicam did not seem to affect the pharmacokinetic profile of the two drugs except for gabapentin that reached significantly (Pflunixin-treated animals compared with control calves. Moreover, circulating log PGE2 concentrations were inversely proportional to log flunixin concentrations (R(2)=0.75; P<0.0001). None of the other drugs significantly affected blood PGE2 levels. Further assessment of oral meloxicam and gabapentin in established pain models is required to formulate science based analgesic recommendations to enhance animal well-being after dehorning. Copyright © 2013 Elsevier Ltd. All rights reserved.

  8. Novel insights into the mechanisms of pregnancy establishment: regulation of prostaglandin synthesis and signaling in the pig.

    Science.gov (United States)

    Waclawik, Agnieszka

    2011-09-01

    Ovarian progesterone induces essential changes leading to a temporary state of uterine receptivity for conceptus implantation. Estrogens secreted by the porcine conceptus on days 11 and 12 of pregnancy provide the initial signal for maternal recognition of pregnancy and maintenance of a functional corpus luteum (CL) for continued production of progesterone. As prostaglandins F(2)(α) (PGF(2)(α)) and E(2) (PGE(2)) exert opposing actions on the CL, a tight control over their synthesis and secretion is critical either for the initiation of luteolysis or maintenance of pregnancy. One of the supportive mechanisms by which conceptus inhibits luteolysis is changing PG synthesis in favor of luteoprotective PGE(2). Conceptus PGE(2) could be amplified by PGE(2) feedback loop in the endometrium. In pigs, as in other species, implantation and establishment of pregnancy is associated with upregulation of expression of proinflammatory factors, which include cytokines, growth factors, and lipid mediators. The conceptus produces inflammatory mediators: interferon γ and interferon δ, interleukins IL1B and IL6, and PGs, which probably activate inflammatory pathways in the endometrium. The endometrium responds to these embryonic signals by enhancing further progesterone-induced uterine receptivity. Understanding the mechanisms of pregnancy establishment is required for translational research to increase reproductive efficiencies and fertility in humans and animals.

  9. Gastroduodenal mucosal prostaglandin generation in patients with Helicobacter pylori before and after treatment with bismuth subsalicylate.

    Science.gov (United States)

    Avunduk, C; Suliman, M; Gang, D; Polakowski, N; Eastwood, G L

    1991-04-01

    To determine whether Helicobacter pylori has an effect on gastroduodenal mucosal prostaglandin generation, mucosal biopsies were obtained from the gastric body, antrum, and duodenal bulb of 30 patients who were undergoing upper gastrointestinal endoscopy for clinical indications. One biopsy from the gastric body and one from the antrum were tested for urease activity (urea broth) and one biopsy from each area including the duodenum was processed for histology. Two other biopsies form each area were incubated and the accumulation of prostaglandin E2 and 6-keto prostaglandin F1 alpha in the incubation medium was measured by radioimmunoassay. Twelve of the 17 H. pylori-positive patients and seven of the 13 H. pylori-negative patients agreed to take bismuth subsalicylate (Pepto-Bismol) two tablets four times a day for four weeks. One week after treatment, these patients again underwent endoscopy and the above studies. This study indicates that: (1) mucosal PGE2 generation may be increased in the duodenum, gastric body, and antrum in H. pylori-positive patients compared to H. pylori-negative patients, and (2) treatment with bismuth subsalicylate for four weeks results in reduction of mucosal PGE2 in the duodenum, gastric body, and antrum of H. pylori-positive patients and fails to eradicate H. pylori or reduce gastric inflammation.

  10. Multiple roles of the prostaglandin D2 signaling pathway in reproduction.

    Science.gov (United States)

    Rossitto, Moïra; Ujjan, Safdar; Poulat, Francis; Boizet-Bonhoure, Brigitte

    2015-01-01

    Prostaglandins signaling molecules are involved in numerous physiological processes. They are produced by several enzyme-limited reactions upon fatty acids, which are catalyzed by two cyclooxygenases and prostaglandin synthases. In particular, the prostaglandins E2 (PGE2), D2 (PGD2), and F2 (PGF2 α) have been shown to be involved in female reproductive mechanisms. Furthermore, widespread expression of lipocalin- and hematopoietic-PGD2 synthases in the male reproductive tract supports the purported roles of PGD2 in the development of both embryonic and adult testes, sperm maturation, and spermatogenesis. In this review, we summarize the putative roles of PGD2 signaling and the roles of both PGD2 synthases in testicular formation and function. We review the data reporting the involvement of PGD2 signaling in the differentiation of Sertoli and germ cells of the embryonic testis. Furthermore, we discuss the roles of lipocalin-PGD2 synthase in steroidogenesis and spermatogenesis, in terms of lipid molecule transport and PGD2 production. Finally, we discuss the hypothesis that PGD2 signaling may be affected in certain reproductive diseases, such as infertility, cryptorchidism, and testicular cancer. © 2015 Society for Reproduction and Fertility.

  11. Plasmodium falciparum Produces Prostaglandins that are Pyrogenic, Somnogenic, and Immunosuppressive Substances in Humans

    OpenAIRE

    Kilunga Kubata, B.; Eguchi, Naomi; Urade, Yoshihiro; Yamashita, Kouwa; Mitamura, Toshihide; Tai, Kumiko; Hayaishi, Osamu; Horii, Toshihiro

    1998-01-01

    Plasmodium falciparum causes the most severe form of human malaria, which kills ∼1.5–2.7 million people every year, but the molecular mechanisms underlying the clinical symptoms and the host–parasite interaction remain unclear. We show here that P. falciparum produces prostaglandins (PGs) D2, E2, and F2α. After incubation with 1 mM arachidonic acid (AA), cell homogenates of P. falciparum produced PGs as determined by enzyme immunoassay and gas chromatography–selected ion monitoring. PG produc...

  12. Intracerebral administration of Mycoplasma fermentans produces sickness behavior: role of prostaglandins.

    Science.gov (United States)

    Yirmiya, R; Barak, O; Avitsur, R; Gallily, R; Weidenfeld, J

    1997-02-21

    Mycoplasmas are small microorganisms, which cause various diseases in animals and in humans, activate the immune system, and induce the release of various cytokines. Some of the effects of mycoplasmas are mediated by the CNS. Moreover, Mycoplasma fermentans (MF) has recently been found in the brain, as well as other tissues of some AIDS patients, who usually display severe neurobehavioral disturbances. The present study was designed to examine the behavioral effects of central administration of MF, and the role of prostaglandins in mediating these effects. In one set of experiments, rats were injected intracerebroventricularly (i.c.v.) with either saline or a dose of MF (5.1-36 microg per rat), and several behavioral parameters were measured. In addition, body temperature and locomotor activity were continuously monitored by a biotelemetric system. MF induced a significant elevation in body temperature and suppression of motor activity levels. MF also significantly reduced the time spent in social exploration, decreased locomotor and exploratory activity in the open field test, suppressed the consumption of food and saccharine solution, and reduced body weight. In a second set of experiments, i.c.v. administration of MF (7.2 microg) was found to produce a significant increase in the production of prostaglandin E2 (PGE2) in hypothalamic, hippocampal, and cortical tissues. This effect was blocked by indomethacin, a prostaglandin synthesis inhibitor. Indomethacin also attenuated the effects of MF on body temperature, motor activity and body weight, suggesting the involvement of prostaglandins in mediating some of the effects of MF. Together, these findings suggest that the presence of MF in the brain may be responsible for some of the neurobehavioral abnormalities in HIV-infected patients.

  13. Exosomes account for vesicle-mediated transcellular transport of activatable phospholipases and prostaglandins[S

    Science.gov (United States)

    Subra, Caroline; Grand, David; Laulagnier, Karine; Stella, Alexandre; Lambeau, Gérard; Paillasse, Michael; De Medina, Philippe; Monsarrat, Bernard; Perret, Bertrand; Silvente-Poirot, Sandrine; Poirot, Marc; Record, Michel

    2010-01-01

    Exosomes are bioactive vesicles released from multivesicular bodies (MVB) by intact cells and participate in intercellular signaling. We investigated the presence of lipid-related proteins and bioactive lipids in RBL-2H3 exosomes. Besides a phospholipid scramblase and a fatty acid binding protein, the exosomes contained the whole set of phospholipases (A2, C, and D) together with interacting proteins such as aldolase A and Hsp 70. They also contained the phospholipase D (PLD) / phosphatidate phosphatase 1 (PAP1) pathway leading to the formation of diglycerides. RBL-2H3 exosomes also carried members of the three phospholipase A2 classes: the calcium-dependent cPLA2-IVA, the calcium-independent iPLA2-VIA, and the secreted sPLA2-IIA and V. Remarkably, almost all members of the Ras GTPase superfamily were present, and incubation of exosomes with GTPγS triggered activation of phospholipase A2 (PLA2)and PLD2. A large panel of free fatty acids, including arachidonic acid (AA) and derivatives such as prostaglandin E2 (PGE2) and 15-deoxy-Δ12,14-prostaglandinJ2 (15-d PGJ2), were detected. We observed that the exosomes were internalized by resting and activated RBL cells and that they accumulated in an endosomal compartment. Endosomal concentrations were in the micromolar range for prostaglandins; i.e., concentrations able to trigger prostaglandin-dependent biological responses. Therefore exosomes are carriers of GTP-activatable phospholipases and lipid mediators from cell to cell. PMID:20424270

  14. Putative role of prostaglandin receptor in intracerebral hemorrhage

    Directory of Open Access Journals (Sweden)

    Shekher eMohan

    2012-10-01

    Full Text Available Each year, approximately 795,000 people experience a new or recurrent stroke. Of all strokes, 84% are ischemic, 13% are intracerebral hemorrhage (ICH strokes and 3% are subarachnoid hemorrhage (SAH strokes. Despite the decreased incidence of ischemic stroke, there has been no change in the incidence of hemorrhagic stroke in the last decade. ICH is a devastating disease 37-38% of patients between the ages of 45-64 die within 30 days. In an effort to prevent ischemic and hemorrhagic strokes we and others have been studying the role of prostaglandins and their receptors. Prostaglandins are bioactive lipids derived from the metabolism of arachidonic acid. They sustain homeostatic functions and mediate pathogenic mechanisms, including the inflammatory response. Most prostaglandins are produced from specific enzymes and act upon cells via distinct G-protein coupled receptors. The presence of multiple prostaglandin receptor’s cross-reactivity and coupling to different signal transduction pathways allow differentiated cells to respond to prostaglandins in a unique manner. Due to the number of prostaglandin receptors, prostaglandin-dependent signaling can function either to promote neuronal survival or injury following acute excitotoxicity, hypoxia, and stress induced by ICH. To better understand the mechanisms of neuronal survival and neurotoxicity mediated by prostaglandin receptors, it is essential to understand downstream signaling. Several groups including ours have discovered unique roles for prostaglandin receptors in rodent models of ischemic stroke, excitotoxicity, and Alzheimer disease, highlighting the emerging role of prostaglandin receptor signaling in hemorrhagic stroke with a focus on cyclic-adenosine monophosphate (cAMP and calcium (Ca2+ signaling. We review current ICH data and discuss future directions notably on prostaglandin receptors, which may lead to the development of unique therapeutic targets against hemorrhagic stroke and

  15. Ovarian steroids affect prostaglandin production in equine endometrial cells in vitro.

    Science.gov (United States)

    Szóstek, Anna Z; Galvão, António M; Ferreira-Dias, Graça M; Skarzynski, Dariusz J

    2014-03-01

    This study aimed to evaluate the influence of ovarian steroids on equine endometrial epithelial and stromal cells, specifically i) prostaglandin (PG) production in a time-dependent manner, ii) specific PG synthases mRNA transcription and protein expression, and iii) cell proliferation. After passage I, cells were exposed to vehicle, oxytocin (OT, positive control, 10(-7) M), progesterone (P4, 10(-7) M), 17β estradiol (E2, 10(-9) M), or P4+E2 for 12, 24, 48, or 72 h. Following treatment, PG concentration was determined using the direct enzyme immunoassay (EIA) method. Alterations in PG synthases mRNA transcriptions, PG synthases protein expression, and cell proliferation in response to the treatments were determined after 24 h using real-time PCR, western blot, or 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide respectively. After 24 h, E2 and P4+E2 increased PGE2 and PGF2α secretion as well as specific prostaglandin-endoperoxide synthase-2 (PTGS2), PGE2 synthases (PGES), and PGF2α synthases (PGFS) expression in the epithelial cells (Pstromal cells after 24 h (Pstromal cells, P4+E2 increased PGE2 production as well as PGES expression after 24 h (Pstromal cells after 24 h (POvarian steroids affected proliferation of stromal and epithelial cells during the 24-h incubation period (Povarian steroids affect PG production in equine endometrial cells, upregulating PTGS2, PGES, and PGFS expression. Ovarian steroid-stimulated PG production could be an important mechanism occurring in the equine endometrium that is involved in the regulation of the estrous cycle and early pregnancy.

  16. Regulation of blood flow by prostaglandins

    DEFF Research Database (Denmark)

    Boushel, Robert Christopher; Langberg, H; Risum, N

    2004-01-01

    Prostaglandins (PGs) belong to the family of prostanoids together with thromboxanes and are produced mainly from arachadonic acid by the enzyme cyclooxygenase. PGs are known to stimulate platelet aggregation, mediate inflammation and edema, play a role in bone metabolism and in biological...... adaptation of connective tissues e.g. tendon. This review covers the role of PG for mediating tissue blood flow at rest and during increases in metabolic demand such as exercise and reactive hyperaemia. There is strong evidence that PGs contribute to elevate blood flow at rest and during reactive hyperaemia...

  17. Many Putative Endocrine Disruptors Inhibit Prostaglandin Synthesis

    DEFF Research Database (Denmark)

    Kristensen, David M.; Skalkam, Maria L.; Audouze, Karine Marie Laure

    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...... 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 it was correlated with a reduced testosterone production. The inhibition of PG synthesis occurs...

  18. Prostaglandin F2-alpha receptor (FPr expression on porcine corpus luteum microvascular endothelial cells (pCL-MVECs

    Directory of Open Access Journals (Sweden)

    Forni Monica

    2007-07-01

    Full Text Available Abstract Background The corpus luteum (CL is a transient endocrine gland and prostaglandin F2-alpha is considered to be the principal luteolysin in pigs. In this species, the in vivo administration of prostaglandin F2-alpha induces apoptosis in large vessels as early as 6 hours after administration. The presence of the prostaglandin F2-alpha receptor (FPr on the microvascular endothelial cells (pCL-MVECs of the porcine corpus luteum has not yet been defined. The aim of the study was to assess FPr expression in pCL-MVECs in the early and mid-luteal phases (EL-p, ML-p, and during pregnancy (P-p. Moreover, the effectiveness of prostaglandin F2-alpha treatment in inducing pCL-MVEC apoptosis was tested. Methods Porcine CLs were collected in the EL and ML phases and during P-p. All CLs from each animal were minced together and the homogenates underwent enzymatic digestion. The pCL-MVECs were then positively selected by an immunomagnetic separation protocol using Dynabeads coated with anti-CD31 monoclonal antibody and seeded in flasks in the presence of EGM 2-MV (Microvascular Endothelial Cell Medium-2. After 4 days of culture, the cells underwent additional immunomagnetic selection and were seeded in flasks until the confluent stage. PCR Real time, western blot and immunodetection assays were utilized to assess the presence of FPr on pCL-MVEC primary cultures. Furthermore, the influence of culture time (freshly isolated, cultured overnight and at confluence and hormonal treatment (P4 and E2 on FPr expression in pCL-MVECs was also investigated. Apoptosis was detected by TUNEL assay of pCL-MVECs exposed to prostaglandin F2-alpha. Results We obtained primary cultures of pCL-MVECs from all animals. FPr mRNA and protein levels showed the highest value (ANOVA in CL-MVECs derived from the early-luteal phase. Moreover, freshly isolated MVECs showed a higher FPr mRNA value than those cultured overnight and confluent cells (ANOVA. prostaglandin F2-alpha

  19. High dietary niacin may increase prostaglandin formation but does not increase tumor formation in ApcMin/+ mice

    Science.gov (United States)

    Kwong, Alan M.; Tippin, Brigette L.; Materi, Alicia M.; Buslon, Virgilio S.; French, Samuel W.; Lin, Henry J.

    2011-01-01

    High doses of niacin (nicotinic acid) used to treat dyslipidemias cause flushing, due to high levels of prostaglandin D2 (PGD2). GPR109A, a G-protein coupled receptor, triggers the flushing in the skin. In addition to boosting PGD2, niacin binding to GPR109A activates the entire prostanoid cascade. We found that GPR109A occurs throughout the gastrointestinal tract. Mice that alternated between a 1% niacin diet and a control diet had higher urinary prostaglandin E2 (PGE2) metabolite levels when on niacin (2.8-fold increase; 95% confidence interval, 1.8–3.9). PGE2 promotes tumors in the intestines, whereas PGD2 may have an opposite effect, on the basis of our report showing that transgenic hematopoietic prostaglandin D synthase suppresses intestinal adenomas in ApcMin/+ mice. To determine if either tumor growth or tumor suppression prevails, we fed ApcMin/+ mice a 1% niacin diet and assessed tumor development. A 1% niacin diet did not affect the number of tumors scored histologically in ApcMin/+ mice at 14 weeks (33 mice on niacin, 33 controls). Although niacin stimulates production of various prostaglandins, our results support an interpretation that very high intakes of niacin are safe in relation to intestinal tumors in this model. PMID:21774590

  20. Cervical ripening with prostaglandin gel and hygroscopic dilators.

    Science.gov (United States)

    Hibbard, J U; Shashoua, A; Adamczyk, C; Ismail, M

    1998-01-01

    To study the effectiveness and morbidity of adding hygroscopic cervical dilators to prostaglandin gel for cervical ripening and labor induction. Patients of at least 34 weeks' gestation with a medical indication for induction of labor and with a modified Bishop score of 5 or less were randomized to receive either prostaglandin gel or prostaglandin gel with hygroscopic cervical dilators. Primary outcomes were time to delivery, change in cervical score, and infection. Secondary outcomes included cesarean delivery rate and deliveries before 24 hours of induction. Continuous variables were analyzed by Wilcoxon sum rank test and categorical data by chi-square or Fisher exact test, with P < 0.05 being significant. Seventeen patients were randomized to intracervical prostaglandin alone and 23 patients received intracervical prostaglandin plus hygroscopic dilators. No demographic differences were noted between the groups. After six hours of ripening, the combined group achieved a greater change in Bishop score (3.6 vs. 2.1, P = 0.007) and tended to have a shorter induction time (21.7 vs. 26.4 hours, P = 0.085). The combined therapy group had a higher infection rate than the prostaglandin-only group (59% vs. 12%, P = 0.003). Combining cervical dilators with prostaglandin gel provides more effective cervical ripening and a more rapid induction to delivery interval than prostaglandin alone but with a significant and prohibitive rate of infection.

  1. Release of prostaglandins after amniotomy is not mediated by oxytocin.

    Science.gov (United States)

    Sellers, S M; Hodgson, H T; Mitchell, M D; Anderson, A B; Turnbull, A C

    1980-01-01

    The rise in peripheral plasma levels of 13,14-dihydro-15-keto-prostaglandin F (PGFM) following amniotomy has now been shown to be maximal within five minutes of the procedure, and levels remain elevated for at least 30 minutes. There was no change in plasma oxytocin levels with amniotomy and therefore a local mechanism for prostaglandin release has been postulated.

  2. Loop 7 of E2 enzymes

    DEFF Research Database (Denmark)

    Papaleo, Elena; Casiraghi, Nicola; Arrigoni, Alberto

    2012-01-01

    of family 3 E2s. The L7 hydrophobic residues turned out to be the main determinant for the stabilization of the E2 inactive conformations by a tight network of interactions in the catalytic cleft. Moreover, phosphorylation is known from previous studies to promote E2 competent conformations for Ub charging...

  3. Prostaglandin Transporter (PGT/SLCO2A1 Protects the Lung from Bleomycin-Induced Fibrosis.

    Directory of Open Access Journals (Sweden)

    Takeo Nakanishi

    Full Text Available Prostaglandin (PG E2 exhibits an anti-fibrotic effect in the lung in response to inflammatory reactions and is a high-affinity substrate of PG transporter (SLCO2A1. The present study aimed to evaluate the pathophysiological relevance of SLCO2A1 to bleomycin (BLM-induced pulmonary fibrosis in mice. Immunohistochemical analysis indicated that Slco2a1 protein was expressed in airway and alveolar type I (ATI and II (ATII epithelial cells, and electron-microscopic immunohistochemistry further demonstrated cell surface expression of Slco2a1 in ATI cells in wild type (WT C57BL/6 mice. PGE2 uptake activity was abrogated in ATI-like cells from Slco2a1-deficient (Slco2a1-/- mice, which was clearly observed in the cells from WT mice. Furthermore, the PGE2 concentrations in lung tissues were lower in Slco2a1-/- than in WT mice. The pathological relevance of SLCO2A1 was further studied in mouse BLM-induced pulmonary fibrosis models. BLM (1 mg/kg or vehicle (phosphate buffered saline was intratracheally injected into WT and Slco2a1-/- mice, and BLM-induced fibrosis was evaluated on day 14. BLM induced more severe fibrosis in Slco2a1-/- than in WT mice, as indicated by thickened interstitial connective tissue and enhanced collagen deposition. PGE2 levels were higher in bronchoalveolar lavage fluid, but lower in lung tissues of Slco2a1-/- mice. Transcriptional upregulation of TGF-β1 was associated with enhanced gene transcriptions of downstream targets including plasminogen activator inhitor-1. Furthermore, Western blot analysis demonstrated a significant activation of protein kinase C (PKC δ along with a modest activation of Smad3 in lung from Slco2a1-/- mice, suggesting a role of PKCδ associated with TGF-β signaling in aggravated fibrosis in BLM-treated Slco2a1-/- mice. In conclusion, pulmonary PGE2 disposition is largely regulated by SLCO2A1, demonstrating that SLCO2A1 plays a critical role in protecting the lung from BLM-induced fibrosis.

  4. Prostaglandin Transporter (PGT/SLCO2A1) Protects the Lung from Bleomycin-Induced Fibrosis.

    Science.gov (United States)

    Nakanishi, Takeo; Hasegawa, Yoshitaka; Mimura, Reo; Wakayama, Tomohiko; Uetoko, Yuka; Komori, Hisakazu; Akanuma, Shin-Ichi; Hosoya, Ken-Ichi; Tamai, Ikumi

    2015-01-01

    Prostaglandin (PG) E2 exhibits an anti-fibrotic effect in the lung in response to inflammatory reactions and is a high-affinity substrate of PG transporter (SLCO2A1). The present study aimed to evaluate the pathophysiological relevance of SLCO2A1 to bleomycin (BLM)-induced pulmonary fibrosis in mice. Immunohistochemical analysis indicated that Slco2a1 protein was expressed in airway and alveolar type I (ATI) and II (ATII) epithelial cells, and electron-microscopic immunohistochemistry further demonstrated cell surface expression of Slco2a1 in ATI cells in wild type (WT) C57BL/6 mice. PGE2 uptake activity was abrogated in ATI-like cells from Slco2a1-deficient (Slco2a1-/-) mice, which was clearly observed in the cells from WT mice. Furthermore, the PGE2 concentrations in lung tissues were lower in Slco2a1-/- than in WT mice. The pathological relevance of SLCO2A1 was further studied in mouse BLM-induced pulmonary fibrosis models. BLM (1 mg/kg) or vehicle (phosphate buffered saline) was intratracheally injected into WT and Slco2a1-/- mice, and BLM-induced fibrosis was evaluated on day 14. BLM induced more severe fibrosis in Slco2a1-/- than in WT mice, as indicated by thickened interstitial connective tissue and enhanced collagen deposition. PGE2 levels were higher in bronchoalveolar lavage fluid, but lower in lung tissues of Slco2a1-/- mice. Transcriptional upregulation of TGF-β1 was associated with enhanced gene transcriptions of downstream targets including plasminogen activator inhitor-1. Furthermore, Western blot analysis demonstrated a significant activation of protein kinase C (PKC) δ along with a modest activation of Smad3 in lung from Slco2a1-/- mice, suggesting a role of PKCδ associated with TGF-β signaling in aggravated fibrosis in BLM-treated Slco2a1-/- mice. In conclusion, pulmonary PGE2 disposition is largely regulated by SLCO2A1, demonstrating that SLCO2A1 plays a critical role in protecting the lung from BLM-induced fibrosis.

  5. A randomized controlled trial of foley catheter, extra-amniotic saline infusion and prostaglandin e2 suppository for labor induction.

    Directory of Open Access Journals (Sweden)

    Mandana Mansour Ghanaie

    2013-06-01

    Full Text Available The aim of this study is to further compare the efficacy of PGE2 suppository, the intracervical foley catheter and extra-amniotic saline infusion in nulliparous women referred for labor induction.Totally 368 nulliparous women with a Bishop score ≤ 4 with singleton gestation, vertex presentation and intact membrane referred for labor induction were randomly assigned to 3 groups; Foley catheter alone, Extra-amniotic saline infusion (EASI and PGE2 suppository. All women received concurrent dilute oxytocine infusion. The change in the Bishop Score, labor progress, various labor endpoints and outcomes of labor were assessed.From 363 women studied after exclusion of 5, 119 were assigned to EASI, 121 to Foley and 118 to PGE2. Patients' demographics did not differ significantly between three groups nor did indication for induction (P = 0.0001. The EASI group had a significant improvement in Bishop Score 6 hours after induction. The mean time to active phase was 357±135min for EASI,457±178 for Foley and 609±238 min for PGE2 group respectively (P < 0.05.rate of spontaneous rupture of membranes was higher in the EASI group (P = 0.0001 and the mean time from the start of induction up to spontaneous rupture of membranes in the EASI group was shorter than other group(P < 0.05. The mean time to vaginal delivery was 14.8±6.1 in EASI group,11.4±4.8 in Foley and 18.9±6.4 in PGE2 group(P < 0.05.there were no differences in Apgar scores, mean neonatal birth weight and neonatal morbidity.Our study showed that pre-induction cervical ripening by EASI with concurrent oxytocin is better than Foley and PGE2 in Bishop score and various labor end point and outcomes.

  6. Muscarinic M1 receptor inhibition reduces gastroduodenal bicarbonate secretion and promotes gastric prostaglandin E2 synthesis in healthy volunteers

    DEFF Research Database (Denmark)

    Mertz-Nielsen, A; Hillingsø, Jens; Eskerod, O

    1995-01-01

    and luminal output of PGE2 into the stomach and the duodenum of nine healthy volunteers using a new technique permitting simultaneous measurements. In the stomach modified sham feeding increased bicarbonate secretion from 382 (62) mumol/h (mean (SEM)) to 959 (224) mumol/h (p ... sham feeding and acid exposure (HCl 0.1 M; 20 ml; 5 min) of the duodenal bulb increased mucosal bicarbonate secretion from 191 (14) mumol/cm x h to 266 (27) mumol/cm x h (p ... stimulated gastric and basal duodenal bicarbonate secretion by about 50% (p stomach, but not the duodenum, basal and vagally stimulated PGE2 output increased significantly (p

  7. Targeting prostaglandin E2 EP1 receptors prevents seizure-associated P-glycoprotein up-regulation

    NARCIS (Netherlands)

    Pekcec, A.; Unkrüer, B.; Schlichtiger, J.; Soerensen, J.; Hartz, A.M.S.; Bauer, B.; van Vliet, E.A.; Gorter, J.A.; Potschka, H.

    2009-01-01

    Up-regulation of the blood-brain barrier efflux transporter P-glycoprotein in central nervous system disorders results in restricted brain access and limited efficacy of therapeutic drugs. In epilepsies, seizure activity strongly triggers expression of P-glycoprotein. Here, we identified the

  8. Lipopolysaccharide induces inflammation and facilitates lung metastasis in a breast cancer model via the prostaglandin E2-EP2 pathway

    National Research Council Canada - National Science Library

    LI, SHANCHENG; XU, XIAOYA; JIANG, MAN; BI, YULI; XU, JIYING; HAN, MINGYONG

    2015-01-01

    .... BALB/c mice were injected intraperitoneally with lipopolysaccharide (LPS) in order to establish an inflammatory animal model and 4T1 murine breast cancer cells were injected through the tail vein to induce lung metastasis...

  9. Release of prostaglandin E2 into gastric juice during stimulation of muscarinic- and gastrin receptors in dogs and in humans

    DEFF Research Database (Denmark)

    Madsen, Jørgen Rask; Bukhave, K; Hovendal, C P

    1981-01-01

    .2-18 ng/Meq H+). The findings are consistent with the hypothesis that activation of muscarinic receptors represents the physiologic mechanism by which gastric release of PGs is regulated. Cyclic variations in gastric PG formation appear to occur in response to vagal stimulation since the peaks in PGE2...

  10. Nitric oxide production in murine spleen cells: role of interferons and prostaglandin E2 in the generation of cytotoxic activity

    Directory of Open Access Journals (Sweden)

    Dominique Vaillier

    1996-01-01

    Full Text Available The production of nitric oxide (NO was measured in cultures of spleen cells stimulated by lipopolysaccharide (LPS, IL-2 or LPS + IL-2. We observed that NO synthesis is increased by IFN-γ but inhibited by IFN-α/β. This is not the case when IL-2 is present in the cultures, since interferons play a minor role in the regulation of the NO production. When IL-2 and LPS were associated in the cultures, the IFN-α/β role seems more important than that of IFN-γ. PGE2 inhibits NO production in LPS supplemented cultures but has a slight effect in the presence of IL-2 and no effect with IL-2 + LPS. 3-isoButyl-1-methylxanthine (IBMX, an inhibitor of phosphodiesterases, induces a decrease of IFN production. In the presence of H-7, an inhibitor of protein kinase C (PKC, NO production is reduced when the cultures are supplemented by LPS or IL-2 but not when IL-2 and LPS are both added. H-7 also reduced IFN production. In the presence of NG-monomethyl-L-arginine (N-MMA, an inhibitor of NO synthesis, IFN production was increased, with no change in the cytotoxic activity. Hence, interferons regulate NO production by mouse spleen cells and, in return, NO modulates the generation of IFN.

  11. Soluble Iron in Alveolar Macrophages Modulates Iron Oxide Particle-Induced Inflammatory Response via Prostaglandin E2 Synthesis

    Science.gov (United States)

    Ambient particulate matter (PM)-associated metals have been shown to play an important role in cardiopulmonary health outcomes. To study the modulation of inflammation by PM-associated soluble metal, we investigated intracellular solubility of radiolabelled iron oxide (59

  12. A biphasic response of urinary prostaglandin E2 excretion to water deprivation in conscious diabetes insipidus Brattleboro rats

    DEFF Research Database (Denmark)

    Kanters, J K; Holstein-Rathlou, N H; Christensen, P

    1989-01-01

    -15 h., IV: 24-28 h. and V: 32-36 h. after removal of water and food. It was found that the PGE2 excretion rate changed in a biphasic pattern. During the first 2 experimental periods it increased. Thereafter it decreased towards the control value. There was an increase in PGE2 excretion with urinary...

  13. The Role of Breast Cancer Derived Prostaglandin E2 in the Elaboration of a Therapeutic Immune Response

    Science.gov (United States)

    2000-07-01

    exhibits no "trans" effect. 3. T cell activation in the MLR is restored in the presence of mEGP when Con A or anti -CD3 antibody is added to the MLR... Trypanosoma cruzi . FEBS Lett, 1997. 401(2-3): p. 259-61. 14. Fineschi, B. and J. Miller, Endosomal proteases and antigen processing. Trends Biochem...T cell stimulation assay in the form of tumor debris, T cell activation was also inhibited. We postulate that mEGP blocks antigen loading into MHC

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

    DEFF Research Database (Denmark)

    Hristovska, Ana-Marija; Rasmussen, Lasse E; Hansen, Pernille B L

    2007-01-01

    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...

  15. Induction of labor with and without primary amniotomy. A randomized study of prostaglandin E2 tablets and intravenous oxytocin.

    Science.gov (United States)

    Secher, N J; Lange, A P; Nielsen, F H; Pedersen, G T; Westergaard, J G

    1981-01-01

    A comparative study of labor induction has been performed on 471 consecutive patients. Primary amniotomy was performed in 227 cases, and 103 of these patients were stimulated, 57 patients with PGE2 tablets and 46 with oxytocin. In the remaining 124 cases labor was induced within 4 hours without medical stimulation. Primary amniotomy was omitted in 244 cases, as the head was not engaged and the cervix was unripe. After random allocation to the treatment groups 125 patients received PGE2 tablets (ProstinR), and 119 patients received oxytocin intravenously. After 2 days of stimulation without primary amniotomy, delivery was induced in 83 per cent of the patients receiving PGE2 and in 84 per cent of the patients receiving oxytocin. All patients on whom primary amniotomy had been performed were delivered on the first day. There was no difference in the success rate between PGE2 and oxytocin treatments in patients with the same Bishop score. The performance of amniotomy at the beginning of induction led to a significantly lower total dose as well as a lower maximal dose of PGE2 and oxytocin. There was no difference in the duration of active labor in patients receiving PGE2 or oxytocin. There were no differences in the incidence of fetal distress and low Apgar scores between the different groups. No serious side effects occurred. Vomiting and diarrhea in 14 patients (8 per cent) receiving PGE2 was in contrast to 3 patients with these symptoms (2 per cent) in the oxytocin group. Oral administration of PGE2 is a convenient, effective and safe alternative to oxytocin for the induction of labor; however, PGE2 was not found superior to oxytocin in cases with a low Bishop score.

  16. Adult human microglia secrete cytokines when exposed to neurotoxic prion protein peptide: no intermediary role for prostaglandin E2

    NARCIS (Netherlands)

    Veerhuis, Robert; Hoozemans, Jeroen J. M.; Janssen, Ingrid; Boshuizen, Ronald S.; Langeveld, Jan P. M.; Eikelenboom, Piet

    2002-01-01

    Prion diseases are characterized by accumulation of protease resistant isoforms of prion protein (termed PrP(SC)), glial activation and neurodegeneration. The time course of PrP deposition, appearance of activated microglia, and of neuronal apoptosis in experimentally-induced prion disease suggests

  17. Progesterone receptor expression declines in the guinea pig uterus during functional progesterone withdrawal and in response to prostaglandins.

    Directory of Open Access Journals (Sweden)

    Toni N Welsh

    Full Text Available 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

  18. Progesterone Receptor Expression Declines in the Guinea Pig Uterus during Functional Progesterone Withdrawal and in Response to Prostaglandins

    Science.gov (United States)

    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

  19. Involvement of prostaglandins in inflammation induced by latex of Calotropis procera.

    Science.gov (United States)

    Kumar, Vijay L; Shivkar, Yatin M

    2004-01-01

    INTRODUCTION:The aerial parts of the plant Calotropis procera produce milky white latex that causes inflammation of the skin and mucous membranes. Prostaglandins are one of the mediators released in an inflammatory response following induction of cyclooxygenase (COX). In the present study, we have evaluated the role of prostaglandins in inflammatory response elicited by the latex of C. procera. METHODS: Aqueous extract of dried latex of C. procera was injected into the 6-day air-pouch in the rat. The inflammatory response was evaluated by studying the air-pouch fluid for its volume, protein and prostaglandin (PG) E2 concentrations, and leucocyte counts. The granulation tissue from the pouch was quantified and studied for COX-2 expression by reverse transcriptase-polymerase chain reaction. The inhibitory effect of celecoxib and dexamethasone was evaluated on the aforementioned parameters. RESULTS: Dried latex produced an inflammatory response that was maximum at 6 h. It was associated with the accumulation of protein-rich fluid, leucocytes and PGE2 production. It also resulted in granulation of the pouch cavity that was a maximum on day 3. COX-2 expression could be detected in the granulation tissue on day 1 and it increased progressively up to day 5. The anti-inflammatory drugs celecoxib and dexamethasone significantly attenuated the inflammatory response and inhibited COX-2 expression in granulation tissue. CONCLUSIONS: Latex of C. procera induces an inflammatory response characterized by an early exudative phase accompanied by PGE2 production and a late proliferative phase associated with COX-2 induction. Both the phases were effectively inhibited by COX-2 inhibitors. PMID:15223605

  20. Hypoxia activates the cyclooxygenase-2–prostaglandin E synthase axis

    Science.gov (United States)

    Lee, James J.; Natsuizaka, Mitsuteru; Ohashi, Shinya; Wong, Gabrielle S.; Takaoka, Munenori; Michaylira, Carmen Z.; Budo, Daniela; Tobias, John W.; Kanai, Michiyuki; Shirakawa, Yasuhiro; Naomoto, Yoshio; Klein-Szanto, Andres J.P.; Haase, Volker H.; Nakagawa, Hiroshi

    2010-01-01

    Hypoxia-inducible factors (HIFs), in particular HIF-1α, have been implicated in tumor biology. However, HIF target genes in the esophageal tumor microenvironment remain elusive. Gene expression profiling was performed upon hypoxia-exposed non-transformed immortalized human esophageal epithelial cells, EPC2-hTERT, and comparing with a gene signature of esophageal squamous cell carcinoma (ESCC). In addition to known HIF-1α target genes such as carbonic anhydrase 9, insulin-like growth factor binding protein-3 (IGFBP3) and cyclooxygenase (COX)-2, prostaglandin E synthase (PTGES) was identified as a novel target gene among the commonly upregulated genes in ESCC as well as the cells exposed to hypoxia. The PTGES induction was augmented upon stabilization of HIF-1α by hypoxia or cobalt chloride under normoxic conditions and suppressed by dominant-negative HIF-1α. Whereas PTGES messenger RNA (mRNA) was negatively regulated by normoxia, PTGES protein remained stable upon reoxygenation. Prostaglandin E2 (PGE2) biosynthesis was documented in transformed human esophageal cells by ectopic expression of PTGES as well as RNA interference directed against PTGES. Moreover, hypoxia stimulated PGE2 production in a HIF-1α-dependent manner. In ESCC, PTGES was overexpressed frequently at the mRNA and protein levels. Finally, COX-2 and PTGES were colocalized in primary tumors along with HIF-1α and IGFBP3. Activation of the COX-2–PTGES axis in primary tumors was further corroborated by concomitant upregulation of interleukin-1β and downregulation of hydroxylprostaglandin dehydrogenase. Thus, PTGES is a novel HIF-1α target gene, involved in prostaglandin E biosynthesis in the esophageal tumor hypoxic microenvironment, and this has implications in diverse tumors types, especially of squamous origin. PMID:20042640

  1. Acetylsalicylic acid interferes with embryonic kidney growth and development by a prostaglandin-independent mechanism.

    Science.gov (United States)

    Welham, Simon J M; Sparrow, Alexander J; Gardner, David S; Elmes, Matthew J

    2017-01-06

    To evaluate the effects of the non-selective, non-steroidal anti-inflammatory drug (NSAID) acetylsalicylic acid (ASA), on ex vivo embryonic kidney growth and development. Pairs of fetal mouse kidneys at embryonic day 12.5 were cultured ex vivo in increasing concentrations of ASA (0.04-0.4 mg/mL) for up to 7 d. One organ from each pair was grown in control media and was used as the internal control for the experimental contralateral organ. In some experiments, organs were treated with ASA for 48 h and then transferred either to control media alone or control media containing 10 μmol/L prostaglandin E2 (PGE2) for a further 5 d. Fetal kidneys were additionally obtained from prostaglandin synthase 2 homozygous null or heterozygous (PTGS2(-/-) and PTGS2(-/+)) embryos and grown in culture. Kidney cross-sectional area was used to determine treatment effects on kidney growth. Whole-mount labelling to fluorescently detect laminin enabled crude determination of epithelial branching using confocal microscopy. Increasing ASA concentration (0.1, 0.2 and 0.4 mg/mL) significantly inhibited metanephric growth (P growth area to control levels. Application of control media alone after cessation of ASA exposure showed no benefit on kidney growth. Despite the apparent recovery of growth area with 10 μmol/L PGE2, no obvious renal tubular structures were formed. The number of epithelial tips generated after 48 h exposure to ASA was reduced by 40% (0.2 mg/mL; P growth of PTGS2(-/-) and PTGS2(+/-) kidneys in organ culture showed no differences, indicating that PTGS2 derived PGE2 may at best have a minor role. ASA reduces early renal growth and development but the role of prostaglandins in this may be minor.

  2. Cervical ripening with prostaglandin gel and hygroscopic dilators.

    Science.gov (United States)

    Hibbard, J U; Shashoua, A; Adamczyk, C; Ismail, M

    1998-01-01

    OBJECTIVE: To study the effectiveness and morbidity of adding hygroscopic cervical dilators to prostaglandin gel for cervical ripening and labor induction. STUDY DESIGN: Patients of at least 34 weeks' gestation with a medical indication for induction of labor and with a modified Bishop score of 5 or less were randomized to receive either prostaglandin gel or prostaglandin gel with hygroscopic cervical dilators. Primary outcomes were time to delivery, change in cervical score, and infection. Secondary outcomes included cesarean delivery rate and deliveries before 24 hours of induction. Continuous variables were analyzed by Wilcoxon sum rank test and categorical data by chi-square or Fisher exact test, with P hygroscopic dilators. No demographic differences were noted between the groups. After six hours of ripening, the combined group achieved a greater change in Bishop score (3.6 vs. 2.1, P = 0.007) and tended to have a shorter induction time (21.7 vs. 26.4 hours, P = 0.085). The combined therapy group had a higher infection rate than the prostaglandin-only group (59% vs. 12%, P = 0.003). CONCLUSION: Combining cervical dilators with prostaglandin gel provides more effective cervical ripening and a more rapid induction to delivery interval than prostaglandin alone but with a significant and prohibitive rate of infection. PMID:9678143

  3. Usability of prostaglandin monotherapy eye droppers.

    Science.gov (United States)

    Drew, Tom; Wolffsohn, James S

    2015-09-01

    To determine the force needed to extract a drop from a range of current prostaglandin monotherapy eye droppers and how this related to the comfortable and maximum pressure subjects could exert. The comfortable and maximum pressure subjects could apply to an eye dropper constructed around a set of cantilevered pressure sensors and mounted above their eye was assessed in 102 subjects (mean 51.2±18.7 years), repeated three times. A load cell amplifier, mounted on a stepper motor controlled linear slide, was constructed and calibrated to test the force required to extract the first three drops from 13 multidose or unidose latanoprost medication eye droppers. The pressure that could be exerted on a dropper comfortably (25.9±17.7 Newtons, range 1.2-87.4) could be exceeded with effort (to 64.8±27.1 Newtons, range 19.9-157.8; F=19.045, p<0.001), and did not differ between repeats (F=0.609, p=0.545). Comfortable and maximum pressures exerted were correlated (r=0.618, p<0.001), neither were influenced strongly by age (r=0.138, p=0.168; r=-0.118, p=0237, respectively), but were lower in women than in men (F=12.757, p=0.001). The force required to expel a drop differed between dropper designs (F=22.528, p<0.001), ranging from 6.4 Newtons to 23.4 Newtons. The force needed to exert successive drops increased (F=36.373, p<0.001) and storing droppers in the fridge further increased the force required (F=7.987, p=0.009). Prostaglandin monotherapy droppers for glaucoma treatment vary in their resistance to extract a drop and with some a drop could not be comfortably achieved by half the population, which may affect compliance and efficacy. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.

  4. E2F1 is crucial for E2F-dependent apoptosis

    DEFF Research Database (Denmark)

    Lazzerini Denchi, Eros; Helin, Kristian

    2005-01-01

    Loss of the retinoblastoma protein, pRB, leads to apoptosis, and several results have suggested that this is dependent on the E2F transcription factors. However, so far, the ability of the different E2F family members to contribute to apoptosis is controversial. Here, we show that ectopic...... of crucial levels of E2F1 activity, and not total E2F activity, is essential for the induction of apoptosis in response to a deregulated pRB pathway. These results are consistent with previous findings that E2F1, but not other E2Fs, can have tumour-suppressing activities....

  5. 6-Keto-prostaglandin E1 is more potent than prostaglandin I2 as a renal vasodilator and renin secretagogue.

    Science.gov (United States)

    Jackson, E K; Herzer, W A; Zimmerman, J B; Branch, R A; Oates, J A; Gerkens, J F

    1981-01-01

    Several studies indicate that prostaglandin (PG) I2 is involved in the control of renin release. This investigation was performed to determine if the active possible metabolite of PGI2, 6-keto-PGE1, is also a renin secretagogue. The relative potencies of PGI2, 6-keto-PGE1 and 6-keto-PGF1 alpha on renin secretion rate (RSR) and renal blood flow (RBF) were assessed in nonfiltering, beta adrenoreceptor blocked kidneys of seven anesthetized dogs. Intrarenal infusions of both PGI2 and 6-keto-PGE1 significantly augmented RSR in a dose-related fashion. However, 6-keto-PGE1 was approximately 5 times more potent than PGI2, producing significantly greater increases in RSR at doses from 3 X 10(-9) to 3 X 10(-8 g/kg/min (P eicosanoides enhanced RBF to an equal extent. Thus, in comparison to PGI2, 6-keto-PGF1 induced a greater increase in RSR for equivalent increases in RBF. 6-keto-PGF 1 alpha had no effect on either RSR or RBF at any of the doses infused. We conclude that, in the canine kidney, 6-keto-PGE1 is more potent than PGI2 in stimulating the juxtaglomerular cells to secrete renin.

  6. Regulation of intraluteal production of prostaglandins

    Directory of Open Access Journals (Sweden)

    Ottobre Joseph S

    2003-11-01

    Full Text Available Abstract There is clear evidence for intraluteal production of prostaglandins (PGs in numerous species and under a variety of experimental conditions. In general, secretion of PGs appears to be elevated in the early corpus luteum (CL and during the period of luteolysis. Regulation of intraluteal PG production is regulated by a variety of factors. An autoamplification pathway in which PGF-2alpha stimulates intraluteal production of PGF-2alpha has been identified in a number of species. The mechanisms underlying this autoamplification pathway appear to differ by species with expression of Cyclooxygenase-2 (Cox-2 and activity of phospholipase A2 acting as important physiological control points. In addition, a number of other responses that are induced by PGF-2alpha (decreased luteal progesterone, increased endothelin-1, increased cytokines also have been found to increase intraluteal PGF-2alpha production. Thus, regulation of intraluteal PG production may serve to initiate or amplify physiological signals to the CL and may be important in specific aspects of luteal physiology particularly during luteal regression.

  7. Prostaglandin therapeutics in the bitch and queen.

    Science.gov (United States)

    Henderson, R T

    1984-10-01

    The use of prostaglandin F2 alpha as an abortifacient and for the treatment of certain diseases affecting the reproductive system of the bitch and queen is reviewed. Doses of 0.5 to 1.0 mg/kg PGF administered by intramuscular or subcutaneous injection at intervals of 24 or 48 h after mid-gestation appears to be a satisfactory luteolytic-- abortifacient regime for use in dogs and cats. Doses of 0.25 to 0.5 mg/kg in the bitch and 0.5 to 1.0 mg/kg PGF in the queen, at intervals of 24 or 48 h, may be used as an adjunct to the therapy of metritis, endometritis or pyometritis. A median lethal dose of 5.13 mg/kg has been derived for use of PGF in the bitch and this is thought to be similar for use of PGF in the queen. Side effects of defecation and/or vomition may be observed in the bitch and queen using routine therapeutic doses.

  8. G-protein coupled receptor-evoked glutamate exocytosis from astrocytes: role of prostaglandins.

    Science.gov (United States)

    Cali, Corrado; Lopatar, Jan; Petrelli, Francesco; Pucci, Luca; Bezzi, Paola

    2014-01-01

    Astrocytes are highly secretory cells, participating in rapid brain communication by releasing glutamate. Recent evidences have suggested that this process is largely mediated by Ca(2+)-dependent regulated exocytosis of VGLUT-positive vesicles. Here by taking advantage of VGLUT1-pHluorin and TIRF illumination, we characterized mechanisms of glutamate exocytosis evoked by endogenous transmitters (glutamate and ATP), which are known to stimulate Ca(2+) elevations in astrocytes. At first we characterized the VGLUT1-pHluorin expressing vesicles and found that VGLUT1-positive vesicles were a specific population of small synaptic-like microvesicles containing glutamate but which do not express VGLUT2. Endogenous mediators evoked a burst of exocytosis through activation of G-protein coupled receptors. Subsequent glutamate exocytosis was reduced by about 80% upon pharmacological blockade of the prostaglandin-forming enzyme, cyclooxygenase. On the other hand, receptor stimulation was accompanied by extracellular release of prostaglandin E2 (PGE2). Interestingly, administration of exogenous PGE2 produced per se rapid, store-dependent burst exocytosis of glutamatergic vesicles in astrocytes. Finally, when PGE2-neutralizing antibody was added to cell medium, transmitter-evoked exocytosis was again significantly reduced (by about 50%). Overall these data indicate that cyclooxygenase products are responsible for a major component of glutamate exocytosis in astrocytes and that large part of such component is sustained by autocrine/paracrine action of PGE2.

  9. Resveratrol inhibits prostaglandin formation in IL-1β-stimulated SK-N-SH neuronal cells

    Directory of Open Access Journals (Sweden)

    Candelario-Jalil Eduardo

    2009-09-01

    Full Text Available Abstract Resveratrol, a polyphenol present in grapes and red wine, has been studied due to its vast pharmacological activity. It has been demonstrated that resveratrol inhibits production of inflammatory mediators in different in vitro and in vivo models. Our group recently demonstrated that resveratrol reduced the production of prostaglandin (PG E2 and 8-isoprostane in rat activated microglia. In a microglial-neuronal coculture, resveratrol reduced neuronal death induced by activated microglia. However, less is known about its direct roles in neurons. In the present study, we investigated the effects of resveratrol on interleukin (IL-1β stimulated SK-N-SH cells. Resveratrol (0.1-5 μM did not reduce the expression of cyclooxygenase (COX-2 and microsomal PGE2 synthase-1 (mPGES-1, although it drastically reduced PGE2 and PGD2 content in IL-1β-stimulated SK-N-SH cells. This effect was due, in part, to a reduction in COX enzymatic activity, mainly COX-2, at lower doses of resveratrol. The production of 8-iso-PGF2α, a marker of cellular free radical generation, was significantly reduced by resveratrol. The present work provides evidence that resveratrol reduces the formation of prostaglandins in neuroblastoma cells by reducing the enzymatic activity of inducible enzymes, such as COX-2, and not the transcription of the PG synthases, as demonstrated elsewhere.

  10. Pyometra in Bitches Induces Elevated Plasma Endotoxin and Prostaglandin F2α Metabolite Levels

    Directory of Open Access Journals (Sweden)

    Hagman R

    2006-03-01

    Full Text Available 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.

  11. G-Protein Coupled Receptor-Evoked Glutamate Exocytosis from Astrocytes: Role of Prostaglandins

    Directory of Open Access Journals (Sweden)

    Corrado Cali

    2014-01-01

    Full Text Available Astrocytes are highly secretory cells, participating in rapid brain communication by releasing glutamate. Recent evidences have suggested that this process is largely mediated by Ca2+-dependent regulated exocytosis of VGLUT-positive vesicles. Here by taking advantage of VGLUT1-pHluorin and TIRF illumination, we characterized mechanisms of glutamate exocytosis evoked by endogenous transmitters (glutamate and ATP, which are known to stimulate Ca2+ elevations in astrocytes. At first we characterized the VGLUT1-pHluorin expressing vesicles and found that VGLUT1-positive vesicles were a specific population of small synaptic-like microvesicles containing glutamate but which do not express VGLUT2. Endogenous mediators evoked a burst of exocytosis through activation of G-protein coupled receptors. Subsequent glutamate exocytosis was reduced by about 80% upon pharmacological blockade of the prostaglandin-forming enzyme, cyclooxygenase. On the other hand, receptor stimulation was accompanied by extracellular release of prostaglandin E2 (PGE2. Interestingly, administration of exogenous PGE2 produced per se rapid, store-dependent burst exocytosis of glutamatergic vesicles in astrocytes. Finally, when PGE2-neutralizing antibody was added to cell medium, transmitter-evoked exocytosis was again significantly reduced (by about 50%. Overall these data indicate that cyclooxygenase products are responsible for a major component of glutamate exocytosis in astrocytes and that large part of such component is sustained by autocrine/paracrine action of PGE2.

  12. Prostaglandins can modify gamma-radiation and chemical induced cytotoxicity and genetic damage in vitro and in vivo

    Energy Technology Data Exchange (ETDEWEB)

    Das, U.N.; Ramadevi, G.; Rao, K.P.; Rao, M.S. (Nizam' s Institute of Medical Sciences, Hyderabad (India))

    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.

  13. Storage in vivo of (/sup 3/H)prostaglandins by rabbit blastocysts

    Energy Technology Data Exchange (ETDEWEB)

    Jones, M.A.; Anderson, W.; Turner, T.G.; Harper, M.J.

    1985-03-01

    Day 6 rabbit blastocysts that had previously been incubated with 10 nM (/sup 3/H)prostaglandin E2 (PGE2), (/sup 3/H) PGF2 alpha, or 0.5 microCi (/sup 3/H)water were surgically transferred to the uteri of day 6 pseudopregnant recipient rabbits. At 1, 3, and 20 h after transfer, blastocysts were collected from the recipient rabbits and evaluated for retention of (/sup 3/H)ligands. The transferred day 6 blastocysts were able to retain a significant proportion of the initial PGs for up to 20 h in vivo. These PGs were not metabolized while they remained in the blastocysts in vivo, as assessed by HPLC. The transferred blastocysts appeared normal and viable after 20 h in vivo, since implantation sites could be detected visually. These data support our hypothesis that blastocysts can sequester PGs from their environment in vivo and retain them unmetabolized during the critical period just before implantation.

  14. Prostaglandins and their receptors in insect biology

    Directory of Open Access Journals (Sweden)

    David eStanley

    2011-12-01

    Full Text Available 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. 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. 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. We conclude that research into PGs and their receptors in insects will lead to important advances in our understanding of insect biology.

  15. Prostaglandin H synthase immunoreactivity in human gut. An immunohistochemical study

    DEFF Research Database (Denmark)

    Mikkelsen, H B; Rumessen, J J; Qvortrup, Klaus

    1991-01-01

    Prostaglandins exhibit a variety of actions on intestinal smooth muscle depending upon the type, dose and muscle layer studied. As the cellular origin of prostaglandin H (PGH) synthase has not been established with certainty in the human gut wall, we studied the localization of PGH synthase in th...... large capacity for PGH synthesis and the present results may provide a basis for a better understanding of both normal physiological functions as well as intestinal disease states involving disorders of prostaglandin synthesis.......Prostaglandins exhibit a variety of actions on intestinal smooth muscle depending upon the type, dose and muscle layer studied. As the cellular origin of prostaglandin H (PGH) synthase has not been established with certainty in the human gut wall, we studied the localization of PGH synthase...... in the human duodenum, jejunum, ileum and colon by immunohistochemistry. PGH synthase immunoreactivity appeared to be similar in all segments of the intestine. Most smooth muscle cells seemed to contain PGH synthase; however, the reaction in the lamina muscularis mucosae was much stronger than...

  16. Prostaglandin F2alpha elevates blood pressure and promotes atherosclerosis

    DEFF Research Database (Denmark)

    Yu, Ying; Lucitt, Margaret B; Stubbe, Jane

    2009-01-01

    Little is known about prostaglandin F(2alpha) in cardiovascular homeostasis. Prostaglandin F(2alpha) dose-dependently elevates blood pressure in WT mice via activation of the F prostanoid (FP) receptor. The FP is expressed in preglomerular arterioles, renal collecting ducts, and the hypothalamus....... Deletion of the FP reduces blood pressure, coincident with a reduction in plasma renin concentration, angiotensin, and aldosterone, despite a compensatory up-regulation of AT1 receptors and an augmented hypertensive response to infused angiotensin II. Plasma and urinary osmolality are decreased in FP KOs...

  17. E2F7, a novel E2F featuring DP-independent repression of a subset of E2F-regulated genes

    DEFF Research Database (Denmark)

    Di Stefano, Luisa; Jensen, Michael Rugaard; Helin, Kristian

    2003-01-01

    The E2F family of transcription factors play an essential role in the regulation of cell cycle progression. In a screen for E2F-regulated genes we identified a novel E2F family member, E2F7. Like the recently identified E2F-like proteins of Arabidopsis, E2F7 has two DNA binding domains and binds ...

  18. E2f3a and E2f3b make overlapping but different contributions to total E2f3 activity

    OpenAIRE

    Danielian, PS; Friesenhahn, LB; Faust, AM; West, JC; Caron, AM; Bronson, RT; Lees, JA

    2008-01-01

    The E2f transcription factors are key downstream targets of the retinoblastoma protein tumor suppressor that control cell proliferation. E2F3 has garnered particular attention because it is amplified in various human tumors. E2f3 mutant mice typically die around birth and E2f3-deficient cells have a proliferation defect that correlates with impaired E2f-target gene activation and also induction of p19Arf and p53. The E2f3 locus encodes two isoforms, E2f3a and E2f3b, which differ in their N-te...

  19. Analytical and preparative resolution of enantiomers of prostaglandin precursors and prostaglandins by liquid chromatography on derivatized cellulose chiral stationary phases.

    Science.gov (United States)

    Miller, L; Weyker, C

    1990-07-06

    Analytical methods were developed for the separation of the enantiomers of four cyclopentenone precursors of prostaglandins. The resolution obtained is correlated with the chemical environment around the chiral center of the cyclopentenones. The analytical methods were scaled up to preparative loadings and the chromatographic parameters were varied to determine their effect on the preparative separations. The correlation between analytical resolution and preparative resolution was also investigated. In addition to the precursors, the preparative resolution of the enantiomers of a synthetic prostaglandin analogue was investigated.

  20. Prostaglandin levels and semen quality in male partners of infertile ...

    African Journals Online (AJOL)

    Objective: To provide data on semen prostaglandins in Nigerian men and relate this to fertility potential as provided by semen analysis results. Design: Prospective study. Setting: Infertility Clinic of Obafemi Awolowo University Teaching Hospitals Complex, Ile-Ife, Nigeria Subjects: All male partners of infertile couples who ...

  1. Prostaglandin phospholipid conjugates with unusual biophysical and cytotoxic properties

    DEFF Research Database (Denmark)

    Pedersen, Palle Jacob; Adolph, Sidsel K.; Andresen, Thomas Lars

    2010-01-01

    The synthesis of two secretory phospholipase A(2) IIA sensitive 15-deoxy-Delta(12,14)-prostaglandin J(2) phospholipid conjugates is described and their biophysical and biological properties are reported. The conjugates spontaneously form particles in the liposome size region upon dispersion...

  2. Separation of prostaglandin metabolites on sephadex LH 20 columns

    DEFF Research Database (Denmark)

    Hansen, Harald S.; Bukhave, K.

    1978-01-01

    Sephadex LH 20 columns have been investigated for the separation of initial prostaglandin metabolites. Solvent systems are described for the separation of the free acids of 15-keto-dihydro-PGE, 15-keto-PGE, PGE, and PGF(1a). Further, one of the solvent systems is described for the separation...

  3. Vitamin D-Prostaglandin Interactions and Effects on Prostate Cancer

    Science.gov (United States)

    2005-10-01

    chloramphenicol ace- at 1300 x g), supernatants were incubated overnight at 4°C, tyltransferase (CAT) under the control of the Herpes virus with the polyclonal...measure of drug Stamey TA, Feldman D. Antiproliferative effects of 18. Badawi AF. The role of prostaglandin synthesis in synergism . Pain 2002;98:163-8

  4. Renin-sodium profile and renal prostaglandins in the pathogenesis ...

    African Journals Online (AJOL)

    Renin-sodium profile and renal prostaglandins in the pathogenesis of systemic arterial hypertension in blacks. L. Somova, J. Mufunda. Thirteen black women with systemic (essential) arterial hypertension, age-matched with normotensives, were examined during two protocols inducing sodium depletion and sodium loading ...

  5. The Hydroxysteroid (17β) Dehydrogenase Family Gene HSD17B12 Is Involved in the Prostaglandin Synthesis Pathway, the Ovarian Function, and Regulation of Fertility.

    Science.gov (United States)

    Kemiläinen, Heidi; Adam, Marion; Mäki-Jouppila, Jenni; Damdimopoulou, Pauliina; Damdimopoulos, Anastasios E; Kere, Juha; Hovatta, Outi; Laajala, Teemu D; Aittokallio, Tero; Adamski, Jerzy; Ryberg, Henrik; Ohlsson, Claes; Strauss, Leena; Poutanen, Matti

    2016-10-01

    The hydroxysteroid (17beta) dehydrogenase (HSD17B)12 gene belongs to the hydroxysteroid (17β) dehydrogenase superfamily, and it has been implicated in the conversion of estrone to estradiol as well as in the synthesis of arachidonic acid (AA). AA is a precursor of prostaglandins, which are involved in the regulation of female reproduction, prompting us to study the role of HSD17B12 enzyme in the ovarian function. We found a broad expression of HSD17B12 enzyme in both human and mouse ovaries. The enzyme was localized in the theca interna, corpus luteum, granulosa cells, oocytes, and surface epithelium. Interestingly, haploinsufficiency of the HSD17B12 gene in female mice resulted in subfertility, indicating an important role for HSD17B12 enzyme in the ovarian function. In line with significantly increased length of the diestrous phase, the HSD17B+/- females gave birth less frequently than wild-type females, and the litter size of HSD17B12+/- females was significantly reduced. Interestingly, we observed meiotic spindle formation in immature follicles, suggesting defective meiotic arrest in HSD17B12+/- ovaries. The finding was further supported by transcriptome analysis showing differential expression of several genes related to the meiosis. In addition, polyovular follicles and oocytes trapped inside the corpus luteum were observed, indicating a failure in the oogenesis and ovulation, respectively. Intraovarian concentrations of steroid hormones were normal in HSD17B12+/- females, whereas the levels of AA and its metabolites (6-keto prostaglandin F1alpha, prostaglandin D2, prostaglandin E2, prostaglandin F2α, and thromboxane B2) were decreased. In conclusion, our study demonstrates that HSD17B12 enzyme plays an important role in female fertility through its role in AA metabolism.

  6. Prostaglandin D2 Attenuates Bleomycin-Induced Lung Inflammation and Pulmonary Fibrosis.

    Directory of Open Access Journals (Sweden)

    Taiki Kida

    Full Text Available Pulmonary fibrosis is a progressive and fatal lung disease with limited therapeutic options. Although it is well known that lipid mediator prostaglandins are involved in the development of pulmonary fibrosis, the role of prostaglandin D2 (PGD2 remains unknown. Here, we investigated whether genetic disruption of hematopoietic PGD synthase (H-PGDS affects the bleomycin-induced lung inflammation and pulmonary fibrosis in mouse. Compared with H-PGDS naïve (WT mice, H-PGDS-deficient mice (H-PGDS-/- represented increased collagen deposition in lungs 14 days after the bleomycin injection. The enhanced fibrotic response was accompanied by an increased mRNA expression of inflammatory mediators, including tumor necrosis factor-α, monocyte chemoattractant protein-1, and cyclooxygenase-2 on day 3. H-PGDS deficiency also increased vascular permeability on day 3 and infiltration of neutrophils and macrophages in lungs on day 3 and 7. Immunostaining showed that the neutrophils and macrophages expressed H-PGDS, and its mRNA expression was increased on day 3and 7 in WT lungs. These observations suggest that H-PGDS-derived PGD2 plays a protective role in bleomycin-induced lung inflammation and pulmonary fibrosis.

  7. Prostaglandin D2 Attenuates Bleomycin-Induced Lung Inflammation and Pulmonary Fibrosis.

    Science.gov (United States)

    Kida, Taiki; Ayabe, Shinya; Omori, Keisuke; Nakamura, Tatsuro; Maehara, Toko; Aritake, Kosuke; Urade, Yoshihiro; Murata, Takahisa

    2016-01-01

    Pulmonary fibrosis is a progressive and fatal lung disease with limited therapeutic options. Although it is well known that lipid mediator prostaglandins are involved in the development of pulmonary fibrosis, the role of prostaglandin D2 (PGD2) remains unknown. Here, we investigated whether genetic disruption of hematopoietic PGD synthase (H-PGDS) affects the bleomycin-induced lung inflammation and pulmonary fibrosis in mouse. Compared with H-PGDS naïve (WT) mice, H-PGDS-deficient mice (H-PGDS-/-) represented increased collagen deposition in lungs 14 days after the bleomycin injection. The enhanced fibrotic response was accompanied by an increased mRNA expression of inflammatory mediators, including tumor necrosis factor-α, monocyte chemoattractant protein-1, and cyclooxygenase-2 on day 3. H-PGDS deficiency also increased vascular permeability on day 3 and infiltration of neutrophils and macrophages in lungs on day 3 and 7. Immunostaining showed that the neutrophils and macrophages expressed H-PGDS, and its mRNA expression was increased on day 3and 7 in WT lungs. These observations suggest that H-PGDS-derived PGD2 plays a protective role in bleomycin-induced lung inflammation and pulmonary fibrosis.

  8. Age dependent increase in prostaglandin pathway coincides with onset of ovarian cancer in laying hens

    Science.gov (United States)

    Eilati, Erfan; Pan, Lurui; Bahr, Janice M.; Hales, Dale Buchanan

    2012-01-01

    Chronic inflammation has been linked to cancer. Prostaglandin E2 (PGE2) is the most pro-inflammatory lipid and one of the downstream products of 2 isoforms of cyclooxygenase (COX) enzymes: COX-1 and COX-2. Ovarian cancer is the most lethal gynecological malignancy and mainly occurs in older women. The factors that contribute to the correlation of age and ovarian cancer are unknown. The purpose of this study was to examine the expression of COX enzymes and PGE2 levels in ovaries and correlate them to ovarian cancer and aging. White Leghorn hens aged 1, 1.5, 2, 2.5, 3 and 3.5 years were used. The incidence of ovarian cancer was determined by gross pathology and histology. COX-1 and COX-2 protein and mRNA expression and PGE2 concentrations in ovaries were measured using Western blot, quantitative real-time PCR and ELISA, respectively. Our results indicated an increase in ovarian cancer incidence and expression of both COX enzymes in ovaries of older hens. In correlation with ovarian cancer incidence and COX enzymes expression, PGE2 concentrations were elevated with age. Ovaries with tumor had elevated COX-1 expression and PGE2 concentration compared to normal ovaries. Our findings suggest that the up-regulation of COX enzymes with age is the main contributing factor in the age associated increase in PGE2. Furthermore, elevated PGE2 in ovaries of hens concomitant with age suggests its important role in early stages of ovarian carcinogenesis. These finding may provide the basis for clinical trials utilizing COX specific inhibitors or dietary intervention targeting prostaglandin biosynthesis for the prevention and treatment of ovarian cancer. PMID:23089186

  9. Chronic intrathecal cannulation enhances nociceptive responses in rats

    Directory of Open Access Journals (Sweden)

    Almeida F.R.C.

    2000-01-01

    Full Text Available The influence of a chronically implanted spinal cannula on the nociceptive response induced by mechanical, chemical or thermal stimuli was evaluated. The hyperalgesia in response to mechanical stimulation induced by carrageenin or prostaglandin E2 (PGE2 was significantly increased in cannulated (Cn rats, compared with naive (Nv or sham-operated (Sh rats. Only Cn animals presented an enhanced nociceptive response in the first phase of the formalin test when low doses were used (0.3 and 1%. The withdrawal latency to thermal stimulation of a paw inflamed by carrageenin was significantly reduced in Cn rats but not in Nv or Sh rats. In contrast to Nv and Sh rats, injection in Cn animals of a standard non-steroid anti-inflammatory drug, indomethacin, either intraperitoneally or into the spinal cord via an implanted cannula or by direct puncture of the intrathecal space significantly blocked the intensity of the hyperalgesia induced by PGE2. Cannulated animals treated with indomethacin also showed a significant inhibition of second phase formalin-induced paw flinches. Histopathological analysis of the spinal cord showed an increased frequency of mononuclear inflammatory cells in the Cn groups. Thus, the presence of a chronically implanted cannula seems to cause nociceptive spinal sensitization to mechanical, chemical and thermal stimulation, which can be blocked by indomethacin, thus suggesting that it may result from the spinal release of prostaglandins due to an ongoing mild inflammation.

  10. CRPS: A contingent hypothesis with prostaglandins as crucial conversion factor.

    Science.gov (United States)

    van der Veen, Phe

    2015-11-01

    CRPS is an acute pain disease expressed as chronic pain with a severe loss of tissue and function. CRPS usually occurs after minor injuries and then progresses in a way that is scarcely controllable, or completely uncontrollable. This article addresses the functional control mechanism of a biological organism, a comparison of techniques, and the way the negative feedback mechanisms fail in regulated feedback systems. The measurement and regulation system is controlled at the local, regional, and central levels in a biological system. Locally generated substances such as prostaglandins and hormones, as well as the central nervous system, play important roles in this process. Prostaglandins fulfil many conversion functions and are involved in vasoactive processes, pain, and inflammation. They play an intermediating role between the activity of the autonomic nervous system and local occurrences. The insufficiently explored conversion function of prostaglandins as a ubiquitously present cofactor may be related to the development of CRPS at sites which have had minor injuries in the past. Chronic Regional Pain Syndrome (CRPS) is a moderately prevalent disease, which occurs more frequently with age. Even though there are diseases known to have a precipitating effect on the aetiology of CRPS, for example Carpal tunnel syndrome, the mechanism of onset is unknown. The disease falls under the category of chronic pain, and seldom has an effective treatment based on scientific research. The economic and psychosocial aspects of the disease are substantial. CRPS is the final position of a positive feedback measurement and control system. Homoeostasis is directed by measurement and control processes. In electronics, a rapid conversion system, which quickly adapts to changing circumstances, superimposed with a delayed conversion system, which ensures a stable basis of homoeostasis. Measured changes are compensatorily controlled. An analogy is expected for a Complex Adaptive System

  11. E2F-5, a new E2F family member that interacts with p130 in vivo

    NARCIS (Netherlands)

    Hijmans, E.M.; Voorhoeve, P.M.; Beijersbergen, R.L.; Veer, L.J. van 't; Bernards, R.A.

    1995-01-01

    E2F DNA binding sites are found in a number of genes whose expression is tightly regulated during the cell cycle. The activity of E2F transcription factors is regulated by association with specific repressor molecules that can bind and inhibit the E2F transactivation domain. For E2F-1, E2F-2, and

  12. The E8 repression domain can replace the E2 transactivation domain for growth inhibition of HeLa cells by papillomavirus E2 proteins.

    Science.gov (United States)

    Stubenrauch, Frank; Straub, Elke; Fertey, Jasmin; Iftner, Thomas

    2007-11-15

    Continuous expression of the human papillomavirus (HPV) oncoproteins E6 and E7 is required for the growth of cervical cancer cell lines. So far, only the overexpression of the wild type papillomavirus E2 protein has been shown to induce growth arrest in HPV18-positive HeLa cells by repressing E6/E7 transcription. Growth arrest by E2 requires the aminoterminal transcription activation domain in addition to the carboxyterminal DNA-binding domain. Several papillomaviruses such as the carcinogenic HPV31 express in addition to E2 an E8(wedge)E2C fusion protein in which the E8 domain, which is required for repression of replication and transcription, replaces the E2 activation domain. In this report, we demonstrate that the HPV31 E8(wedge)E2C protein is able to inhibit the growth of HeLa cells but not of HPV-negative C33A cervical cancer cells. Growth repression by E8(wedge)E2C correlates with repression of the endogenous HPV18 E6/E7 promoter and the reappearance of E6- and E7-regulated p53, pRb and p21 proteins, suggesting that E8(wedge)E2C inhibits growth by reactivating dormant tumor suppressor pathways. Growth inhibition requires an intact E8 repression domain in addition to the carboxyterminal E2C DNA binding domain. Chromatin immunoprecipitation experiments suggest that the E8 repression domain enhances binding to the HPV18 promoter sequence in vivo. In summary, our results demonstrate that the small E8 repression domain can functionally replace the large E2 transactivation domain for growth inhibition of HeLa cervical cancer cells. (c) 2007 Wiley-Liss, Inc.

  13. Prostaglandin treatment is associated with a withdrawal of progesterone and androgen at the receptor level in the uterine cervix

    Science.gov (United States)

    Vladic-Stjernholm, Ylva; Vladic, Tomislav; Blesson, Chellakkan S; Ekman-Ordeberg, Gunvor; Sahlin, Lena

    2009-01-01

    Treatment with prostaglandin(PG)-E2 is clinically efficient for cervical priming. The aim of this study was to evaluate the impact of PG-E2 on the expression of the progesterone (PR), androgen (AR) and glucocorticoid (GR) receptors in human uterine cervix in prolonged pregnancy. The study groups were postterm nulliparous women with unripe cervices undergoing cervical priming with PG-E2 before labor induction. Responders (n = 12) who delivered vaginally were compared with non-responders (n = 10), who underwent cesarean section due to failure to progress to the active phase of labor. Controls (n = 18) with vaginal partus at a normal gestational age served as a reference group. Cervical levels of PR-A and PR- B isoforms, AR and GR, serum levels of their ligands and sex hormone-binding globulin (SHBG) were quantified. The responder group displayed lower total PR-AB and AR protein levels as compared to non-responders, and lower PR-B and AR protein levels as compared to controls. In addition, the PR mRNA level was lower in responders as compared to non-responders. The GR protein level did not differ between the groups. We conclude that successful PG-E2 priming was followed by a progesterone and androgen withdrawal at the receptor level in the uterine cervix. PMID:19852793

  14. Prostaglandin treatment is associated with a withdrawal of progesterone and androgen at the receptor level in the uterine cervix

    Directory of Open Access Journals (Sweden)

    Ekman-Ordeberg Gunvor

    2009-10-01

    Full Text Available Abstract Treatment with prostaglandin(PG-E2 is clinically efficient for cervical priming. The aim of this study was to evaluate the impact of PG-E2 on the expression of the progesterone (PR, androgen (AR and glucocorticoid (GR receptors in human uterine cervix in prolonged pregnancy. The study groups were postterm nulliparous women with unripe cervices undergoing cervical priming with PG-E2 before labor induction. Responders (n = 12 who delivered vaginally were compared with non-responders (n = 10, who underwent cesarean section due to failure to progress to the active phase of labor. Controls (n = 18 with vaginal partus at a normal gestational age served as a reference group. Cervical levels of PR-A and PR- B isoforms, AR and GR, serum levels of their ligands and sex hormone-binding globulin (SHBG were quantified. The responder group displayed lower total PR-AB and AR protein levels as compared to non-responders, and lower PR-B and AR protein levels as compared to controls. In addition, the PR mRNA level was lower in responders as compared to non-responders. The GR protein level did not differ between the groups. We conclude that successful PG-E2 priming was followed by a progesterone and androgen withdrawal at the receptor level in the uterine cervix.

  15. Prostaglandin H synthase immunoreactivity in human gut. An immunohistochemical study

    DEFF Research Database (Denmark)

    Mikkelsen, H B; Rumessen, J J; Qvortrup, K

    1991-01-01

    Prostaglandins exhibit a variety of actions on intestinal smooth muscle depending upon the type, dose and muscle layer studied. As the cellular origin of prostaglandin H (PGH) synthase has not been established with certainty in the human gut wall, we studied the localization of PGH synthase...... in the human duodenum, jejunum, ileum and colon by immunohistochemistry. PGH synthase immunoreactivity appeared to be similar in all segments of the intestine. Most smooth muscle cells seemed to contain PGH synthase; however, the reaction in the lamina muscularis mucosae was much stronger than...... in the longitudinal and circular muscle layers. Endothelial cells in capillaries and larger vessels showed a positive reaction. In addition, unidentified cells in subserosa, at the level of Auerbach's plexus and in the submucosa were stained. We concluded that the smooth muscle cells of the human gut has a rather...

  16. Prostaglandins in menstrual fluid in menorrhagia and dysmenorrhoea.

    Science.gov (United States)

    Rees, M C; Anderson, A B; Demers, L M; Turnbull, A C

    1984-07-01

    Menstrual fluid was collected in vaginal cups inserted for 2 h during the first 2 days of menstruation and menstrual serum concentrations of prostaglandins PGF2 alpha and PGE2 were measured by radioimmunoassay. In 16 women from whom menstrual fluid was collected on both days, PGF2 alpha and PGE2 concentrations were significantly higher on day 1 than on day 2. The highest concentrations of PGF2 alpha and PGE2 were found in dysmenorrhoeic women on day 1. In non-dysmenorrhoeic women, the amount of PGF2 alpha and PGE2 collected in 2 h correlated directly with total menstrual blood loss. There was no statistically significant difference in the amount of prostaglandins collected in 2 h in pain-free menorrhagic women and dysmenorrhoeic women with normal loss. There was also no significant 9-ketoreductase or 9-hydroxydehydrogenase activity present in menstrual fluid which could suggest PGE2 to PGF2 alpha interconversion.

  17. Sex differences in prostaglandin biosynthesis in neutrophils during acute inflammation

    OpenAIRE

    Pace, Simona; Rossi, Antonietta; Krauth, Verena; Dehm, Friederike; Troisi, Fabiana; Bilancia, Rossella; Weinigel, Christina; Rummler, Silke; Werz, Oliver; Sautebin, Lidia

    2017-01-01

    The severity and course of inflammatory processes differ between women and men, but the biochemical mechanisms underlying these sex differences are elusive. Prostaglandins (PG) and leukotrienes (LT) are lipid mediators linked to inflammation. We demonstrated superior LT biosynthesis in human neutrophils and monocytes, and in mouse macrophages from females, and we confirmed these sex differences in vivo where female mice produced more LTs during zymosan-induced peritonitis versus males. Here, ...

  18. [Prostaglandin E binding by plasmatic membranes of thyroid gland cells].

    Science.gov (United States)

    Malinkovich, V D; Gal'chinskaia, V Iu

    1979-03-01

    The binding of prostaglandins E (PGE) with human and bovine thyrocyte plasmatic membranes was investigated by the new method with material from the kit for radioimmunoassay of PGE. There was a high affinity and a low affinity site for the specific PGE binding on human and bovine thyrocytes plasmic membranes. The effect of thyrotropin and cyclic nucleotides on the PGE binding by the membranes was revealed.

  19. Prostaglandin F2 alpha in benign and malignant breast tumours.

    OpenAIRE

    Vergote, I.B.; Laekeman, G. M.; Keersmaekers, G. H.; Uyttenbroeck, F L; Vanderheyden, J S; Albertyn, G. P.; Haensch, C. F.; De Roy, G. J.; Herman, A.G.

    1985-01-01

    Prostaglandin F2 alpha (PGF2 alpha) was determined by radioimmunoassay in 57 breast carcinomata, 16 fibroadenomata, and 33 sclero-cystic-disease (SCD) specimens. In 41 cases of carcinoma and 10 cases of fibroadenoma, histologically non-malignant tissue was also obtained from the same breast. PGF2 alpha levels were significantly elevated in breast cancer when compared with the normal tissues and benign diseases (P less than 0.005 for each group). High PGF2 alpha levels were positively correlat...

  20. Characterization of E2F8, a novel E2F-like cell-cycle regulated repressor of E2F-activated transcription

    DEFF Research Database (Denmark)

    Christensen, Jesper; Cloos, Paul; Toftegaard, Ulla

    2005-01-01

    The E2F family of transcription factors are downstream effectors of the retinoblastoma protein, pRB, pathway and are essential for the timely regulation of genes necessary for cell-cycle progression. Here we describe the characterization of human and murine E2F8, a new member of the E2F family...

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

    Science.gov (United States)

    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. E2F1-Mediated Induction of NFYB Attenuates Apoptosis via Joint Regulation of a Pro-Survival Transcriptional Program.

    Directory of Open Access Journals (Sweden)

    Xiaolei Jiang

    Full Text Available The E2F1 transcription factor regulates cell proliferation and apoptosis through the control of a considerable variety of target genes. Previous work has detailed the role of other transcription factors in mediating the specificity of E2F function. Here we identify the NF-YB transcription factor as a novel direct E2F1 target. Genome-wide expression analysis of the effects of NFYB knockdown on E2F1-mediated transcription identified a large group of genes that are co-regulated by E2F1 and NFYB. We also provide evidence that knockdown of NFYB enhances E2F1-induced apoptosis, suggesting a pro-survival function of the NFYB/E2F1 joint transcriptional program. Bioinformatic analysis suggests that deregulation of these NFY-dependent E2F1 target genes might play a role in sarcomagenesis as well as drug resistance.

  3. E2F-6: a novel member of the E2F family is an inhibitor of E2F-dependent transcription

    DEFF Research Database (Denmark)

    Cartwright, P; Müller, H; Wagener, C

    1998-01-01

    The E2F family of transcription factors are essential for the regulation of genes required for appropriate progression through the cell cycle. Five members of the E2F family have been previously reported, namely E2F1-5. All five are key elements in transcriptional regulation of essential genes......, and they can be divided into two functional groups, those that induce S-phase progression when overexpressed in quiescent cells (E2Fs 1-3), and those that do not (E2Fs 4-5). Here, we describe the identification of a novel member of this family, which we refer to as E2F-6. E2F-6 shares significant homology...... promoter (TTTCGCGC). In contrast to the other members of the E2F family, ectopic expression of E2F-6 inhibits transcription from promoters possessing E2F recognition sites rather than activating transcription. In addition, overexpression of E2F-6 suppresses the transactivational effects of coexpression...

  4. In vivo suppression of NK cell cytotoxicity by stress and surgery: glucocorticoids have a minor role compared to catecholamines and prostaglandins.

    Science.gov (United States)

    Rosenne, Ella; Sorski, Liat; Shaashua, Lee; Neeman, Elad; Matzner, Pini; Levi, Ben; Ben-Eliyahu, Shamgar

    2014-03-01

    Most in vitro and ex-vivo studies indicate a profound suppression of NK cell cytotoxicity (NKCC) by glucocorticoids; while catecholamines and prostaglandins were reported both to suppress and to enhance NKCC. However, methodological considerations hinder our ability to deduce from these findings to the impact of endogenous release of these factors on in vivo levels of NKCC and their implications to NK-dependent resistance to pathologies in living humans or animals. Here we used an in vivo approach that sensitively and specifically reflects NKCC in living F344 rats, based on lung clearance of NK-sensitive tumor cells (MADB106), and based on comparing effects between NK-intact and NK-depleted rats. To study the role of corticosterone, epinephrine, and prostaglandins, we administered these factors to rats, or antagonized their endogenous release following different stress paradigms or surgery. The results indicated that endogenous or exogenous elevated corticosterone levels can suppress in vivo NKCC levels, but only under some conditions, and mostly secondarily to the NK-suppressing impact of epinephrine. Specifically, corticosterone-induced NKCC suppression occurred (i) only under prolonged, but not short exposure to stress, and mainly in males; (ii) was smaller than the prominent impact of epinephrine; (iii) was mostly ascribed to corticosterone-induced potentiation of the effects of epinephrine or/and prostaglandins; and (iv) was completely abolished through antagonizing epinephrine or/and prostaglandins. Overall, these findings markedly limit the significance of stress/surgery-induced corticosterone release in the in vivo suppression of NKCC, and highlight the blockade of epinephrine or/and prostaglandins as effective and clinically feasible approaches to overcome such immuno-suppressive effects. Copyright © 2013 Elsevier Inc. All rights reserved.

  5. In vivo suppression of NK cell cytotoxicity by stress and surgery in F344 rats: Glucocorticoids have a minor role compared to catecholamines and prostaglandins

    Science.gov (United States)

    Rosenne, Ella; Sorski, Liat; Shaashua, Lee; Neeman, Elad; Matzner, Pini; Levi, Ben; Ben-Eliyahu, Shamgar

    2015-01-01

    Most in vitro and ex-vivo studies indicate a profound suppression of NK cell cytotoxicity (NKCC) by glucocorticoids; while catecholamines and prostaglandins were reported both to suppress and to enhance NKCC. However, methodological considerations hinder our ability to deduce from these findings to the impact of endogenous release of these factors on in vivo levels of NKCC and their implications to NK-dependent resistance to pathologies in living humans or animals. Here we used an in vivo approach that sensitively and specifically reflects NKCC in living F344 rats, based on lung clearance of NK-sensitive tumor cells (MADB106), and based on comparing effects between NK-intact and NK-depleted rats. To study the role of corticosterone, epinephrine, and prostaglandins, we administered these factors to rats, or antagonized their endogenous release following different stress paradigms or surgery. The results indicated that endogenous or exogenous elevated corticosterone levels can suppress in vivo NKCC levels, but only under some conditions, and mostly secondarily to the NK-suppressing impact of epinephrine. Specifically, corticosterone-induced NKCC suppression occurred (i) only under prolonged, but not short exposure to stress, and mainly in males; (ii) was smaller than the prominent impact of epinephrine; (iii) was mostly ascribed to corticosterone-induced potentiation of the effects of epinephrine or/and prostaglandins; and (iv) was completely abolished through antagonizing epinephrine or/and prostaglandins. Overall, these findings markedly limit the significance of stress/surgery-induced corticosterone release in the in vivo suppression of NKCC, and highlight the blockade of epinephrine or/and prostaglandins as effective and clinically feasible approaches to overcome such immuno-suppressive effects. PMID:24333572

  6. Induction of DNA synthesis and apoptosis are separable functions of E2F-1

    DEFF Research Database (Denmark)

    Phillips, A C; Bates, S; Ryan, K M

    1997-01-01

    The family of E2F transcription factors have an essential role in mediating cell cycle progression, and recently, one of the E2F protein family, E2F-1, has been shown to participate in the induction of apoptosis. Cooperation between E2F and the p53 tumor suppressor protein in this apoptotic...... response had led to the suggestion that cell cycle progression induced by E2F-1 expression provides an apoptotic signal when placed in conflict with an arrest to cell cycle progression, such as provided by p53. We show here that although apoptosis is clearly enhanced by p53, E2F-1 can induce significant...... apoptosis in the absence of p53. Furthermore, this apoptotic function of E2F-1 is separable from the ability to accelerate entry into DNA synthesis. Analysis of E2F-1 mutants indicates that although DNA-binding is required, transcriptional transactivation is not necessary for the induction of apoptosis by E...

  7. Clinical utility and differential effects of prostaglandin analogs in the management of raised intraocular pressure and ocular hypertension

    Directory of Open Access Journals (Sweden)

    Anne J Lee

    2010-07-01

    Full Text Available Anne J Lee1,2, Peter McCluskey2,31Manchester Royal Eye Hospital, Manchester, UK; 2University of Sydney, Sydney, Australia; 3Sydney Eye Hospital, Sydney, AustraliaAbstract: Prostaglandin analogs (PGA are powerful topical ocular hypotensive agents available for the treatment of elevated intraocular pressure (IOP. Latanoprost 0.005% and travoprost 0.004% are prodrugs and analogs of prostaglandin F2a. Bimatoprost 0.03% is regarded as a prostamide, and debate continues as to whether it is a prodrug. The free acids of all 3 PGAs reduce IOP by enhancing uveoscleral and trabecular outflow via direct effects on ciliary muscle relaxation and remodeling of extracellular matrix. The vast majority of clinical trials demonstrate IOP-lowering superiority of latanoprost, bimatoprost and travoprost compared with timolol 0.5%, brimonidine 0.2%, or dorzolamide 2% monotherapy. Bimatoprost appears to be more efficacious in IOP-lowering compared with latanoprost, with weighted mean difference in IOP reduction documented in one meta-analysis of 2.59% to 5.60% from 1- to 6-months study duration. PGAs reduce IOP further when used as adjunctive therapy. Fixed combinations of latanoprost, bimatoprost or travoprost formulated with timolol 0.5% and administered once daily are superior to monotherapy of its constituent parts. PGA have near absence of systemic side effects, although do have other commonly encountered ocular adverse effects. The adverse effects of PGA, and also those found more frequently with bimatoprost use include ocular hyperemia, eyelash growth, and peri-ocular pigmentary changes. Iris pigmentary change is unique to PGA treatment. Once daily administration and near absence of systemic side effects enhances tolerance and compliance. PGAs are often prescribed as first-line treatment for ocular hypertension and open-angle glaucoma.Keywords: prostaglandin analog, glaucoma, ocular hypertension, latanoprost, bimatoprost, travoprost

  8. Increased renal sodium absorption by inhibition of prostaglandin synthesis during fasting in healthy man. A possible role of the epithelial sodium channels

    Directory of Open Access Journals (Sweden)

    Graffe Carolina C

    2010-10-01

    Full Text Available Abstract Background Treatment with prostaglandin inhibitors can reduce renal function and impair renal water and sodium excretion. We tested the hypotheses that a reduction in prostaglandin synthesis by ibuprofen treatment during fasting decreased renal water and sodium excretion by increased absorption of water and sodium via the aquaporin2 water channels and the epithelial sodium channels. Methods The effect of ibuprofen, 600 mg thrice daily, was measured during fasting in a randomized, placebo-controlled, double-blinded crossover study of 17 healthy humans. The subjects received a standardized diet on day 1, fasted at day 2, and received an IV infusion of 3% NaCl on day 3. The effect variables were urinary excretions of aquaporin2 (u-AQP2, the beta-fraction of the epithelial sodium channel (u-ENaCbeta, cyclic-AMP (u-cAMP, prostaglandin E2 (u-PGE2. Free water clearance (CH2O, fractional excretion of sodium (FENa, and plasma concentrations of vasopressin, angiotensin II, aldosterone, atrial-, and brain natriuretic peptide. Results Ibuprofen decreased u-AQP2, u-PGE2, and FENa at all parts of the study. During the same time, ibuprofen significantly increased u-ENaCbeta. Ibuprofen did not change the response in p-AVP, u-c-AMP, urinary output, and free water clearance during any of these periods. Atrial-and brain natriuretic peptide were higher. Conclusion During inhibition of prostaglandin synthesis, urinary sodium excretion decreased in parallel with an increase in sodium absorption and increase in u-ENaCbeta. U-AQP2 decreased indicating that water transport via AQP2 fell. The vasopressin-c-AMP-axis did not mediate this effect, but it may be a consequence of the changes in the natriuretic peptide system and/or the angiotensin-aldosterone system Trial Registration Clinical Trials Identifier: NCT00281762

  9. Plasmodium falciparum produces prostaglandins that are pyrogenic, somnogenic, and immunosuppressive substances in humans.

    Science.gov (United States)

    Kilunga Kubata, B; Eguchi, N; Urade, Y; Yamashita, K; Mitamura, T; Tai, K; Hayaishi, O; Horii, T

    1998-09-21

    Plasmodium falciparum causes the most severe form of human malaria, which kills approximately 1.5-2.7 million people every year, but the molecular mechanisms underlying the clinical symptoms and the host-parasite interaction remain unclear. We show here that P. falciparum produces prostaglandins (PGs) D2, E2, and F2alpha. After incubation with 1 mM arachidonic acid (AA), cell homogenates of P. falciparum produced PGs as determined by enzyme immunoassay and gas chromatography-selected ion monitoring. PG production in the parasite homogenate was not affected by the nonsteroidal antiinflammatory drugs aspirin and indomethacin, and was partially heat resistant, whereas PG biosynthesis by mammalian cyclooxygenase was completely inhibited by these chemicals and by heat treatment. Addition of AA to the parasite cell culture markedly increased an ability of the parasite cell homogenate to produce PGs and of parasitized red blood cells to accumulate PGs in the culture medium. PGD2 and PGE2 accumulated in the culture medium at the stages of trophozoites and schizonts more actively than at the ring stage. These findings are the first evidence of the direct involvement of a malaria parasite in the generation of substances that are pyrogenic and injurious to the host defenses. We will discuss a possible contribution of the parasite-produced PGs to pathogenesis and host-parasite interaction of P. falciparum.

  10. Analysis list: E2f1 [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available E2f1 Blood,Liver + mm9 http://dbarchive.biosciencedbc.jp/kyushu-u/mm9/target/E2f1.1....tsv http://dbarchive.biosciencedbc.jp/kyushu-u/mm9/target/E2f1.5.tsv http://dbarchive.biosciencedbc.jp/kyushu-u/mm9/target/E2f1....10.tsv http://dbarchive.biosciencedbc.jp/kyushu-u/mm9/colo/E2f1.Blood.tsv,http://dbarch...ive.biosciencedbc.jp/kyushu-u/mm9/colo/E2f1.Liver.tsv http://dbarchive.bioscience

  11. Analysis list: E2f3 [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available E2f3 Digestive tract,Embryonic fibroblast + mm9 http://dbarchive.biosciencedbc.jp/kyushu-u/mm9/target/E2f3....1.tsv http://dbarchive.biosciencedbc.jp/kyushu-u/mm9/target/E2f3.5.tsv http://dbarch...ive.biosciencedbc.jp/kyushu-u/mm9/target/E2f3.10.tsv http://dbarchive.biosciencedbc.jp/kyushu-u/mm9/colo/E2f3....Digestive_tract.tsv,http://dbarchive.biosciencedbc.jp/kyushu-u/mm9/colo/E2f3.Em

  12. A bilateral antidiuresis to renal artery infusion of prostaglandin E1 in dogs treated with phenylbutazone

    Science.gov (United States)

    Hall, W. J.; Hensey, O. J.; O'Neill, P.; Sheehan, J. D.

    1978-01-01

    1. In acute experiments, high levels of endogenous prostaglandins, provoked by operative stress, could obscure or alter the actions of infused prostaglandins on the kidney. For this reason we decided to compare the effects of infusing prostaglandin E1 into the renal artery of the dog before and after the administration of phenylbutazone, a prostaglandin synthetase inhibitor. 2. Infusion of prostaglandin E1 into the left renal artery of the pre-phenylbutazone treated dog undergoing a mannitol diuresis increased renal plasma flow, glomerular filtration rate and the excretion of salt and water. The findings are in general agreement with those reported by others. 3. Following phenylbutazone administration the vascular and saluretic actions of prostaglandin E1 were unchanged but a reduced diuretic effect was observed. The response to a low dose of prostaglandin E1 (0·05 μg/min) was reduced from 1·46 ± 0·15 to 0·96 ± 0·16 ml./min (P phenylbutazone treatment than before. The reduction in the diuretic response was of the same order as the decrease in the free water clearance response, while the increase in osmolar clearance was unchanged. 5. In water-loaded dogs treated with phenylbutazone, infusion of prostaglandin E1 into the left renal artery had a biphasic effect on urine output from the left kidney. An initial diuretic response to a low dose of prostaglandin E1 disappeared with the infusion of higher doses, and antidiuresis developed in the immediate post-infusion period. 6. As prostaglandin was infused into the left kidney progressive antidiuresis was seen in the non-infused right kidney. 7. It is concluded that endogenous prostaglandins do not obscure or alter the vascular and saluretic actions of intrarenal prostaglandin E1. The findings question the proposed link between the vascular and saluretic actions of this compound. 8. It is suggested that the reduced diuretic effect of prostaglandin E1 in series no. 1, and the antidiuresis in the water-loaded dogs

  13. Prostaglandin-associated periorbitopathy in latanoprost users

    Directory of Open Access Journals (Sweden)

    Nakakura S

    2014-12-01

    Full Text Available Shunsuke Nakakura,1 Minamai Yamamoto,1 Etsuko Terao,1 Nozomi Nagatomi,1 Naoko Matsuo,1 Yausko Fujisawa,1 Yuki Fujio,1 Hitoshi Tabuchi,1 Yoshiaki Kiuchi2 1Department of Ophthalmology, Saneikai Tsukazaki Hospital, Himeji, Japan; 2Department of Ophthalmology and Visual Sciences, Graduate School of Biomedical Sciences, Hiroshima University, Hiroshima, Japan Purpose: We investigated the incidence of prostaglandin-associated periorbitopathy (PAP in subjects with glaucoma treated with latanoprost ophthalmic solution.Subjects and methods: One eye and the forehead in 22 subjects were evaluated. All patients had used latanoprost for more than 1 year (range, 12 to 45 months; mean, 26.0 months and were prostaglandin F2α analogue treatment-naïve. Digital photographs of the subjects obtained before latanoprost therapy and at the last examination were compared retrospectively. Four signs of PAP (deepening of the upper eyelid sulcus (DUES, upper eyelid ptosis, flattening of the lower eyelid bags, and inferior scleral show and supplemental side effects around the eyelids (eyelash growth, poliosis, and eyelid pigmentation were judged to be negative or positive by three independent observers. If the observers unanimously rated a sign as positive, the result was defined as positive.Results: Twelve subjects (54.5% had no apparent signs. Three subjects were judged to have DUES (13.6%, and two subjects each were judged to have flattening of the lower eyelid bags and eyelid pigmentation (9.0%. The other signs were judged as positive in only one subject each, respectively (4.5%. A univariate logistic regression analysis showed no significant associations between any of the signs and age, sex, or the duration of therapy.Conclusion: Latanoprost induced DUES, upper eyelid ptosis, flattening of the lower eyelid bags, inferior scleral show, and supplemental side effects around the eyelids; however, the rates of such occurrence might be relatively low. Keywords: glaucoma

  14. On the pathogenetic role of prostaglandins in Bartter's syndrome.

    Science.gov (United States)

    Nielsen, I; Hesse, B; Christensen, P

    1979-01-01

    Two patients, one with Bartter's syndrome and one with severe abuse of diuretics, were investigated before and after indomethacin treatment. Before indomethacin the two patients showed a similar pattern of hypokalaemic alcalosis, secondary hyperaldosteronism, and increased urinary excretion of PGE2 and kallikrein. After a few days on peroral indomethacin medication the hypokalaemia was significantly improved, the plasma renin activity, and the urinary excretion of aldosterone, PGE2 and kallikrein were normalized in both patients. It is concluded that the beneficial effect of indomethacin cannot be used as a proof of prostaglandin overproduction as the primary defect in Bartter's syndrome.

  15. Biotechnological approach towards a highly efficient production of natural prostaglandins.

    Science.gov (United States)

    Guder, J C; Buchhaupt, M; Huth, I; Hannappel, A; Ferreirós, N; Geisslinger, G; Schrader, J

    2014-11-01

    Prostaglandins (PGs) act as potent local hormones in nearly all tissues of the human body and are used for various medical applications. Heterologous expression of PG endoperoxide H-synthase from the alga, Gracilaria vermiculophylla, into E. coli and the application of this strain in biotransformation experiments resulted in a highly efficient conversion of arachidonic acid (ARA) yielding up to 130 mg natural PGs l(-1) in a laboratory scale approach. Detailed analyses of the products and production kinetics were performed, confirming a rapid conversion of ARA to PGs.

  16. Enteral feeding in prostaglandin-dependent neonates: is it a safe practice?

    Science.gov (United States)

    Willis, Lisa; Thureen, Patti; Kaufman, Jonathan; Wymore, Erica; Skillman, Heather; da Cruz, Eduardo

    2008-12-01

    In many centers presurgical term neonates with prostaglandin-dependent cardiac lesions experience nutritional deficiency because of postponed enteral feeds. We recently adopted early enteral feeding in these infants. This retrospective study demonstrates feeding tolerance in 33 of 34 neonates fed enterally while receiving prostaglandin, suggesting the safety of this practice.

  17. Involvement of prostaglandins in inflammation induced by latex of Calotropis procera

    Directory of Open Access Journals (Sweden)

    Yatin M. Shivkar

    1992-01-01

    Full Text Available INTRODUCTION: The aerial parts of the plant Calotropis procera produce milky white latex that causes inflammation of the skin and mucous membranes. Prostaglandins are one of the mediators released in an inflammatory response following induction of cyclooxygenase (COX. In the present study, we have evaluated the role of prostaglandins in inflammatory response elicited by the latex of C. procera.

  18. DcE2F, a functional plant E2F-like transcriptional activator from Daucus carota.

    Science.gov (United States)

    Albani, D; Mariconti, L; Ricagno, S; Pitto, L; Moroni, C; Helin, K; Cella, R

    2000-06-23

    In animal cells the progression of the cell cycle through G(1)/S transition and S phase is under the control of the pRB/E2F regulatory pathway. The E2F transcription factors are key activators of genes coding for several regulatory proteins and for enzymes involved in nucleotide and DNA synthesis. In this report we have detected the presence of E2F-like DNA binding activities in carrot nuclear extracts, and we have isolated a carrot cDNA (DcE2F) encoding a plant E2F homologue. The DcE2F gene is expressed in proliferating cells and is induced during the G(1)/S transition of the cell cycle. Supershift experiments using anti-DcE2F antiserum have confirmed that the DcE2F protein is a component of the carrot E2F-like nuclear activities. DNA binding assays have demonstrated that the DcE2F protein can recognize a canonical E2F cis-element in association with a mammalian DP protein. Furthermore, transactivation assays have revealed that DcE2F is a functional transcription factor that can transactivate, together with a DP partner, an E2F-responsive reporter gene in both plant and mammalian cells.

  19. Prostaglandin E₂ protects murine lungs from bleomycin-induced pulmonary fibrosis and lung dysfunction.

    Science.gov (United States)

    Dackor, Ryan T; Cheng, Jennifer; Voltz, James W; Card, Jeffrey W; Ferguson, Catherine D; Garrett, Ryan C; Bradbury, J Alyce; DeGraff, Laura M; Lih, Fred B; Tomer, Kenneth B; Flake, Gordon P; Travlos, Gregory S; Ramsey, Randle W; Edin, Matthew L; Morgan, Daniel L; Zeldin, Darryl C

    2011-11-01

    Prostaglandin E(2) (PGE(2)) is a lipid mediator that is produced via the metabolism of arachidonic acid by cyclooxygenase enzymes. In the lung, PGE(2) acts as an anti-inflammatory factor and plays an important role in tissue repair processes. Although several studies have examined the role of PGE(2) in the pathogenesis of pulmonary fibrosis in rodents, results have generally been conflicting, and few studies have examined the therapeutic effects of PGE(2) on the accompanying lung dysfunction. In this study, an established model of pulmonary fibrosis was used in which 10-12-wk-old male C57BL/6 mice were administered a single dose (1.0 mg/kg) of bleomycin via oropharyngeal aspiration. To test the role of prostaglandins in this model, mice were dosed, via surgically implanted minipumps, with either vehicle, PGE(2) (1.32 μg/h), or the prostacyclin analog iloprost (0.33 μg/h) beginning 7 days before or 14 days after bleomycin administration. Endpoints assessed at 7 days after bleomycin administration included proinflammatory cytokine levels and measurement of cellular infiltration into the lung. Endpoints assessed at 21 days after bleomycin administration included lung function assessment via invasive (FlexiVent) analysis, cellular infiltration, lung collagen content, and semiquantitative histological analysis of the degree of lung fibrosis (Ashcroft method). Seven days after bleomycin administration, lymphocyte numbers and chemokine C-C motif ligand 2 expression were significantly lower in PGE(2)- and iloprost-treated animals compared with vehicle-treated controls (P bleomycin challenge, PGE(2) also protected against the decline in lung static compliance, lung fibrosis, and collagen production that is associated with 3 wk of bleomycin exposure. However, PGE(2) had no therapeutic effect on these parameters when administered 14 days after bleomycin challenge. In summary, PGE(2) prevented the decline in lung static compliance and protected against lung fibrosis when it

  20. Emerging therapies for atopic dermatitis: The prostaglandin/leukotriene pathway.

    Science.gov (United States)

    Yanes, Daniel A; Mosser-Goldfarb, Joy L

    2018-03-01

    The role of leukotrienes and prostaglandins in development of atopy has been prototypically established in studies of asthma pathogenesis. Likewise, both in vitro and in vivo studies of atopic dermatitis have demonstrated that these molecules maintain important pathophysiologic roles. Thus, it follows that targeted therapies against these molecules may be promising in management of atopic dermatitis. Montelukast has had questionable efficacy in patients with atopic dermatitis, whereas small pilots using zileuton did have some clinically significant improvement. There are several agents in development that target leukotrienes and/or prostaglandins as well, including OC000459, Q301, and ZPL-521. In atopic dermatitis, OC000459 did not demonstrate efficacy in clinical trials, and the efficacy of the other 2 agents remains to be seen. Should these medications prove promising, these topical agents may play a future role in chronic maintenance therapy and flare prophylaxis in atopic dermatitis, as antileukotriene therapy does in asthma. Copyright © 2017 American Academy of Dermatology, Inc. Published by Elsevier Inc. All rights reserved.

  1. Data of evolutionary structure change: 1AKMC-3E2PB [Confc[Archive

    Lifescience Database Archive (English)

    Full Text Available 1AKMC-3E2PB 1AKM 3E2P C B SGFYHKHFLKLLDFTPAELNSLLQLAAKLKADKKSGKEEAKLTGKNIALIFEKDST...3E2P B 3E2PB SSVAKGESLID ...3E2P B 3E2PB GDLKYGRTVHS ...3E2P B 3E2PB LSLFENVEMYF ...3E2P B 3E2PB KVKGSYKIKRE

  2. Data of evolutionary structure change: 1AKMB-3E2PB [Confc[Archive

    Lifescience Database Archive (English)

    Full Text Available 1AKMB-3E2PB 1AKM 3E2P B B SGFYHKHFLKLLDFTPAELNSLLQLAAKLKADKKSGKEEAKLTGKNIALIFEKDST...3E2P B 3E2PB SSVAKGESLID ...3E2P B 3E2PB GDLKYGRTVHS ...3E2P B 3E2PB LSLFENVEMYF ...3E2P B 3E2PB KVKGSYKIKRE

  3. An E2-Substituted Chimeric Pestivirus With DIVA Vaccine Properties

    DEFF Research Database (Denmark)

    Rasmussen, Thomas Bruun; Uttenthal, Åse; Nielsen, Jens

    An advantage of the use of chimeric pestiviruses as modified live vaccines against classical swine fever (CSF) resides in their capacity to be manipulated to achieve the characteristics desired for safe and efficacious DIVA vaccines. We have recently generated a new chimeric virus, Riems26_E2gif...... engineered specifically for this purpose. The E2-substituted Riems26_E2gif was derived by homologues recombination of the complete E2 protein encoding genome region from Border disease strain Gifhorn into a bacterial artificial chromosome (BAC) harbouring the genome of the CSFV vaccine strain C......-Riems. The virulence, immunogenicity and vaccine properties of Riems26_E2gif were tested in a vaccine-challenge experiment in pigs. Riems26_E2gif vaccinated pigs could be differentiated from infected pigs using a CSFV-E2 specific ELISA. Following challenge infection with highly virulent CSFV strain Koslov, all...

  4. Analysis list: E2f4 [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available E2f4 Blood,Embryonic fibroblast,Liver,Muscle,Pluripotent stem cell + mm9 http://dba...rchive.biosciencedbc.jp/kyushu-u/mm9/target/E2f4.1.tsv http://dbarchive.biosciencedbc.jp/kyushu-u/mm9/target/E2f4....5.tsv http://dbarchive.biosciencedbc.jp/kyushu-u/mm9/target/E2f4.10.tsv http://dbarchive.biosciencedbc....jp/kyushu-u/mm9/colo/E2f4.Blood.tsv,http://dbarchive.biosciencedbc.jp/kyushu-u/mm9/colo/E2f4....Embryonic_fibroblast.tsv,http://dbarchive.biosciencedbc.jp/kyushu-u/mm9/colo/E2f4.Liver.tsv,htt

  5. Induction of human microsomal prostaglandin E synthase 1 by activated oncogene RhoA GTPase in A549 human epithelial cancer cells

    Energy Technology Data Exchange (ETDEWEB)

    Choi, Hye Jin [Laboratory of Systems Mucosal Biomodulation, Department of Microbiology and Immunology, Pusan National University School of Medicine, Yangsan (Korea, Republic of); Lee, Dong-Hyung [Department of Obstetrics and Gynecology, Medical Research Institute, Pusan National University, Busan (Korea, Republic of); Park, Seong-Hwan; Kim, Juil; Do, Kee Hun [Laboratory of Systems Mucosal Biomodulation, Department of Microbiology and Immunology, Pusan National University School of Medicine, Yangsan (Korea, Republic of); An, Tae Jin; Ahn, Young Sup; Park, Chung Berm [Department of Herbal Crop Research, NIHHS, RDA, Eumseong (Korea, Republic of); Moon, Yuseok, E-mail: moon@pnu.edu [Laboratory of Systems Mucosal Biomodulation, Department of Microbiology and Immunology, Pusan National University School of Medicine, Yangsan (Korea, Republic of); Medical Research Institute and Research Institute for Basic Sciences, Pusan National University, Busan (Korea, Republic of)

    2011-09-30

    Highlights: {yields} As a target of oncogene RhoA-linked signal, a prostaglandin metabolism is assessed. {yields} RhoA activation increases PGE{sub 2} levels and its metabolic enzyme mPGES-1. {yields} RhoA-activated NF-{kappa}B and EGR-1 are positively involved in mPGES-1 induction. -- Abstract: Oncogenic RhoA GTPase has been investigated as a mediator of pro-inflammatory responses and aggressive carcinogenesis. Among the various targets of RhoA-linked signals, pro-inflammatory prostaglandin E{sub 2} (PGE{sub 2}), a major prostaglandin metabolite, was assessed in epithelial cancer cells. RhoA activation increased PGE{sub 2} levels and gene expression of the rate-limiting PGE{sub 2} producing enzymes, cyclooxygenase-2 and microsomal prostaglandin E synthase 1 (mPGES-1). In particular, human mPGES-1 was induced by RhoA via transcriptional activation in control and interleukin (IL)-1{beta}-activated cancer cells. To address the involvement of potent signaling pathways in RhoA-activated mPGES-1 induction, various signaling inhibitors were screened for their effects on mPGES-1 promoter activity. RhoA activation enhanced basal and IL-1{beta}-mediated phosphorylated nuclear factor-{kappa}B and extracellular signal-regulated kinase1/2 proteins, all of which were positively involved in RhoA-induced gene expression of mPGES-1. As one potent down-stream transcription factor of ERK1/2 signals, early growth response gene 1 product also mediated RhoA-induced gene expression of mPGES-1 by enhancing transcriptional activity. Since oncogene-triggered PGE{sub 2} production is a critical modulator of epithelial tumor cells, RhoA-associated mPGES-1 represents a promising chemo-preventive or therapeutic target for epithelial inflammation and its associated cancers.

  6. Magnetic imaging of antiferromagnetic and superconducting phases in R bxF e2 -yS e2 crystals

    Science.gov (United States)

    Hazi, J.; Mousavi, T.; Dudin, P.; van der Laan, G.; Maccherozzi, F.; Krzton-Maziopa, A.; Pomjakushina, E.; Conder, K.; Speller, S. C.

    2018-02-01

    High-temperature superconducting (HTS) cuprate materials, with the ability to carry large electrical currents with no resistance at easily reachable temperatures, have stimulated enormous scientific and industrial interest since their discovery in the 1980's. However, technological applications of these promising compounds have been limited by their chemical and microstructural complexity and the challenging processing strategies required for the exploitation of their extraordinary properties. The lack of theoretical understanding of the mechanism for superconductivity in these HTS materials has also hindered the search for new superconducting systems with enhanced performance. The unexpected discovery in 2008 of HTS iron-based compounds has provided an entirely new family of materials for studying the crucial interplay between superconductivity and magnetism in unconventional superconductors. Alkali-metal-doped iron selenide (AxF e2 -yS e2 , A =alkali metal ) compounds are of particular interest owing to the coexistence of superconductivity at relatively high temperatures with antiferromagnetism. Intrinsic phase separation on the mesoscopic scale is also known to occur in what were intended to be single crystals of these compounds, making it difficult to interpret bulk property measurements. Here, we use a combination of two advanced microscopy techniques to provide direct evidence of the magnetic properties of the individual phases. First, x-ray linear dichroism studies in a photoelectron emission microscope, and supporting multiplet calculations, indicate that the matrix (majority) phase is antiferromagnetic whereas the minority phase is nonmagnetic at room temperature. Second, cryogenic magnetic force microscopy demonstrates unambiguously that superconductivity occurs only in the minority phase. The correlation of these findings with previous microstructural studies and bulk measurements paves the way for understanding the intriguing electronic and magnetic

  7. Assessment of the role of in situ generated (E)-2,4-diene-valproic acid in the toxicity of valproic acid and (E)-2-ene-valproic acid in sandwich-cultured rat hepatocytes

    Energy Technology Data Exchange (ETDEWEB)

    Surendradoss, Jayakumar; Chang, Thomas K.H.; Abbott, Frank S., E-mail: frank.abbott@ubc.ca

    2012-11-01

    Valproic acid (VPA) undergoes cytochrome P450-mediated desaturation to form 4-ene-VPA, which subsequently yields (E)-2,4-diene-VPA by β-oxidation. Another biotransformation pathway involves β-oxidation of VPA to form (E)-2-ene-VPA, which also generates (E)-2,4-diene-VPA by cytochrome P450-mediated desaturation. Although the synthetic form of (E)-2,4-diene-VPA is more hepatotoxic than VPA as shown in various experimental models, there is no conclusive evidence to implicate the in situ generated (E)-2,4-diene-VPA in VPA hepatotoxicity. The present study investigated the effects of modulating the in situ formation of (E)-2,4-diene-VPA on markers of oxidative stress (formation of 2′,7′-dichlorofluorescein; DCF), steatosis (accumulation of BODIPY 558/568 C{sub 12}), necrosis (release of lactate dehydrogenase; LDH), and on cellular total glutathione (GSH) levels in sandwich-cultured rat hepatocytes treated with VPA or (E)-2-ene-VPA. Treatment with either of these chemicals alone increased each of the toxicity endpoints. In VPA-treated hepatocytes, (E)-2,4-diene-VPA was detected only at trace levels, even after phenobarbital (PB) pretreatment and there was no effect on the toxicity of VPA. Furthermore, pretreatment with a cytochrome P450 enzyme inhibitor, 1-aminobenzotriazole (1-ABT), did not influence the extent of VPA toxicity in both PB-pretreated and vehicle-pretreated hepatocytes. However, in (E)-2-ene-VPA-treated hepatocytes, PB pretreatment greatly enhanced the levels of (E)-2,4-diene-VPA and this was accompanied by a further enhancement of the effects of (E)-2-ene-VPA on DCF formation, BODIPY accumulation, LDH release, and GSH depletion. Pretreatment with 1-ABT reduced the concentrations of (E)-2,4-diene-VPA and the extent of (E)-2-ene-VPA toxicity; however, this occurred in PB-pretreated hepatocytes, but not in control hepatocytes. In conclusion, in situ generated (E)-2,4-diene-VPA is not responsible for the hepatocyte toxicity of VPA, whereas it

  8. DcE2F, a functional plant E2F-like transcriptional activator from Daucus carota

    DEFF Research Database (Denmark)

    Albani, D; Mariconti, L; Ricagno, S

    2000-01-01

    In animal cells the progression of the cell cycle through G(1)/S transition and S phase is under the control of the pRB/E2F regulatory pathway. The E2F transcription factors are key activators of genes coding for several regulatory proteins and for enzymes involved in nucleotide and DNA synthesis...... experiments using anti-DcE2F antiserum have confirmed that the DcE2F protein is a component of the carrot E2F-like nuclear activities. DNA binding assays have demonstrated that the DcE2F protein can recognize a canonical E2F cis-element in association with a mammalian DP protein. Furthermore, transactivation...

  9. Pharmacologic increase in HIF1α enhances hematopoietic stem and progenitor homing and engraftment.

    Science.gov (United States)

    Speth, Jennifer M; Hoggatt, Jonathan; Singh, Pratibha; Pelus, Louis M

    2014-01-09

    Hematopoietic stem cell (HSC) transplantation is a lifesaving therapy for a number of immunologic disorders. For effective transplant, HSCs must traffic from the peripheral blood to supportive bone marrow niches. We previously showed that HSC trafficking can be enhanced by ex vivo treatment of hematopoietic grafts with 16-16 dimethyl prostaglandin E2 (dmPGE2). While exploring regulatory molecules involved in dmPGE2 enhancement, we found that transiently increasing the transcription factor hypoxia-inducible factor 1-α (HIF1α) is required for dmPGE2-enhanced CXCR4 upregulation and enhanced migration and homing of stem and progenitor cells and that pharmacologic manipulation of HIF1α is also capable of enhancing homing and engraftment. We also now identify the specific hypoxia response element required for CXCR4 upregulation. These data define a precise mechanism through which ex vivo pulse treatment with dmPGE2 enhances the function of hematopoietic stem and progenitor cells; these data also define a role for hypoxia and HIF1α in enhancement of hematopoietic transplantation.

  10. Role of omega-3 polyunsaturated fatty acids in the production of prostaglandin E2 and nitric oxide during experimental murine paracoccidioidomycosis.

    Science.gov (United States)

    Sargi, S C; Dalalio, M M O; Moraes, A G; Visentainer, J E L; Morais, D R; Visentainer, J V

    2013-01-01

    There has recently been increased interest in the potential health effects of omega-3 polyunsaturated fatty acids on the immune system. Paracoccidioidomycosis is the most important endemic mycosis in Latin America. Macrophages have a fundamental role and act as first line of organism defense. The purpose of this study was to analyze the effect of n-3 fatty acids on the production of PGE2 and NO by mice infected with Pb18 and fed a diet enriched with LNA for 8 weeks. To study the effect of omega-3 fatty acids on macrophage activity during experimental paracoccidioidomycosis, mice were infected with Pb18 and fed a diet supplemented with LNA. PGE2 in the serum of animals was analyzed and NO in the supernatants of macrophages cultured and challenged in vitro with Pb18 was measured. Omega-3 fatty acids seemed to decrease the production of PGE2 in vivo in the infected group fed an LNA-supplemented diet during the 4th and 8th weeks of the experiment. At the same time, we observed an increase in synthesis of NO by peritoneal macrophages in this group. Omega-3 fatty acids thus appear to have an immunomodulatory effect in paracoccidioidomycosis.

  11. Prostaglandin E2 EP2 and EP4 receptor activation mediates cAMP-dependent hyperpolarization and exocytosis of renin in juxtaglomerular cells

    DEFF Research Database (Denmark)

    Friis, Ulla Glenert; Stubbe, Jane; Uhrenholt, Torben Rene

    2005-01-01

    PGE(2) and PGI(2) stimulate renin secretion and cAMP accumulation in juxtaglomerular granular (JG) cells. We addressed, at the single-cell level, the receptor subtypes and intracellular transduction mechanisms involved. Patch clamp was used to determine cell capacitance (C(m)), current, and membr...

  12. Rosmarinic Acid in Prunella vulgaris Ethanol Extract Inhibits LPS-induced Prostaglandin E2 and Nitric Oxide in RAW264.7 Mouse Macrophages

    Science.gov (United States)

    Prunella vulgaris has been used therapeutically for inflammation related conditions for centuries, but systematic studies of its anti-inflammatory activity are lacking and no specific active components have been identified. In this study, water and ethanol extracts of four P. vulgaris accessions we...

  13. Sustained Release of Prostaglandin E2 in Fibroblasts Expressing Ectopically Cyclooxygenase 2 Impairs P2Y-Dependent Ca2+-Mobilization

    Directory of Open Access Journals (Sweden)

    María Pimentel-Santillana

    2014-01-01

    Full Text Available The nucleotide uridine trisphosphate (UTP released to the extracellular milieu acts as a signaling molecule via activation of specific pyrimidine receptors (P2Y. P2Y receptors are G protein-coupled receptors expressed in many cell types. These receptors mediate several cell responses and they are involved in intracellular calcium mobilization. We investigated the role of the prostanoid PGE2 in P2Y signaling in mouse embryonic fibroblasts (MEFs, since these cells are involved in different ontogenic and physiopathological processes, among them is tissue repair following proinflammatory activation. Interestingly, Ca2+-mobilization induced by UTP-dependent P2Y activation was reduced by PGE2 when this prostanoid was produced by MEFs transfected with COX-2 or when PGE2 was added exogenously to the culture medium. This Ca2+-mobilization was important for the activation of different metabolic pathways in fibroblasts. Moreover, inhibition of COX-2 with selective coxibs prevented UTP-dependent P2Y activation in these cells. The inhibition of P2Y responses by PGE2 involves the activation of PKCs and PKD, a response that can be suppressed after pharmacological inhibition of these protein kinases. In addition to this, PGE2 reduces the fibroblast migration induced by P2Y-agonists such as UTP. Taken together, these data demonstrate that PGE2 is involved in the regulation of P2Y signaling in these cells.

  14. FE2O3 PARTICLE-INDUCED PROSTAGLANDIN E2 (PGE2) SYNTHESIS IN ALVEOLAR MACROPHAGES (AM) DETERMINES PARTICULATE INFLAMMATORY POTENTIAL

    Science.gov (United States)

    As shown by epidemiologic studies, acute exposure to ambient particles is associated with exacerbation of pulmonary and cardiovascular diseases. Metals associated with particles are able to mediate lung injury via oxidant-catalyzed reactions. However, the underlying mechanism i...

  15. Bowman-Birk inhibitor and genistein among soy compounds that synergistically inhibit nitric oxide and prostaglandin E2 pathways in lipopolysaccharide-induced macrophages

    Science.gov (United States)

    Inflammation has an important role in the development of chronic diseases. In this study, we evaluated the anti-inflammatory properties of eight soybean bioactive compounds using lipopolysaccharide-induced RAW 264.7 macrophages. Genistein, daidzein, mix isoflavone glucosides, saponin A group glyco...

  16. The role of prostaglandin E2 (PGE 2 in toll-like receptor 4 (TLR4-mediated colitis-associated neoplasia

    Directory of Open Access Journals (Sweden)

    Hayes Lory A

    2010-07-01

    Full Text Available Abstract Background We have previously found that TLR4-deficient (TLR4-/- mice demonstrate decreased expression of mucosal PGE 2 and are protected against colitis-associated neoplasia. However, it is still unclear whether PGE 2 is the central factor downstream of TLR4 signaling that promotes intestinal tumorigenesis. To further elucidate critical downstream pathways involving TLR4-mediated intestinal tumorigenesis, we examined the effects of exogenously administered PGE 2 in TLR4-/- mice to see if PGE 2 bypasses the protection from colitis-associated tumorigenesis. Method Mouse colitis-associated neoplasia was induced by azoxymethane (AOM injection followed by two cycles of dextran sodium sulfate (DSS treatment. Two different doses of PGE 2 (high dose group, 200 μg, n = 8; and low dose group, 100 μg, n = 6 were administered daily during recovery period of colitis by gavage feeding. Another group was given PGE 2 during DSS treatment (200 μg, n = 5. Inflammation and dysplasia were assessed histologically. Mucosal Cox-2 and amphiregulin (AR expression, prostanoid synthesis, and EGFR activation were analyzed. Results In control mice treated with PBS, the average number of tumors was greater in WT mice (n = 13 than in TLR4-/- mice (n = 7. High dose but not low dose PGE 2 treatment caused an increase in epithelial proliferation. 28.6% of PBS-treated TLR4-/- mice developed dysplasia (tumors/animal: 0.4 ± 0.2. By contrast, 75.0% (tumors/animal: 1.5 ± 1.2, P 2 treatment. Endogenous prostanoid synthesis was differentially affected by PGE 2 treatment during acute and recovery phases of colitis. Exogenous administration of PGE 2 increased colitis-associated tumorigenesis but this only occurred during the recovery phase. Lastly, PGE 2 treatment increased mucosal expression of AR and Cox-2, thus inducing EGFR activation and forming a positive feedback mechanism to amplify mucosal Cox-2. Conclusions These results highlight the importance of PGE 2 as a central downstream molecule involving TLR4-mediated intestinal tumorigenesis.

  17. Prostaglandin E2 Leads to the Acquisition of DNMT3A-Dependent Tolerogenic Functions in Human Myeloid-Derived Suppressor Cells.

    Science.gov (United States)

    Rodríguez-Ubreva, Javier; Català-Moll, Francesc; Obermajer, Nataša; Álvarez-Errico, Damiana; Ramirez, Ricardo N; Company, Carlos; Vento-Tormo, Roser; Moreno-Bueno, Gema; Edwards, Robert P; Mortazavi, Ali; Kalinski, Pawel; Ballestar, Esteban

    2017-10-03

    Myeloid-derived suppressor cells (MDSCs) and dendritic cells (DCs) arise from common progenitors. Tumor-derived factors redirect differentiation from immune-promoting DCs to tolerogenic MDSCs, an immunological hallmark of cancer. Indeed, in vitro differentiation of DCs from human primary monocytes results in the generation of MDSCs under tumor-associated conditions (PGE2 or tumor cell-conditioned media). Comparison of MDSC and DC DNA methylomes now reveals extensive demethylation with specific gains of DNA methylation and repression of immunogenic-associated genes occurring in MDSCs specifically, concomitant with increased DNA methyltransferase 3A (DNMT3A) levels. DNMT3A downregulation erases MDSC-specific hypermethylation, and it abolishes their immunosuppressive capacity. Primary MDSCs isolated from ovarian cancer patients display a similar hypermethylation signature in connection with PGE2-dependent DNMT3A overexpression. Our study links PGE2- and DNMT3A-dependent hypermethylation with immunosuppressive MDSC functions, providing a promising target for therapeutic intervention. Copyright © 2017 The Author(s). Published by Elsevier Inc. All rights reserved.

  18. Role of Omega-3 Polyunsaturated Fatty Acids in the Production of Prostaglandin E2 and Nitric Oxide during Experimental Murine Paracoccidioidomycosis

    Directory of Open Access Journals (Sweden)

    S. C. Sargi

    2013-01-01

    Full Text Available There has recently been increased interest in the potential health effects of omega-3 polyunsaturated fatty acids on the immune system. Paracoccidioidomycosis is the most important endemic mycosis in Latin America. Macrophages have a fundamental role and act as first line of organism defense. The purpose of this study was to analyze the effect of n-3 fatty acids on the production of PGE2 and NO by mice infected with Pb18 and fed a diet enriched with LNA for 8 weeks. To study the effect of omega-3 fatty acids on macrophage activity during experimental paracoccidioidomycosis, mice were infected with Pb18 and fed a diet supplemented with LNA. PGE2 in the serum of animals was analyzed and NO in the supernatants of macrophages cultured and challenged in vitro with Pb18 was measured. Omega-3 fatty acids seemed to decrease the production of PGE2 in vivo in the infected group fed an LNA-supplemented diet during the 4th and 8th weeks of the experiment. At the same time, we observed an increase in synthesis of NO by peritoneal macrophages in this group. Omega-3 fatty acids thus appear to have an immunomodulatory effect in paracoccidioidomycosis.

  19. Additive effects of estrogen and mechanical stress on nitric oxide and prostaglandin E2 production by bone cells from osteoporotic donors.

    NARCIS (Netherlands)

    Bakker, A.D.; Klein-Nulend, J.; Tanck, E.J.M.; Albers, G.H.; Lips, P.; Burger, E.H.

    2005-01-01

    Mechanical loading is thought to provoke a cellular response via loading-induced flow of interstitial fluid through the lacuno-canalicular network of osteocytes. This response supposedly leads to an adaptation of local bone mass and architecture. It has been suggested that loss of estrogen during

  20. Long-Term Prostaglandin E1 Infusion for Newborns with Critical Congenital Heart Disease.

    Science.gov (United States)

    Aykanat, Alper; Yavuz, Taner; Özalkaya, Elif; Topçuoğlu, Sevilay; Ovalı, Fahri; Karatekin, Güner

    2016-01-01

    Prostaglandin E1 is crucial for keeping the patent ductus arteriosus in critical congenital heart disease for the survival and palliation of particularly prematurely born babies until a cardiosurgical intervention is available. In this study, the side effects of prostaglandin E1 in newborns with critical congenital heart disease and clinical outcomes were evaluated. Thirty-five newborns diagnosed with critical congenital heart disease were treated with prostaglandin E1 between January 2012 and September 2014 at our hospital. Patient charts were examined for prostaglandin E1 side effects (metabolic, gastric outlet obstruction, apnea), clinical status, and prognosis. Acquired data were analyzed in the SPSS 20.0 program. Patients with birth weight under 2500 g needed more days of prostaglandin E1 infusion than ones with birthweight over 2500 g (P = 0.016). The ratio of patients with birth weight under 2500 g who received prostaglandin E1 longer than 7 days was higher than the patients with birth weight over 2500 g (P = 0.02). Eighteen side effects were encountered in 11 of 35 patients (31%). Of these side effects, 1 patient had 4, 4 patients had 2, and 6 patients had only 1 side effect. Discontinuation of the therapy was never needed. Prostaglandin E1 is an accepted therapy modality for survival and outcome in critical congenital heart disease in particularly low-birth-weight babies until a surgical intervention is available. Side effects are not less encountered but are almost always manageable, and discontinuation is not needed.

  1. NSAID Pretreatment Inhibits Prostaglandin Release in Femtosecond Laser-Assisted Cataract Surgery.

    Science.gov (United States)

    Schultz, Tim; Joachim, Stephanie C; Szuler, Marek; Stellbogen, Mathias; Dick, H Burkhard

    2015-12-01

    To investigate whether short-term nonsteroidal anti-inflammatory drug (NSAID) pretreatment on the day of surgery inhibits prostaglandin release. Previous studies detected elevated prostaglandin levels after femtosecond laser treatment and identified them as a potential mediator for laser-induced miosis. Patients underwent either image-guided femtosecond laser cataract surgery or conventional cataract surgery (n = 75). Half of the eyes per group received topical NSAID treatment on the day of surgery. Aqueous humor was collected from all patients. ELISA measurements were performed to detect aqueous humor prostaglandin levels. Femtosecond laser cataract surgery led to higher prostaglandin levels than conventional cataract surgery (P = .007). In both groups, NSAID pretreatment led to reduced prostaglandin release. In the femtosecond laser group, patients pretreated with NSAIDs had significantly lower prostaglandin values (65.3 ± 13.2 pg/mL) than patients not pretreated with NSAIDs (294.4 ± 66.5 pg/mL) (P = .0009). The short-term NSAID treatment prevented prostaglandin release in patients treated with image-guided femtosecond laser. Therefore, it has potential to limit intraoperative laser-induced miosis. Copyright 2015, SLACK Incorporated.

  2. Plasma 8-iso-Prostaglandin F2α concentrations and outcomes after acute intracerebral hemorrhage.

    Science.gov (United States)

    Du, Quan; Yu, Wen-Hua; Dong, Xiao-Qiao; Yang, Ding-Bo; Shen, Yong-Feng; Wang, Hao; Jiang, Li; Du, Yuan-Feng; Zhang, Zu-Yong; Zhu, Qiang; Che, Zhi-Hao; Liu, Qun-Jie

    2014-11-01

    Higher plasma 8-iso-Prostaglandin F2α concentrations have been associated with poor outcome of severe traumatic brain injury. We further investigated the relationships between plasma 8-iso-Prostaglandin F2α concentrations and clinical outcomes in patients with acute intracerebral hemorrhage. Plasma 8-iso-Prostaglandin F2α concentrations of 128 consecutive patients and 128 sex- and gender-matched healthy subjects were measured by enzyme-linked immunosorbent assay. We assessed their relationships with disease severity and clinical outcomes including 1-week mortality, 6-month mortality and unfavorable outcome (modified Rankin Scale score>2). Plasma 8-iso-Prostaglandin F2α concentrations were substantially higher in patients than in healthy controls. Plasma 8-iso-Prostaglandin F2α concentrations were positively associated with National Institutes of Health Stroke Scale (NIHSS) scores and hematoma volume using a multivariate linear regression. It emerged as an independent predictor for clinical outcomes of patients using a forward stepwise logistic regression. ROC curves identified the predictive values of plasma 8-iso-Prostaglandin F2α concentrations, and found its predictive value was similar to NIHSS scores and hematoma volumes. However, it just numerically added the predictive values of NIHSS score and hematoma volume. Increased plasma 8-iso-Prostaglandin F2α concentrations are associated with disease severity and clinical outcome after acute intracerebral hemorrhage. Copyright © 2014 Elsevier B.V. All rights reserved.

  3. Analysis list: Gtf2e2 [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available Gtf2e2 Blood,Liver + mm9 http://dbarchive.biosciencedbc.jp/kyushu-u/mm9/target/Gtf2...e2.1.tsv http://dbarchive.biosciencedbc.jp/kyushu-u/mm9/target/Gtf2e2.5.tsv http://dbarchive.biosciencedbc.j...p/kyushu-u/mm9/target/Gtf2e2.10.tsv http://dbarchive.biosciencedbc.jp/kyushu-u/mm9/colo/Gtf2e2.Blood.tsv,http://dbarchive.bioscience...dbc.jp/kyushu-u/mm9/colo/Gtf2e2.Liver.tsv http://dbarchive.bioscience...dbc.jp/kyushu-u/mm9/colo/Blood.gml,http://dbarchive.biosciencedbc.jp/kyushu-u/mm9/colo/Liver.gml ...

  4. On the role of prostaglandins in parturition in the rat.

    Science.gov (United States)

    Strauss, J F; Sokoloski, J; Caploe, P; Duffy, P; Mintz, G; Stambaugh, R L

    1975-04-01

    Treatment of both intact and hypophysectomized pregnant rats on days 19 and 20 of pregnancy with PGF2alpha results in a rapid fall in plasma progesterone concentrations by day 20 followed by premature delivery on day 21. Administration of depoprovera did not prevent the PGF2alpha-induced fall in progesterone levels but premature littering was adverted. Indomethacin, an inhibitor of prostaglandin biosynthesis, postponed the onset of parturition by 20 h when administered in late pregnancy but rats treated with both indomethacin and PGF2alpha delivered at the normal time. Treatment of both intact and hypophysectomized animals with indomethacin delayed the fall in plasma progesterone concentrations which normally occurs between days 21 and 22 of pregnancy. Concomitant PGF2alpha treatment of rats receiving indomethacin caused plasma progesterone levels to fall in a pattern similar to controls. These findings indicate that endogenous PGF2alpha induces a fall in blood progesterone concentrations which is followed by increased myometrial activity.

  5. Follicular Dynamics in Crossbred cows undergoing prostaglandin induced luteolysis

    Directory of Open Access Journals (Sweden)

    Manjusha Patil

    2008-04-01

    Full Text Available Growth and regression of ovarian follicles were studied in crossbred cows (n=6, induced with prostaglandin (PGF2 alpha analogue for luteolysis. After PGF2 alpha treatment, four cows (Group A ovulated from dominant follicle of first follicular wave and remaining 2 animals ovulated from second dominant follicle (Group B. The intervals from treatment to estrus (P<0.01 and treatment to ovulation (P<0.01 were significantly longer in animals of group B compared to the animals of group A. Significant differences were observed in growth profile of ovulatory follicle between animals of group A and group B with respect to daily growth rate (P<0.01, increase in diameter (P<0.01 and size of the follicle on day 0 (P<0.01. [Veterinary World 2008; 1(2.000: 42-44

  6. Biosynthesis of prostaglandins in gingiva of patients with chronic periodontitis

    Energy Technology Data Exchange (ETDEWEB)

    Mendieta, C.F.; Reeve, C.M.; Romero, J.C.

    1985-01-01

    This study was undertaken to determine the ability of inflamed and normal gingival tissues to synthesize prostaglandins (PGs) from the precursor arachidonic acid. Thirteen samples of inflamed human gingival tissue and six samples of normal human gingival tissue were studied. The inflammation was characterized histologically. After incubation of the tissue with (/sup 14/C)arachidonate, PG metabolites were separated by thin-layer chromatography and identified by comparison with co-chromatographed standards. Inflamed gingival tissue synthesized significantly larger amounts, compared to normal tissue, of 6-keto-PGF1 alpha (P less than 0.05), thromboxane B2, PGD2, and PGA2. Some unidentified metabolites, possibly lipoxygenase products were detected in significantly larger amounts in inflamed than in normal tissue.

  7. The first human epitope map of the alphaviral E1 and E2 proteins reveals a new E2 epitope with significant virus neutralizing activity.

    Directory of Open Access Journals (Sweden)

    Ann R Hunt

    2010-07-01

    of a cocktail of F5n and Hy4 IgGs, which bind to different E2 epitopes, could provide enhanced prophylaxis or immunotherapy for VEEV, while reducing the possibility of generating possibly harmful virus neutralization-escape variants in vivo.

  8. Prostaglandin E receptor subtype 4 regulates lipid droplet size and mitochondrial activity in murine subcutaneous white adipose tissue.

    Science.gov (United States)

    Ying, Fan; Cai, Yin; Cai, Yu; Wang, Yu; Tang, Eva Hoi Ching

    2017-09-01

    The purpose of this study was to investigate whether genetic ablation of prostaglandin E receptor subtype 4 (EP4) affects white adipose tissue (WAT) remodeling mediated by β3-adrenergic stimulation. The selective β3-adrenergic agonist, CL316243 (1 mg/kg/d, i.p.) caused a greater increase in metabolic rate in EP4-knockout mice. CL316243 fragmented the unilocular lipid droplet into multilocular lipid vacuoles and increased mitochondrial biogenesis and its activity. These changes were amplified in mice with EP4 deficiency and were selectively seen in subcutaneous WAT. The expression of fat-specific protein (FSP)-27, a protein that promotes fusion of triglycerides and formation of unilocular lipid droplets were diminished, whereas the expression of phosphorylated AMPK, the upstream regulator of FSP27, was enhanced in EP4-deficient mice. The present study showed that EP4 acts as a negative regulator of WAT remodeling, it tightly coordinates rates of triglyceride storage in lipid droplets and mitochondrial respiratory function in subcutaneous white adipocytes through the phosphorylated AMPK-FSP27 signaling axis. Thus, deletion of EP4 increases mitochondrial biogenesis and oxidative capacity in WAT, and fat mass loss ensues in mice.-Ying, F., Cai, Y., Cai, Y., Wang, Y., Tang, E. H. C. Prostaglandin E receptor subtype 4 regulates lipid droplet size and mitochondrial activity in murine subcutaneous white adipose tissue. © FASEB.

  9. Prostaglandin F2 alpha in benign and malignant breast tumours.

    Science.gov (United States)

    Vergote, I B; Laekeman, G M; Keersmaekers, G H; Uyttenbroeck, F L; Vanderheyden, J S; Albertyn, G P; Haensch, C F; De Roy, G J; Herman, A G

    1985-06-01

    Prostaglandin F2 alpha (PGF2 alpha) was determined by radioimmunoassay in 57 breast carcinomata, 16 fibroadenomata, and 33 sclero-cystic-disease (SCD) specimens. In 41 cases of carcinoma and 10 cases of fibroadenoma, histologically non-malignant tissue was also obtained from the same breast. PGF2 alpha levels were significantly elevated in breast cancer when compared with the normal tissues and benign diseases (P less than 0.005 for each group). High PGF2 alpha levels were positively correlated with differentiation, positive oestrogen and progestagen receptor status, and low mitotic index. Tumours with good prognosis (less than 20 mm, negative lymph nodes, some degree of differentiation) showed significantly higher PGF2 alpha levels than tumours with a bad prognosis (greater than 20 mm, positive nodes and undifferentiated). A tendency for elevated PGF2 alpha levels was observed with negative lymphatic permeation, postmenopausal status, low grade of nuclear and cellular polymorphism and high degree of elastosis and fibrosis. No correlation was observed between PGF2 alpha levels and host-cell reaction. Plasma levels of 15-keto-13, 14-dihydro-PGF2 alpha were not elevated in cancer patients when compared with the SCD-group. The present study demonstrates that PGF2 alpha levels are high in tumours with good prognosis. However, since other authors have suggested that a high PGE2 production is a bad prognostic index, it is possible that conversion of PGE2 to PGF2 alpha by 9-keto-reductase explains this relationship. Nevertheless, the presented results question the unrestricted use of prostaglandin-synthesis-inhibitors in the treatment of breast cancer.

  10. Atypical E2f functions are critical for pancreas polyploidization.

    Science.gov (United States)

    Matondo, Ramadhan B; Moreno, Eva; Toussaint, Mathilda J M; Tooten, Peter C J; van Essen, Saskia C; van Liere, Elsbeth A; Youssef, Sameh A; Bongiovanni, Laura; de Bruin, Alain

    2018-01-01

    The presence of polyploid cells in the endocrine and exocrine pancreas has been reported for four decades. In rodents, pancreatic polyploidization is initiated after weaning and the number of polyploid cells increases with age. Surprisingly the molecular regulators and biological functions of polyploidization in the pancreas are still unknown. We discovered that atypical E2f activity is essential for polyploidization in the pancreas, using an inducible Cre/LoxP approach in new-born mice to delete ubiquitously the atypical E2f transcription factors, E2f7 and E2f8. In contrast to its critical role in embryonic survival, conditional deletion of both of both atypical E2fs in newborn mice had no impact on postnatal survival and mice lived until old age. However, deficiency of E2f7 or E2f8 alone was sufficient to suppress polyploidization in the pancreas and associated with only a minor decrease in blood serum levels of glucose, insulin, amylase and lipase under 4 hours starvation condition compared to wildtype littermates. In mice with fewer pancreatic polyploid cells that were fed ad libitum, no major impact on hormones or enzymes levels was observed. In summary, we identified atypical E2fs to be essential for polyploidization in the pancreas and discovered that postnatal induced loss of both atypical E2fs in many organs is compatible with life until old age.

  11. Plain film and CT observations in prostaglandin-induced bone changes

    Energy Technology Data Exchange (ETDEWEB)

    Matzinger, M.A.; Briggs, V.A.; Dunlap, H.J.; Udjus, K.; Martin, D.J.; McDonald, P. (Children' s Hospital of Eastern Ontario, Ottawa, ON (Canada). Dept. of Radiology)

    1992-08-01

    Prostaglandin E[sub 1] intravenous infusion is used in infants with ductal-dependent cogenital heart disease to maintain ductal patency and prolong life until palliative or corrective surgery is feasible. Complications of prostaglandin administration include fever, diarrhoea, hypotension, apnoea, bradycardia, pseudowidening of the cranial sutures, underossification of the calvarial bones, periostitis, and skin edema. This paper presents dramatic plain radiographic features of prostaglandin-induced bone disease, inlcuding periosteal proliferation and the unusual bone-within-bone apperance, and provides the previously unpublished CT correlation. (orig.).

  12. Fluid shear stress stimulates prostaglandin and nitric oxide release in bone marrow-derived preosteoclast-like cells

    Science.gov (United States)

    McAllister, T. N.; Du, T.; Frangos, J. A.

    2000-01-01

    Bone is a porous tissue that is continuously perfused by interstitial fluid. Fluid flow, driven by both vascular pressure and mechanical loading, may generate significant shear stresses through the canaliculi as well as along the bone lining at the endosteal surface. Both osteoblasts and osteocytes produce signaling factors such as prostaglandins and nitric in response to fluid shear stress (FSS); however, these humoral agents appear to have more profound affects on osteoclast activity at the endosteal surface. We hypothesized that osteoclasts and preosteoclasts may also be mechanosensitive and that osteoclast-mediated autocrine signaling may be important in bone remodeling. In this study, we investigated the effect of FSS on nitric oxide (NO), prostaglandin E(2) (PGE(2)), and prostacyclin (PGI(2)) release by neonatal rat bone marrow-derived preosteoclast-like cells. These cells were tartrate-resistant acid phosphatase (TRAP) positive, weakly nonspecific esterase (NSE) positive, and capable of fusing into calcitonin-responsive, bone-resorbing, multinucleated cells. Bone marrow-derived preosteoclast-like cells exposed for 6 h to a well-defined FSS of 16 dynes/cm(2) produced NO at a rate of 7.5 nmol/mg protein/h, which was 10-fold that of static controls. This response was completely abolished by 100 microM N(G)-amino-L-arginine (L-NAA). Flow also stimulated PGE(2) production (3.9 microg/mg protein/h) and PGI(2) production (220 pg/mg protein/h). L-NAA attenuated flow-induced PGE(2) production by 30%, suggesting that NO may partially modulate PGE(2) production. This is the first report demonstrating that marrow derived cells are sensitive to FSS and that autocrine signaling in these cells may play an important role in load-induced remodeling and signal transduction in bone. Copyright 2000 Academic Press.

  13. Unusual proliferation arrest and transcriptional control properties of a newly discovered E2F family member, E2F-6.

    Science.gov (United States)

    Gaubatz, S; Wood, J G; Livingston, D M

    1998-08-04

    E2F transcription factors play an important role in the regulation of cell cycle progression. We report here the cloning and characterization of an additional member of this family, E2F-6. E2F-6 lacks pocket protein binding and transactivation domains, and it is a potent transcriptional repressor that contains a modular repression domain at its carboxyl terminus. Overproduction of E2F-6 had no specific effect on cell cycle progression in asynchronously growing Saos2 and NIH 3T3 cells, but it inhibited entry into S phase of NIH 3T3 cells stimulated to exit G0. Taken together, these data suggest that E2F-6 can regulate a subset of E2F-dependent genes whose products are required for entry into the cell cycle but not for normal cell cycle progression.

  14. Prostaglandin E₂ and polyenylphosphatidylcholine protect against intestinal fibrosis and regulate myofibroblast function.

    Science.gov (United States)

    Baird, Angela C; Lloyd, Frances; Lawrance, Ian C

    2015-06-01

    Intestinal fibrosis is a serious and often recurrent complication of inflammatory bowel disease despite surgical intervention. The anti-fibrotic potential of prostaglandin E2 (PGE2) and polyenylphosphatidylcholine (PC) was investigated using the murine model of 2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced chronic intestinal inflammation and fibrosis, and murine and human intestinal myofibroblasts. Mice were treated with TNBS enemas weekly for 2 or 6 weeks ± PGE2 (10 mg/kg/day orally) or PC (200 mg/kg/day orally). Inflammation and fibrosis were histologically assessed and scored. Pro-inflammatory cytokines, TLR4, and ECM-related gene expression from the colonic tissue and cultured myofibroblasts were assessed by RT-qPCR. The levels of α-SMA(+) staining and endogenous PGE2 in vivo were also assessed. Both PGE2 and PC treatment significantly decreased TNBS-induced intestinal inflammation and excess collagen deposition in vivo. This was accompanied by decreased α-SMA(+) staining in the lamina propria and lower collagen type I (COL1α1) expression. Endogenous PGE2 levels demonstrated that PC was not being converted into PGE2, thus mediating its effects primarily via PGE2-independent pathways. Both PGE2 and the PC isoform, 1,2-dilinoleoylphosphatidylcholine (DLPC), regulated primary mouse myofibroblast and CCD-18co COL1α1 production, and induced lower collagen type I to III and TGF-β1 to TGF-β3 ratios, demonstrating their ability to induced normal healing in the presence of phorbol 12-myristate 13-acetate (protein kinase C-dependent inducer of collagen production). PGE2 and PC both have potent anti-fibrogenic potentials in their ability to regulate inflammatory cell and myofibroblast accumulation within inflamed tissue, to decrease pro-inflammatory cytokine expression and to maintain normal healing in an inflammatory environment.

  15. Polymorphisms in the prostaglandin receptor EP2 gene confers susceptibility to tuberculosis.

    Science.gov (United States)

    Liang, Li; Zhang, Qing; Luo, Liu-Lin; Yue, Jun; Zhao, Yan-Lin; Han, Min; Liu, Li-Rong; Xiao, He-Ping

    2016-12-01

    Prostaglandin E2 (PGE2) is an important lipid mediator of the inflammatory immune response during acute and chronic infections. PGE2 modulates a variety of immune functions via four receptors (EP1-EP4), which mediate distinct PGE2 effects. Mice lacking EP2 are more susceptible to infection by Mycobacterium tuberculosis (M.tb), have a higher bacterial load, and increase size and number of granulomatous lesions. Our aim was to assess whether single nucleotide polymorphisms (SNPs) in EP2 increase the risk of tuberculosis. DNA re-sequencing revealed five common EP2 variants in the Chinese Han population. We sequenced the EP2 gene from 600 patients and 572 healthy controls to measure SNP frequencies in association with tuberculosis infections (TB) within the population. The rs937337 polymorphism is associated with increased risk to tuberculosis (p=0.0044, odds ratio [OR], 1.67; 95% confidential interval,1.22-2.27). The rs937337 AA genotype and the rs1042618 CC genotype were significantly associated with TB. An estimation of the frequencies of haplotypes revealed a single protective haplotype GACGC for tuberculosis (p=0.00096, odds ratio [OR], 0.56; 95% confidential interval, 0.41-0.77). Furthermore, we determined that the remaining SNPs of EP2 were nominally associated with clinical patterns of disease. We identified genetic polymorphisms in EP2 associated with susceptibility to tuberculosis within a Chinese population. Our data support that EP2 SNPs are genetic predispositions of increased susceptibility to TB and to different clinical patterns of disease. Copyright © 2016 Elsevier B.V. All rights reserved.

  16. The atmospheric photolysis of E-2-hexenal, Z-3-hexenal and E,E-2,4-hexadienal.

    Science.gov (United States)

    O'Connor, Margaret P; Wenger, John C; Mellouki, Abdelwahid; Wirtz, Klaus; Muñoz, Amalia

    2006-11-28

    The atmospheric photolysis of E-2-hexenal, Z-3-hexenal and E,E-2,4-hexadienal has been investigated at the large outdoor European Photoreactor (EUPHORE) in Valencia, Spain. E-2-Hexenal and E,E-2,4-hexadienal were found to undergo rapid isomerization to produce Z-2-hexenal and a ketene-type compound (probably E-hexa-1,3-dien-1-one), respectively. Both isomerization processes were reversible with formation of the reactant slightly favoured. Values of j(E-2-hexenal)/j(NO(2)) = (1.80 +/- 0.18) x 10(-2) and j(E,E-2,4-hexadienal)/j(NO(2)) = (2.60 +/- 0.26) x 10(-2) were determined. The gas phase UV absorption cross-sections of E-2-hexenal and E,E-2,4-hexadienal were measured and used to derive effective quantum yields for photoisomerization of 0.36 +/- 0.04 for E-2-hexenal and 0.23 +/- 0.03 for E,E-2,4-hexadienal. Although photolysis appears to be an important atmospheric degradation pathway for E-2-hexenal and E,E-2,4-hexadienal, the reversible nature of the photolytic process means that gas phase reactions with OH and NO(3) radicals are ultimately responsible for the atmospheric removal of these compounds. Atmospheric photolysis of Z-3-hexenal produced CO, with a molar yield of 0.34 +/- 0.03, and 2-pentenal via a Norrish type I process. A value of j(Z-3-hexenal)/j(NO(2)) = (0.4 +/- 0.04) x 10(-2) was determined. The results suggest that photolysis is likely to be a minor atmospheric removal process for Z-3-hexenal.

  17. The effect of two different routes of administration of oxytocin on peripheral plasma prostaglandin F(2α) metabolite levels in early post-partum dairy cows.

    Science.gov (United States)

    Bajcsy, A C S; Kindahl, H; Szenci, O; van der Weijden, G C; Bartyik, J; Taverne, M A M

    2012-04-01

    Various parenteral treatment forms of oxytocin, as often used under praxis circumstances, may act differently on contractility of the uterus during the first days of the puerperium. Various patterns of such induced uterotonic responses may lead to alterations in the emptying characteristics of the uterine lumen, thus influencing, as a late consequence, the process of involution. Therefore, this study was designed to test whether two different parenteral administration forms of oxytocin induce changes in peripheral plasma concentrations of 15-ketodihydro-prostaglandin F(2α) (PGF(2α) metabolite) in early post-partum cows. Between 13 and 15 h after uncomplicated calving, healthy dairy cows without retained foetal membranes were treated with 50 IU oxytocin, either intramuscularly (OT-IM group; n = 15) or intravenously (OT-IV group; n = 16). Saline solution was administered intramuscularly as controls (CON group; n = 15). Jugular blood samples were taken at 10-min intervals from 1 h before to 2 h after treatment. Plasma PGF(2α) metabolite levels were measured by radioimmunoassay. No significant differences in peripheral plasma PGF(2α) metabolite concentrations occurred in the OT-IM and CON groups, but mean values significantly increased in the OT-IV group, peaking at 20 min after treatment and reaching pre-treatment baseline values again at 120 min. Although the source of prostaglandins was not investigated in this study, our results suggest that exogenous oxytocin may enhance secretion of prostaglandins by the uterus during the first day after normal calving. These prostaglandins might contribute, by an endocrine or paracrine route, to the stimulation of myometrial contractility when exogenous oxytocin is given during this early post-partum stage. © 2011 Blackwell Verlag GmbH.

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

    Science.gov (United States)

    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. Copyright © 2014 Elsevier B.V. All rights reserved.

  19. Enhanced

    Directory of Open Access Journals (Sweden)

    Martin I. Bayala

    2014-06-01

    Full Text Available Land Surface Temperature (LST is a key parameter in the energy balance model. However, the spatial resolution of the retrieved LST from sensors with high temporal resolution is not accurate enough to be used in local-scale studies. To explore the LST–Normalised Difference Vegetation Index relationship potential and obtain thermal images with high spatial resolution, six enhanced image sharpening techniques were assessed: the disaggregation procedure for radiometric surface temperatures (TsHARP, the Dry Edge Quadratic Function, the Difference of Edges (Ts∗DL and three models supported by the relationship of surface temperature and water stress of vegetation (Normalised Difference Water Index, Normalised Difference Infrared Index and Soil wetness index. Energy Balance Station data and in situ measurements were used to validate the enhanced LST images over a mixed agricultural landscape in the sub-humid Pampean Region of Argentina (PRA, during 2006–2010. Landsat Thematic Mapper (TM and Moderate Resolution Imaging Spectroradiometer (EOS-MODIS thermal datasets were assessed for different spatial resolutions (e.g., 960, 720 and 240 m and the performances were compared with global and local TsHARP procedures. Results suggest that the Ts∗DL technique is the most adequate for simulating LST to high spatial resolution over the heterogeneous landscape of a sub-humid region, showing an average root mean square error of less than 1 K.

  20. E2F1 promote the aggressiveness of human colorectal cancer by activating the ribonucleotide reductase small subunit M2

    Energy Technology Data Exchange (ETDEWEB)

    Fang, Zejun [Sanmen People' s Hospital of Zhejiang, Sanmen, Zhejiang, 317100 (China); Gong, Chaoju [Department of Pathology and Pathophysiology, Zhejiang University School of Medicine, Hangzhou, Zhejiang, 310058 (China); Liu, Hong [Zhejiang Normal University – Jinhua People' s Hospital Joint Center for Biomedical Research, Jinhua, Zhejiang, 321004 (China); Zhang, Xiaomin; Mei, Lingming [Sanmen People' s Hospital of Zhejiang, Sanmen, Zhejiang, 317100 (China); Song, Mintao [Department of Pathophysiology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences (CAMS), School of Basic Medicine, Peking Union Medical College (PUMC), Beijing, 100005 (China); Qiu, Lanlan; Luo, Shuchai; Zhu, Zhihua; Zhang, Ronghui; Gu, Hongqian [Sanmen People' s Hospital of Zhejiang, Sanmen, Zhejiang, 317100 (China); Chen, Xiang, E-mail: sychenxiang@126.com [Sanmen People' s Hospital of Zhejiang, Sanmen, Zhejiang, 317100 (China)

    2015-08-21

    As the ribonucleotide reductase small subunit, the high expression of ribonucleotide reductase small subunit M2 (RRM2) induces cancer and contributes to tumor growth and invasion. In several colorectal cancer (CRC) cell lines, we found that the expression levels of RRM2 were closely related to the transcription factor E2F1. Mechanistic studies were conducted to determine the molecular basis. Ectopic overexpression of E2F1 promoted RRM2 transactivation while knockdown of E2F1 reduced the levels of RRM2 mRNA and protein. To further investigate the roles of RRM2 which was activated by E2F1 in CRC, CCK-8 assay and EdU incorporation assay were performed. Overexpression of E2F1 promoted cell proliferation in CRC cells, which was blocked by RRM2 knockdown attenuation. In the migration and invasion tests, overexpression of E2F1 enhanced the migration and invasion of CRC cells which was abrogated by silencing RRM2. Besides, overexpression of RRM2 reversed the effects of E2F1 knockdown partially in CRC cells. Examination of clinical CRC specimens demonstrated that both RRM2 and E2F1 were elevated in most cancer tissues compared to the paired normal tissues. Further analysis showed that the protein expression levels of E2F1 and RRM2 were parallel with each other and positively correlated with lymph node metastasis (LNM), TNM stage and distant metastasis. Consistently, the patients with low E2F1 and RRM2 levels have a better prognosis than those with high levels. Therefore, we suggest that E2F1 can promote CRC proliferation, migration, invasion and metastasis by regulating RRM2 transactivation. Understanding the role of E2F1 in activating RRM2 transcription will help to explain the relationship between E2F1 and RRM2 in CRC and provide a novel predictive marker for diagnosis and prognosis of the disease. - Highlights: • E2F1 promotes RRM2 transactivation in CRC cells. • E2F1 promotes the proliferation of CRC cells by activating RRM2. • E2F1 promotes the migration and

  1. Prostaglandin in Algae, Investigation on Halopteris filicina (Kütz.) Extract

    OpenAIRE

    Güven, K.C.; Kull, Z.; Özdemir, O.; Kaya, G.; Ulutin, O. N.; Türker, R K

    2004-01-01

    Abstract In this work the prostaglandin - like activity was investigated in extract of Halopteris fllicina (Kütz.). The methods used for examination of prostaglandin activity of the algal extract were; ADP, adrenaline and collagen induced aggregation in human platelet rich plasma. The results showed that H. filicina extract, depending on this concentration, inhibited the secondary waves of platelet aggregation induced by ADP and adrenaline and also aggregation waves induced by collagen....

  2. Effect of Amniotomy on Uterine Muscle Electrical Activity During Labor Induction with Oxytocin and Prostaglandins

    OpenAIRE

    Toth, Tibor

    2006-01-01

    The aim of the study was to find out whether noninvasive recording of uterine muscle electrical activity could help monitor the development of mechanical myometrial activity during induced labor. Myometrium electrical activity during labor induction was analyzed in 110 gravidas hospitalized at Maternity Ward, Bjelovar General Hospital in Bjelovar. The means used for labor induction was oxytocin infusion in 54, intracervical prostaglandin (dinoprostone 0.5 mg) in 20, intravaginal prostaglandin...

  3. Effects of drugs inhibiting prostaglandin or leukotriene biosynthesis on postirradiation haematopoiesis in mouse

    Energy Technology Data Exchange (ETDEWEB)

    Kozubik, A.; Hofmanova, J.; Pospisil, M.; Netikova, J.; Hola, J.; Lojek, A. (Ceskoslovenska Akademie Ved, Brno (Czech Republic). Biofysikalni Ustav)

    1994-03-01

    Two non-steroidal anti-inflammatory drugs, i.e. indomethacin (INDO), an inhibitor of prostaglandin production, and esculetin (ESCUL), an inhibitor of leukotriene production, were tested for their ability to modify haematopoiesis in three experimental systems: (a) in vitro clonal proliferation of marrow GM-CFC from the irradiated mouse was found to be augmented by addition of INDO at a low concentration, and inhibited by ESCUL in a dose-dependent manner; (b) in the lethally irradiated and bone marrow-transplanted mice treated with the drugs in the postirradiation period, stimulatory effects of INDO on CFU-S and GM-CFC populations and an inhibitory effect of ESCUL on GM-CFC were observed; and (c) when the drugs were administered i.p. to mice 1 h before 5-Gy irradiation, INDO enhanced the postirradiation recovery of haematopoietic indices such the numbers of CFU-S, GM-CFC, peripheral blood granuloctyes, and nucleated bone marrow cells, while ESCUL had no effect or even inhibited the recovery of these indices. (author).

  4. Role of nitric oxide and prostaglandin in the maintenance of cortical and renal medullary blood flow

    Directory of Open Access Journals (Sweden)

    S.I Gomez

    2008-02-01

    Full Text Available This study was undertaken in anesthetized dogs to evaluate the relative participation of prostaglandins (PGs and nitric oxide (NO in the maintenance of total renal blood flow (TRBF, and renal medullary blood flow (RMBF. It was hypothesized that the inhibition of NO should impair cortical and medullary circulation because of the synthesis of this compound in the endothelial cells of these two territories. In contrast, under normal conditions of perfusion pressure PG synthesis is confined to the renal medulla. Hence PG inhibition should predominantly impair the medullary circulation. The initial administration of 25 µM kg-1 min-1 NG-nitro-L-arginine methyl ester produced a significant 26% decrease in TRBF and a concomitant 34% fall in RMBF, while the subsequent inhibition of PGs with 5 mg/kg meclofenamate further reduced TRBF by 33% and RMBF by 89%. In contrast, the initial administration of meclofenamate failed to change TRBF, while decreasing RMBF by 49%. The subsequent blockade of NO decreased TRBF by 35% without further altering RMBF. These results indicate that initial PG synthesis inhibition predominantly alters the medullary circulation, whereas NO inhibition decreases both cortical and medullary flow. This latter change induced by NO renders cortical and RMBF susceptible to a further decrease by PG inhibition. However, the decrease in medullary circulation produced by NO inhibition is not further enhanced by subsequent PG inhibition.

  5. Plasma 8-iso-Prostaglandin F2α, a possible prognostic marker in aneurysmal subarachnoid hemorrhage.

    Science.gov (United States)

    Pan, De-Sheng; Yan, Min; Hassan, Muhammad; Fang, Ze-Bin; Chen, Man-Tao

    2017-06-01

    8-iso-Prostaglandin F2α (8-iso-PGF2α) is a potential biomarker of oxidative stress. This study clarified whether plasma 8-iso-PGF2α concentrations were affected and its underlying relevance to prognosis in aneurysmal subarachnoid hemorrhage (aSAH). In this prospective, observational study, a total of 170 controls and 170 aSAH patients were enrolled. Plasma 8-iso-PGF2α concentrations were detected using an ELISA. Severity was assessed by World Federation of Neurological Surgeons (WFNS) scale and modified Fisher grading scale. Clinical outcomes included 6-month mortality and poor outcome referred to as Glasgow outcome scale score of 1-3. As compared to controls, admission plasma 8-iso-PGF2α concentrations were significantly enhanced. Increased concentrations of plasma 8-iso-PGF2α correlated with WFNS scores and modified Fisher scores. 8-iso-PGF2α in plasma was an independent predictor for clinical outcomes. Under ROC curve, the predictive values of 8-iso-PGF2α concentrations resembled those of WFNS scores and modified Fisher scores for clinical outcomes. An elevation in plasma 8-iso-PGF2α concentrations is associated with the severity and poor outcome after aSAH, substantializing 8-iso-PGF2α as a potential prognostic biomarker of aSAH. Copyright © 2017. Published by Elsevier B.V.

  6. Importancia de las prostaglandinas en la amibiasis hepática The importance of prostaglandins in hepatic amebiasis

    Directory of Open Access Journals (Sweden)

    Blanca Sánchez-Ramírez

    2002-06-01

    Full Text Available Las prostaglandinas son importantes mediadores inflamatorios, pero también desempeñan un papel importante como reguladoras de las funciones de los linfocitos y los macrófagos. La inoculación por vía intrahepática o intraportal de trofozoitos viables de Entamoeba histolytica en hámsteres se caracteriza por una rápida respuesta inflamatoria aguda, en la cual los trofozoitos amibianos se ven rodeados sucesivamente por leucocitos polimorfonucleares, linfocitos y macrófagos. La incapacidad de estas células para contrarrestar la invasión amibiana ha sido demostrada en varios estudios. La prostaglandina E2 (PGE2 tiene potentes efectos sobre las células de la respuesta inmune; su participación durante la formación del absceso hepático se reportó recientemente. En este artículo hacemos una revisión de los hallazgos de los últimos años en relación con el estudio de los mediadores bioquímicos de la inflamación durante la infección con E. histolytica, y su posible participación en el establecimiento de la respuesta inmune en el huésped.Prostaglandins are important mediators of inflammation; they also play a role in the regulation of both lymphocyte and macrophage functions. Hamster's liver lesions resulting from intraportal or intrahepatic inoculation of living Entamoeba histolytica trophozoites are characterized by an acute inflammatory response, where trophozoites are successively surrounded by polymorphonuclear leukocytes, lymphocytes, and macrophages. Incapability of these cells to counteract amebic invasion has been demonstrated in some studies. Prostaglandin E2 (PGE2 has potent effects on immune cells; its participation in amebic liver abscess has been reported recently. This paper presents a review of recent discoveries on biochemical mediators produced during inflammation due to Entamoeba histolytica infection, and their possible role in establishing the host's immune response.

  7. Inhibition of Prostaglandin Transporter (PGT Promotes Perfusion and Vascularization and Accelerates Wound Healing in Non-Diabetic and Diabetic Rats.

    Directory of Open Access Journals (Sweden)

    Zhongbo Liu

    Full Text Available Peripheral ischemia, resulting from diminished arterial flow and defective local vascularization, is one of the main causes of impaired wound healing in diabetes. Vasodilatory prostaglandins (PGs, including PGE2 and PGI2, regulate blood flow in peripheral tissues. PGs also stimulate angiogenesis by inducing vascular endothelial growth factor. However, PG levels are reduced in diabetes mainly due to enhanced degradation. We hypothesized that inhibition of the prostaglandin transporter (PGT (SLCO2A1, which mediates the degradation of PGs, would increase blood flow and stimulate vascularization, thereby mitigating peripheral ischemia and accelerating wound healing in diabetes. Here we report that inhibiting PGT with intravenously injected PGT inhibitor, T26A, increased blood flow in ischemic hind limbs created in non-diabetic rats and streptozotocin induced diabetic rats. Systemic, or combined with topical, T26A accelerated closure of cutaneous wounds. Immunohistochemical examination revealed that inhibition of PGT enhanced vascularization (marked by larger numbers of vessels formed by CD34+ cells, and accelerated re-epithelialization of cutaneous wounds. In cultured primary human bone marrow CD34+ cells and human epidermal keratinocytes (HEKs either inhibiting or silencing PGT increased migration in both cell lines. Thus PGT directly regulates mobilization of endothelial progenitor cells (EPCs and HEKs, which could contribute to PGT-mediated vascularization and re-epithelialization. At the molecular level, systemic inhibition of PGT raised circulating PGE2. Taken together, our data demonstrate that PGT modulates arterial blood flow, mobilization of EPCs and HEKs, and vascularization and epithelialization in wound healing by regulating vasodilatory and pro-angiogenic PGs.

  8. Prostaglandins temporally regulate cytoplasmic actin bundle formation during Drosophila oogenesis

    Science.gov (United States)

    Spracklen, Andrew J.; Kelpsch, Daniel J.; Chen, Xiang; Spracklen, Cassandra N.; Tootle, Tina L.

    2014-01-01

    Prostaglandins (PGs)—lipid signals produced downstream of cyclooxygenase (COX) enzymes—regulate actin dynamics in cell culture and platelets, but their roles during development are largely unknown. Here we define a new role for Pxt, the Drosophila COX-like enzyme, in regulating the actin cytoskeleton—temporal restriction of actin remodeling during oogenesis. PGs are required for actin filament bundle formation during stage 10B (S10B). In addition, loss of Pxt results in extensive early actin remodeling, including actin filaments and aggregates, within the posterior nurse cells of S9 follicles; wild-type follicles exhibit similar structures at a low frequency. Hu li tai shao (Hts-RC) and Villin (Quail), an actin bundler, localize to all early actin structures, whereas Enabled (Ena), an actin elongation factor, preferentially localizes to those in pxt mutants. Reduced Ena levels strongly suppress early actin remodeling in pxt mutants. Furthermore, loss of Pxt results in reduced Ena localization to the sites of bundle formation during S10B. Together these data lead to a model in which PGs temporally regulate actin remodeling during Drosophila oogenesis by controlling Ena localization/activity, such that in S9, PG signaling inhibits, whereas at S10B, it promotes Ena-dependent actin remodeling. PMID:24284900

  9. Possible role of prostaglandin F in blastocyst implantation

    Energy Technology Data Exchange (ETDEWEB)

    Kasamo, M.; Ishikawa, M.; Yamashita, K.; Sengoku, K.; Shimizu, T.

    1986-02-01

    The synthesis and release of Prostaglandin F (PGF) by the rabbit blastocyst and endometrium were investigated on Day 6 and Day 7, using radioimmunoassay, autoradiography and conversion experiments. The following results were obtained: The content of PGF in the blastocyst increased significantly (P less than 0.01) from Day 6 to Day 7. The content of PGF in the endometrium was significantly higher (P less than 0.05) on Day 7 implantation sites compared to the other areas. The in vitro synthesis and release of PGF by Day 6 blastocysts sharply increased after one and two hours of culture, respectively. Thereafter both values declined with time. The in vitro synthesis and release of PGF by Day 6 endometria increased continuously with time. /sup 14/C-arachidonic acid (/sup 14/C-AA) was incorporated into Day 6 blastocysts in vitro and converted to PGF2 alpha. These results suggest that both the endometrium and the blastocyst are the sources of the PGs involved in implantation, and that PGF derived from the blastocysts may act as the trigger of implantation.

  10. Effect of topical prostaglandin analogues on corneal hysteresis.

    Science.gov (United States)

    Bolívar, Gema; Sánchez-Barahona, Cristina; Teus, Miguel; Castejón, Miguel A; Paz-Moreno-Arrones, Javier; Gutiérrez-Ortiz, Consuelo; Mikropoulos, Dimitrios G

    2015-09-01

    To evaluate possible changes in corneal hysteresis (CH) after topical treatment with a prostaglandin analogue in medication-naïve eyes. This was a prospective, observational cohort study. Sixty-eight eyes of 68 patients were prospectively included who were newly diagnosed with primary open-angle glaucoma or ocular hypertension in our institution. All patients were treatment-naïve. Patients were evaluated at baseline and after 6 months of treatment with latanoprost in the eye with the lower intraocular pressure (IOP) measured by Goldmann applanation tonometry (GAT). The ocular response analyzer was used to measure CH. CH increased significantly (p = 0.0001) from 8.96 ± 2.3 mmHg to 9.79 ± 1.97 mmHg, and this increase was correlated significantly (p = 0.0001, r = 0.64, r(2) = 0.41) with the basal CH. We identified a weak but significant (r(2) = 0.06, p = 0.01) relationship between the basal CH and the drug-induced reduction of the GAT IOP. Nevertheless, the increase in the drug-induced CH was not correlated with the decrease in the GAT IOP. Treatment with latanoprost increases CH. The CH increase was not correlated with the drug-induced decrease in the GAT IOP, which suggested a direct effect of latanoprost on the viscoelastic corneal properties. © 2015 Acta Ophthalmologica Scandinavica Foundation. Published by John Wiley & Sons Ltd.

  11. Energy Efficiency Management Platform (E2MP) Project

    Data.gov (United States)

    National Aeronautics and Space Administration — The Energy Efficiency Management Platform (E2MP) is a power-aware, "Green" computing technology for managing energy consumption on High End Computing (HEC) systems...

  12. Long-term untreated streptozotocin-diabetes leads to increased expression and elevated activity of prostaglandin H2 synthase in blood platelets.

    Science.gov (United States)

    Siewiera, Karolina; Kassassir, Hassan; Talar, Marcin; Wieteska, Lukasz; Watala, Cezary

    2016-01-01

    In diabetes-related states of chronic hyperglycaemia elevated concentrations of glucose may alter the functioning of platelet enzymes involved in arachidonic acid metabolism, including prostaglandin H2 synthase (cyclooxygenase) (PGHS, COX). Therefore, the principal aim of this study was to assess the effects of experimental chronic hyperglycaemia on platelet PGHS-1 (COX-1) expression and activity. Blood platelet activation and reactivity were assessed in Sprague-Dawley rats with the 5-month streptozotocin (STZ) diabetes. The PGHS-1 abundance in platelets was evaluated with flow cytometry and Western blotting, while its activity monitored using a high resolution respirometry and the peroxidase fluorescent assay. The production of prostaglandin E2 (PGE2) and thromboxane B2 (TXB2) in platelets were assayed immunoenzymatically. Circulating platelets from diabetic were characterised by increased size, elevated 'priming' and altered reactivity, compared to non-diabetic animals. Both Western blot analysis and flow cytometry revealed significantly elevated expressions of platelet PGHS-1 in STZ-diabetic rats (p platelet PGHS-1-related arachidonic acid metabolism in diabetic vs. non-diabetic animals, with the use of polarographic (p platelet PGHS-1 abundance. Therefore, our results further contribute to the explanation of the increased metabolism of arachidonic acid observed in diabetes.

  13. Piglet mortality: the impact of induction of farrowing using prostaglandins and oxytocin.

    Science.gov (United States)

    Kirkden, R D; Broom, D M; Andersen, I L

    2013-04-01

    Induction is usually carried out by administering prostaglandins (prostaglandin F2α or a synthetic analogue). Other hormones, most commonly oxytocin, may also be given. The primary objective is to increase the synchrony of farrowing. This facilitates farrowing supervision, early fostering and 'all in, all out' management of the farrowing house, all of which have the potential to decrease piglet mortality. However, there are also risks, including decreased piglet viability when farrowing is induced too early and an increased probability of dystocia associated with oxytocin use. What are the effects of induction procedures on mortality in pigs? With respect to prostaglandins, studies show that the date of induction and the level of supervision provided are important factors affecting piglet mortality. We recommend administering prostaglandins no earlier than 2d before the expected farrowing date for the herd. Some studies have reported that prostaglandin induction decreases stillbirth and live-born mortality and this is probably due to increased farrowing supervision. The incidence of postpartum dysgalactia syndrome is also decreased in herds with a high prevalence of this condition. Inconsistent effects on the progress of farrowing are reported following the routine administration of oxytocin 20-24h after prostaglandin. Although there is generally no effect on stillbirth rate, dystocia may increase. Earlier administration of low doses may decrease stillbirths, but this requires further research. Carbetocin, a long-acting analogue of oxytocin, is a possible alternative. We recommend that prostaglandin induction be used in conjunction with skilled farrowing supervision to decrease piglet mortality. Copyright © 2013 Elsevier B.V. All rights reserved.

  14. Attenuation of niacin-induced prostaglandin D2 generation by omega-3 fatty acids in THP-1 macrophages and Langerhans dendritic cells

    Directory of Open Access Journals (Sweden)

    VanHorn J

    2012-03-01

    suggests that the regular use of omega-3 PUFAs along with niacin can potentially reduce the niacin-induced flushing response in sensitive patients.Keywords: flushing, prostaglandin E2, phospholipids, GPR109A, cardiovascular, docosahexaenoic acid, arachidonic acid

  15. E2F6 Impairs Glycolysis and Activates BDH1 Expression Prior to Dilated Cardiomyopathy.

    Directory of Open Access Journals (Sweden)

    Jennifer L Major

    Full Text Available The E2F pathway plays a critical role in cardiac growth and development, yet its role in cardiac metabolism remains to be defined. Metabolic changes play important roles in human heart failure and studies imply the ketogenic enzyme β-hydroxybutyrate dehydrogenase I (BDH1 is a potential biomarker.To define the role of the E2F pathway in cardiac metabolism and dilated cardiomyopathy (DCM with a focus on BDH1.We previously developed transgenic (Tg mice expressing the transcriptional repressor, E2F6, to interfere with the E2F/Rb pathway in post-natal myocardium. These Tg mice present with an E2F6 dose dependent DCM and deregulated connexin-43 (CX-43 levels in myocardium. Using the Seahorse platform, a 22% decrease in glycolysis was noted in neonatal cardiomyocytes isolated from E2F6-Tg hearts. This was associated with a 39% reduction in the glucose transporter GLUT4 and 50% less activation of the regulator of glucose metabolism AKT2. The specific reduction of cyclin B1 (70% in Tg myocardium implicates its importance in supporting glycolysis in the postnatal heart. No changes in cyclin D expression (known to regulate mitochondrial activity were noted and lipid metabolism remained unchanged in neonatal cardiomyocytes from Tg hearts. However, E2F6 induced a 40-fold increase of the Bdh1 transcript and 890% increase in its protein levels in hearts from Tg pups implying a potential impact on ketolysis. By contrast, BDH1 expression is not activated until adulthood in normal myocardium. Neonatal cardiomyocytes from Wt hearts incubated with the ketone β-hydroxybutyrate (β-OHB showed a 100% increase in CX-43 protein levels, implying a role for ketone signaling in gap junction biology. Neonatal cardiomyocyte cultures from Tg hearts exhibited enhanced levels of BDH1 and CX-43 and were not responsive to β-OHB.The data reveal a novel role for the E2F pathway in regulating glycolysis in the developing myocardium through a mechanism involving cyclin B1. We

  16. E2F6 Impairs Glycolysis and Activates BDH1 Expression Prior to Dilated Cardiomyopathy.

    Science.gov (United States)

    Major, Jennifer L; Dewan, Aaraf; Salih, Maysoon; Leddy, John J; Tuana, Balwant S

    2017-01-01

    The E2F pathway plays a critical role in cardiac growth and development, yet its role in cardiac metabolism remains to be defined. Metabolic changes play important roles in human heart failure and studies imply the ketogenic enzyme β-hydroxybutyrate dehydrogenase I (BDH1) is a potential biomarker. To define the role of the E2F pathway in cardiac metabolism and dilated cardiomyopathy (DCM) with a focus on BDH1. We previously developed transgenic (Tg) mice expressing the transcriptional repressor, E2F6, to interfere with the E2F/Rb pathway in post-natal myocardium. These Tg mice present with an E2F6 dose dependent DCM and deregulated connexin-43 (CX-43) levels in myocardium. Using the Seahorse platform, a 22% decrease in glycolysis was noted in neonatal cardiomyocytes isolated from E2F6-Tg hearts. This was associated with a 39% reduction in the glucose transporter GLUT4 and 50% less activation of the regulator of glucose metabolism AKT2. The specific reduction of cyclin B1 (70%) in Tg myocardium implicates its importance in supporting glycolysis in the postnatal heart. No changes in cyclin D expression (known to regulate mitochondrial activity) were noted and lipid metabolism remained unchanged in neonatal cardiomyocytes from Tg hearts. However, E2F6 induced a 40-fold increase of the Bdh1 transcript and 890% increase in its protein levels in hearts from Tg pups implying a potential impact on ketolysis. By contrast, BDH1 expression is not activated until adulthood in normal myocardium. Neonatal cardiomyocytes from Wt hearts incubated with the ketone β-hydroxybutyrate (β-OHB) showed a 100% increase in CX-43 protein levels, implying a role for ketone signaling in gap junction biology. Neonatal cardiomyocyte cultures from Tg hearts exhibited enhanced levels of BDH1 and CX-43 and were not responsive to β-OHB. The data reveal a novel role for the E2F pathway in regulating glycolysis in the developing myocardium through a mechanism involving cyclin B1. We reveal BDH1

  17. Rabbit blastocysts accumulate (/sup 3/H)prostaglandins in vitro

    Energy Technology Data Exchange (ETDEWEB)

    Jones, M.A.; Harper, M.J.

    1984-08-01

    Rabbit blastocysts obtained on days 5, 6, and 6.8 of pregnancy were incubated in vitro in Tyrode's buffer with /sup 3/H-labeled prostaglandins (PGs). Accumulation of PGs was studied, using Whatman GF/F filters to separate bound and free ligands. The uptake and efflux of (/sup 3/H)PGs were studied as a function of PG type, incubation time, temperature, and effect of metabolic inhibitors as well as age and number of blastocysts. Blastocysts of the same age accumulated approximately the same amount of (/sup 3/H)PGE2 and (/sup 3/H)PGF2 alpha from their environment; however, there was no apparent saturation over a PG concentration range of 1-1000 nM. Both the uptake and efflux of PG were age dependent, with older blastocysts accumulating more PGs. Approximately 90% of the (/sup 3/H)PGs appear to be transported into the blastocoelic fluid, with little PG remaining in the blastomeres. PG accumulation was relatively insensitive to azide, ouabain, cyanide, or bromcresol green, but was affected by incubation at 0 C or the addition of indomethacin (10 micrograms/ml). No catabolism of the accumulated PGs was observed. The release of PGE2 in general did not differ from that of PGF2 alpha, except on day 6.8 of pregnancy when PGE2 was released more rapidly than on day 6. The authors conclude that rabbit blastocysts can accumulate PGs from their environment, which may imply a storage potential in the blastocyst and release before implantation.

  18. An audit about labour induction, using prostaglandin, in women with a scarred uterus.

    Science.gov (United States)

    Cogan, Alexandra; Barlow, Patricia; Benali, Nordine; Murillo, Daniel; Manigart, Yannick; Belhomme, Julie; Rozenberg, Serge

    2012-12-01

    Induction of labour after a previous caesarean section is still controversial. We aim to analyse, in a population of women who have a uterine scar, the maternal, foetal and neonatal complications in relation to the mode of labour and delivery. Retrospective analysis of collected data from all the singleton deliveries of patients with a scarred uterus (N=798), admitted to the hospital between August 2006 and March 2009. maternal and perinatal complications. Among 798 singleton deliveries, 36.1% had a spontaneous labour, 12.6% a prostaglandin-induced labour and 2.9% an ocytocin-induced labour, and 48.4% had an elective caesarean section. The chance of delivering vaginally was respectively 84.4% for those who had a spontaneous labour, 75.2% for those who were induced using prostaglandin, 82.6% after induction using ocytocin. There were eight uterine ruptures, four after spontaneous labour (1.4%), two after prostaglandin induction (2%) and two at the time of an iterative caesarean section (0.5%). There were no differences between groups, except the risk of haemorrhage (17.4% after spontaneously induced labour, 34.8% after ocytocin, 17.8% after prostaglandin and 44.6% after iterative caesarean section; plabour, 9.1% after ocytocin, 12% after prostaglandin and 16.8% after iterative caesarean section; plabour after caesarean section, this study is too underpowered to exclude an increased risk.

  19. Large scale genotype comparison of human papillomavirus E2-host interaction networks provides new insights for e2 molecular functions.

    Directory of Open Access Journals (Sweden)

    Mandy Muller

    Full Text Available Human Papillomaviruses (HPV cause widespread infections in humans, resulting in latent infections or diseases ranging from benign hyperplasia to cancers. HPV-induced pathologies result from complex interplays between viral proteins and the host proteome. Given the major public health concern due to HPV-associated cancers, most studies have focused on the early proteins expressed by HPV genotypes with high oncogenic potential (designated high-risk HPV or HR-HPV. To advance the global understanding of HPV pathogenesis, we mapped the virus/host interaction networks of the E2 regulatory protein from 12 genotypes representative of the range of HPV pathogenicity. Large-scale identification of E2-interaction partners was performed by yeast two-hybrid screenings of a HaCaT cDNA library. Based on a high-confidence scoring scheme, a subset of these partners was then validated for pair-wise interaction in mammalian cells with the whole range of the 12 E2 proteins, allowing a comparative interaction analysis. Hierarchical clustering of E2-host interaction profiles mostly recapitulated HPV phylogeny and provides clues to the involvement of E2 in HPV infection. A set of cellular proteins could thus be identified discriminating, among the mucosal HPV, E2 proteins of HR-HPV 16 or 18 from the non-oncogenic genital HPV. The study of the interaction networks revealed a preferential hijacking of highly connected cellular proteins and the targeting of several functional families. These include transcription regulation, regulation of apoptosis, RNA processing, ubiquitination and intracellular trafficking. The present work provides an overview of E2 biological functions across multiple HPV genotypes.

  20. Hepatitis C Virus E2 Envelope Glycoprotein Core Structure

    Energy Technology Data Exchange (ETDEWEB)

    Kong, Leopold; Giang, Erick; Nieusma, Travis; Kadam, Rameshwar U.; Cogburn, Kristin E.; Hua, Yuanzi; Dai, Xiaoping; Stanfield, Robyn L.; Burton, Dennis R.; Ward, Andrew B.; Wilson, Ian A.; Law, Mansun

    2014-08-26

    Hepatitis C virus (HCV), a Hepacivirus, is a major cause of viral hepatitis, liver cirrhosis, and hepatocellular carcinoma. HCV envelope glycoproteins E1 and E2 mediate fusion and entry into host cells and are the primary targets of the humoral immune response. The crystal structure of the E2 core bound to broadly neutralizing antibody AR3C at 2.65 angstroms reveals a compact architecture composed of a central immunoglobulin-fold β sandwich flanked by two additional protein layers. The CD81 receptor binding site was identified by electron microscopy and site-directed mutagenesis and overlaps with the AR3C epitope. The x-ray and electron microscopy E2 structures differ markedly from predictions of an extended, three-domain, class II fusion protein fold and therefore provide valuable information for HCV drug and vaccine design.

  1. Dynamic Vectorization in the E2 Dynamic Multicore System

    OpenAIRE

    Putnam, Andrew; Smith, Aaron; Burger, Doug

    2010-01-01

    Previous research has shown that Explicit Data Graph Execution (EDGE) instruction set architectures (ISA) allow for power efficient performance scaling. In this paper we describe the preliminary design of a new dynamic multicore processor called E2 that utilizes an EDGE ISA to allow for the dynamic composition of physical cores into logical processors. We provide details of E2’s support for dynamic reconfigurability and show how the EDGE ISA facilities out-of-order vector execution.

  2. Curriculum for EPS Hockey E2-C2-juniors

    OpenAIRE

    Heinonen, Aleksi

    2017-01-01

    Coaching in hockey has changed in direction from coach-centered coaching to player-centered coaching. Nowadays it is more holistic; it is not just coaching tactics and trying to win games at all costs. The way of thinking has changed; instead of the former “what does a team need” way of thinking, nowadays it is more important to ask, “What does an individual need?” This thesis has been written for EPS Hockey E2-C2 juniors and E2-C2 coaches. The Executive Manager of EPS Hockey requested...

  3. Performance Evaluation of Triple Play Services Delivery with E2E QoS Provisioning

    Directory of Open Access Journals (Sweden)

    Nikolaos Zotos

    2010-01-01

    Full Text Available The creation and wide use of new high quality demanding services (VoIP, High Quality Video Streaming and the delivery of them over already saturated core and access network infrastructures have created the necessity for E2E QoS provisioning. Network Providers use at their infrastructures several kinds of mechanisms and techniques for providing QoS. Most known and widely used technologies are MPLS and DiffServ. The IEEE 802.16-2004 standard (WiMAX refers to a promising wireless broadband technology with enhanced QoS support algorithms. This document presents an experimental network infrastructure providing E2E QoS, using a combination of MPLS and DiffServ technologies in the core network and WiMAX technology as the wireless access medium for high priority services (VoIP, High Quality Video Streaming transmission. The main scope is to map the traffic prioritization and classification attributes of the core network to the access network in a way which does not affect the E2E QoS provisioning. The performance evaluation will be done by introducing different kinds of traffic scenarios in a saturated and overloaded network environment. The evaluation will prove that this combination made feasible the E2E QoS provisioning while keeping the initial constrains as well as the services delivered over a wireless network.

  4. E2F7 and E2F8 promote angiogenesis through transcriptional activation of VEGFA in cooperation with HIF1

    NARCIS (Netherlands)

    Weijts, B.G.; Bakker, W.J.; Cornelissen, P.W.; Liang, K.H.; Schaftenaar, F.H.; Westendorp, B.; de Wolf, C.A.; Paciejewska, M.; Scheele, C.L.; Kent, L.; Leone, G.; Schulte-Merker, S.; de Bruin, A.

    2012-01-01

    The E2F family of transcription factors plays an important role in controlling cell-cycle progression. While this is their best-known function, we report here novel functions for the newest members of the E2F family, E2F7 and E2F8 (E2F7/8). We show that simultaneous deletion of E2F7/8 in zebrafish

  5. Vaginal prostaglandin gel to induce labour in women with one previous caesarean section.

    LENUS (Irish Health Repository)

    Agnew, G

    2012-02-01

    This retrospective study reviewed the mode of delivery when vaginal prostaglandins were used to induce labour in women with a single previous lower segment caesarean section. Over a 4-year period, PGE 2 gel was used cautiously in low doses in 54 women. Induction with PGE 2 gel was associated with an overall vaginal birth after caesarean section (VBAC) rate of 74%, which compared favourably with the 74% VBAC rate in women who went into spontaneous labour (n = 1969). There were no adverse outcomes recorded after the prostaglandin inductions but the number reported are too small to draw any conclusions about the risks, such as uterine rupture. We report our results because they may be helpful in assessing the chances of a successful VBAC in the uncommon clinical circumstances where prostaglandin induction is being considered.

  6. Morphological changes in the placenta and decidua after induction of abortion by extra-amniotic prostaglandin.

    Science.gov (United States)

    Fox, H; Herd, M E; Harilal, K R

    1978-03-01

    Seventeen placentae from second trimester abortions induced by the injection of extra-amniotic prostaglandin have been examined. The extraplacental membranes, the chorionic plate of the placenta, the placental intervillous space and the placental villi were normal in all cases. In all but one specimen lesions were, however, noted in the decidua, these including focal decidual necrosis, intradecidual haemorrhage, thrombosis of maternal vessels and dilatation and congestion of the maternal vasculature. Similar decidual lesions were also seen in placentae from spontaneous and surgical second trimester abortions and it is concluded that prostaglandins do not produce any specific lesions in the placenta or decidua. It is suggested that the negative findings of this study indicate that prostaglandins do not induce abortion by either direct injury to the placenta or by provoking utero-placental ischaemia.

  7. A new convenient access to highly functionalized (E)-2-arylvinyl ...

    Indian Academy of Sciences (India)

    Administrator

    A new convenient access to highly functionalized (E)-2-arylvinyl bromides. 1037. Scheme 2. Formation of (E)-4-(2-bromovinyl) phenyl acetate. Table 2. Esterification condition of acetic acid with (E)-4-(2-bromovinyl)phenol (4). Entries CH3CO2H equiv. DCC/DMAP equiv. Solvent. Yield (%) a,b. 1. 1. 1/cat. DMF. <5. 2. 1.

  8. COLICIN E2 PRODUCING BACTERIA FROM YARE RIVER

    African Journals Online (AJOL)

    Studies on the recombinant DNA, pATll and pATlZ revealed that the E colicin operon, set of genes, the structural, immunity, and lysis genes of pColE2-AT resides within the same EcoRI fragment. Key words/phrases: ColE-factor, E colicin operon, recombinant plasmid, transformation. INTRODUCTION. Bacteriocins are ...

  9. E2F target genes: unraveling the biology

    DEFF Research Database (Denmark)

    Bracken, Adrian P; Ciro, Marco; Cocito, Andrea

    2004-01-01

    The E2F transcription factors are downstream effectors of the retinoblastoma protein (pRB) pathway and are required for the timely regulation of numerous genes essential for DNA replication and cell cycle progression. Several laboratories have used genome-wide approaches to discover novel target...

  10. [Ecbolic and hormonal action of synthetic prostaglandin F2a in fetal mummification in two Holstein cows (author's transl)].

    Science.gov (United States)

    Guay, P; Lamothe, P

    1979-02-01

    Ecbolic and Hormonal Action of Synthetic Prostaglandin F(2)a in Fetal Mummification in Two Holstein CowsThe effects of treatment with synthetic prostaglandin F(2)a (500mug i.m.) to correct cases of fetal mummification in two Holstein cows are described.

  11. E2F1 and p53 Transcription Factors as Accessory Factors for Nucleotide Excision Repair

    Directory of Open Access Journals (Sweden)

    David G. Johnson

    2012-10-01

    Full Text Available Many of the biochemical details of nucleotide excision repair (NER have been established using purified proteins and DNA substrates. In cells however, DNA is tightly packaged around histones and other chromatin-associated proteins, which can be an obstacle to efficient repair. Several cooperating mechanisms enhance the efficiency of NER by altering chromatin structure. Interestingly, many of the players involved in modifying chromatin at sites of DNA damage were originally identified as regulators of transcription. These include ATP-dependent chromatin remodelers, histone modifying enzymes and several transcription factors. The p53 and E2F1 transcription factors are well known for their abilities to regulate gene expression in response to DNA damage. This review will highlight the underappreciated, transcription-independent functions of p53 and E2F1 in modifying chromatin structure in response to DNA damage to promote global NER.

  12. VirE2: a unique ssDNA-compacting molecular machine.

    Directory of Open Access Journals (Sweden)

    Wilfried Grange

    2008-02-01

    Full Text Available The translocation of single-stranded DNA (ssDNA across membranes of two cells is a fundamental biological process occurring in both bacterial conjugation and Agrobacterium pathogenesis. Whereas bacterial conjugation spreads antibiotic resistance, Agrobacterium facilitates efficient interkingdom transfer of ssDNA from its cytoplasm to the host plant cell nucleus. These processes rely on the Type IV secretion system (T4SS, an active multiprotein channel spanning the bacterial inner and outer membranes. T4SSs export specific proteins, among them relaxases, which covalently bind to the 5' end of the translocated ssDNA and mediate ssDNA export. In Agrobacterium tumefaciens, another exported protein-VirE2-enhances ssDNA transfer efficiency 2000-fold. VirE2 binds cooperatively to the transferred ssDNA (T-DNA and forms a compact helical structure, mediating T-DNA import into the host cell nucleus. We demonstrated-using single-molecule techniques-that by cooperatively binding to ssDNA, VirE2 proteins act as a powerful molecular machine. VirE2 actively pulls ssDNA and is capable of working against 50-pN loads without the need for external energy sources. Combining biochemical and cell biology data, we suggest that, in vivo, VirE2 binding to ssDNA allows an efficient import and pulling of ssDNA into the host. These findings provide a new insight into the ssDNA translocation mechanism from the recipient cell perspective. Efficient translocation only relies on the presence of ssDNA binding proteins in the recipient cell that compacts ssDNA upon binding. This facilitated transfer could hence be a more general ssDNA import mechanism also occurring in bacterial conjugation and DNA uptake processes.

  13. Dosage-dependent copy number gains in E2f1 and E2f3 drive hepatocellular carcinoma

    NARCIS (Netherlands)

    Kent, Lindsey N.; Bae, Sooin; Tsai, Shih-Yin; Tang, Xing; Srivastava, Arunima; Koivisto, Christopher; Martin, Chelsea K.; Ridolfi, Elisa; Miller, Grace C.; Zorko, Sarah M.; Plevris, Emilia; Hadjiyannis, Yannis; Perez, Miguel; Nolan, Eric; Kladney, Raleigh; Westendorp, Bart; de Bruin, Alain; Fernandez, Soledad; Rosol, Thomas J.; Pohar, Kamal S.; Pipas, James M.; Leone, Gustavo

    2017-01-01

    Disruption of the retinoblastoma (RB) tumor suppressor pathway, either through genetic mutation of upstream regulatory components or mutation of RB1 itself, is believed to be a required event in cancer. However, genetic alterations in the RB-regulated E2F family of transcription factors are

  14. p53 inactivation upregulates p73 expression through E2F-1 mediated transcription.

    Directory of Open Access Journals (Sweden)

    Chaitali Tophkhane

    Full Text Available While p73 overexpression has been associated with increased apoptosis in cancer tissues, p73 overexpressing tumors appear to be of high grade malignancy. Why this putative tumor suppressor is overexpressed in cancer cells and what the function of overexpressed p73 is in breast cancers are critical questions to be addressed. By investigating the effect of p53 inactivation on p73 expression, we found that both protein and mRNA levels of TAp73 were increased in MCF-7/p53siRNA cells, MCF-7/p53mt135 cells and HCT-116/p53-/- cells, as compared to wild type control, suggesting that p53 inactivation by various forms upregulates p73. We showed that p53 knockdown induced p73 was mainly regulated at the transcriptional level. However, although p53 has a putative binding site in the TAp73 promoter, deletion of this binding site did not affect p53 knockdown mediated activation of TAp73 promoter. Chromatin immuno-precipitation (ChIP data demonstrated that loss of p53 results in enhanced occupancy of E2F-1 in the TAp73 promoter. The responsive sequence of p53 inactivation mediated p73 upregulation was mapped to the proximal promoter region of the TAp73 gene. To test the role of E2F-1 in p53 inactivation mediated regulation of p73 transcription, we found that p53 knockdown enhanced E2F-1 dependent p73 transcription, and mutations in E2F-1 binding sites in the TAp73 promoter abrogated p53 knockdown mediated activation of TAp73 promoter. Moreover, we demonstrated that p21 is a mediator of p53-E2F crosstalk in the regulation of p73 transcription. We concluded that p53 knockdown/inactivation may upregulate TAp73 expression through E2F-1 mediated transcriptional regulation. p53 inactivation mediated upregulation of p73 suggests an intrinsic rescuing mechanism in response to p53 mutation/inactivation. These findings support further analysis of the correlation between p53 status and p73 expression and its prognostic/predictive significance in human cancers.

  15. Synergistic functions of E2F7 and E2F8 are critical to suppress stress-induced skin cancer

    NARCIS (Netherlands)

    Thurlings, I.; Lopez-Martinez, Maria J.; Westendorp, B.; Zijp, M.; Kuiper, R.; Tooten, PCJ; Kent, Lindsey N.; Leone, Gustavo; Vos, H.J.; Burgering, B; de Bruin, A.

    2017-01-01

    E2F transcription factors are important regulators of the cell cycle, and unrestrained activation of E2F-dependent transcription is considered to be an important driver of tumor formation and progression. Although highly expressed in normal skin and skin cancer, the role of the atypical E2Fs, E2F7

  16. Chang'e-2 spacecraft observations of asteroid 4179 Toutatis

    Science.gov (United States)

    Ji, Jianghui; Jiang, Yun; Zhao, Yuhui; Wang, Su; Yu, Liangliang

    2016-01-01

    On 13 December 2012, Chang'e-2 completed a successful flyby of the near-Earth asteroid 4179 Toutatis at a closest distance of 770 meters from the asteroid's surface. The observations show that Toutatis has an irregular surface and its shape resembles a ginger-root of a smaller lobe (head) and a larger lobe (body). Such bilobate shape is indicative of a contact binary origin for Toutatis. In addition, the high-resolution images better than 3 meters provide a number of new discoveries about this asteroid, such as an 800-meter depression at the end of the large lobe, a sharply perpendicular silhouette near the neck region, boulders, indicating that Toutatis is probably a rubble-pile asteroid. Chang'e-2 observations have significantly revealed new insights into the geological features and the formation and evolution of this asteroid. In final, we brief the future Chinese asteroid mission concept.

  17. Interactions of prostaglandin A2 with the glutathione-mediated biotransformation system

    NARCIS (Netherlands)

    Iersel, M.L.P.S. van; Cnubben, N.H.P.; Smink, N.; Koeman, J.H.; Bladeren, P.J. van

    1999-01-01

    The cyclopentenone prostaglandin A2 (PGA2) is known to inhibit cell proliferation, and metabolism of this compound thus might be important in controlling its ultimate function. The glutathione-related metabolism of PGA2 was therefore investigated both with purified glutathione S-transferase P1-1

  18. Indomethacin and paracetamol : Interaction with prostaglandin synthesis in the rat stomach

    NARCIS (Netherlands)

    Kolfschoten, A.A. van; Hagelen, F.; Noordwijk, J. van

    1982-01-01

    Using ex vivo incubation of mucosal strips the production of prostaglandins (I2- and E-like PGs) in the rat stomach was demonstrated by bioassay. Indomethacin inhibited this PG synthesis 1 and 4 h after oral drug administration. Paracetamol stimulated the production of PGs when given by itself but

  19. Preferential binding of growth inhibitory prostaglandins by the target protein of a carcinogen

    Energy Technology Data Exchange (ETDEWEB)

    Khan, S.H.; Sorof, S. (Fox Chase Cancer Center, Philadelphia, PA (United States))

    1990-12-01

    Liver fatty acid binding protein (L-FABP) is the principal target protein of the hepatic carcinogen N-(2-fluorenyl)acetamide (2-acetylaminofluorene) in rat liver. In addition, the cyclopentenone prostaglandins (PG), PGA, PGJ{sub 2}, and {Delta}{sup 12}-PGJ{sub 2}, inhibit the growth of many cell types in vitro. This report describes the preferential binding of the growth inhibitory prostaglandins by L-FABP and the reversible inhibition of thymidine incorporation into DNA by PGA{sub 2} and {Delta}{sup 12}-PGJ{sub 2} in primary cultures of purified rat hepatocytes. As a model ligand, ({sup 3}H)PGA{sub 1} bound to L-FABP specifically, reversibly, rapidly, and with high affinity. Its dissociation constants were 134 nM (high affinity) and 3.6 {mu}M (low affinity). The high-affinity finding of ({sup 3}H)PGA{sup 1} correlated with their growth inhibitory activities reported previously and here. The in vitro actions of L-FABP are compatible with those of a specific and dissociable carrier of growth inhibitory prostaglandins in rat hepatocytes and suggest that the carcinogen may usurp the cellular machinery of the growth inhibitory prostaglandins.

  20. The role of the prostaglandin D2 receptor, DP, in eosinophil trafficking

    DEFF Research Database (Denmark)

    Schratl, Petra; Royer, Julia F; Kostenis, Evi

    2007-01-01

    Prostaglandin (PG) D2 is a major mast cell product that acts via two receptors, the D-type prostanoid (DP) and the chemoattractant receptor-homologous molecule expressed on Th2 cells (CRTH2) receptors. Whereas CRTH2 mediates the chemotaxis of eosinophils, basophils, and Th2 lymphocytes, the role...

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

    Directory of Open Access Journals (Sweden)

    Yuling Chi

    Full Text Available 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.

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

    Directory of Open Access Journals (Sweden)

    Marjolein M J Caron

    Full Text Available 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.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.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.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.

  3. Changes in salivary prostaglandin levels during menstrual migraine with associated dysmenorrhea.

    Science.gov (United States)

    Durham, Paul L; Vause, Carrie V; Derosier, Frederick; McDonald, Susan; Cady, Roger; Martin, Vincent

    2010-05-01

    To measure prostaglandin levels in the saliva of individuals during menstrual migraine associated with dysmenorrhea (MMaD) and in response to treatment with a single tablet combination of sumatriptan succinate and naproxen sodium. Prostaglandins are thought to play a role in MMaD as elevated serum prostaglandin levels have been reported during attacks of menstrual migraine and are increased in the menstrual fluid of women with dysmenorrhea. While triptans are the primary line of migraine treatment, nonsteriodal anti-inflammatory drugs are the most commonly prescribed therapy for dysmenorrhea symptoms. Data from recent clinical studies have provided evidence that treatment with a single tablet combination of sumatriptan and naproxen sodium is an effective abortive therapy for attacks of MMaD. Women diagnosed with MMaD were treated with a sumatriptan succinate and naproxen sodium single tablet combination or placebo at time of migraine attack. Saliva samples were collected at time of attack as well as 2 and 4 hours after treatment. PGD(2), PGE(2), PGF(2), PGI(2), and TXA(2) levels were determined by enzyme-linked immunosorbent assay. Elevated levels of PGD(2), PGF(2), and TXA(2) at 2 and 4 hours and PGE(2) at 4 hours were found in saliva obtained from placebo subjects when compared with onset of attack levels. However, in subjects treated with a single tablet combination of sumatriptan and naproxen sodium, the levels of PGD(2), PGF(2), and PGE(2) were not elevated at either time point while TXA(2) levels were still elevated at 4 hours. Data from this pilot study provide evidence that saliva levels of several prostaglandins increase during attacks of MMaD and that treatment with a single tablet combination of sumatriptan and naproxen sodium prevents elevation of prostaglandin levels.

  4. The retinoblastoma protein binds to a family of E2F transcription factors

    DEFF Research Database (Denmark)

    Lees, J A; Saito, M; Vidal, M

    1993-01-01

    for E2F-2 and E2F-3 were mapped to 1p36 and 6q22, respectfully, confirming their independence from E2F-1. However, the E2F-2 and E2F-3 proteins are closely related to E2F-1. Both E2F-2 and E2F-3 bound to wild-type but not mutant E2F recognition sites, and they bound specifically to the retinoblastoma...... of a family of proteins....

  5. Topical prostaglandin F2alpha treatment reduces collagen types I, III, and IV in the monkey uveoscleral outflow pathway.

    Science.gov (United States)

    Sagara, T; Gaton, D D; Lindsey, J D; Gabelt, B T; Kaufman, P L; Weinreb, R N

    1999-06-01

    Topical prostaglandin F2alpha isopropyl ester increases uveoscleral outflow in monkeys and humans. To investigate the effects of prostaglandin F2alpha isopropyl ester with topical administration on collagen types I, III, and IV within the anterior segment tissue of monkey eyes. Eight eyes of 4 cynomolgus monkeys were evaluated. One eye of each monkey was treated with 2 microg of prostaglandin F2alpha isopropyl ester twice daily for 5 days, and intraocular pressure reduction was confirmed. These eyes were fixed in methacarn, and paraffin sections were immunostained using antibodies to collagen types I, II, or IV. To measure staining intensity, optical density (OD) was determined using 2-dimensional imaging densitometry. Mean OD scores along line segments placed over the ciliary muscle were determined. Mean+/-SD OD scores for collagen types I, III, and IV were less in the ciliary muscle of prostaglandin-treated eyes than in vehicle-treated eyes by 52%+/-7%, 45%+/-6%, and 45%+/-5%, respectively. In the sclera adjacent to the ciliary body, mean OD scores for collagen types I and III were less in prostaglandin-treated eyes, by 43%+/-32% and 45%+/-13%, respectively. The scleral stroma was minimally immunoreactive for collagen type IV. All differences were significant by the paired Student t test (Pcollagen types I, III, and IV immunoreactivity in the ciliary muscle and adjacent sclera following topical prostaglandin F2alpha isopropyl ester treatment. These reductions may contribute to the increased uveoscleral outflow observed with topical prostaglandin treatment. The cellular mechanism by which certain prostaglandins lower intraocular pressure is not known. The present study provides immunohistochemical data demonstrating that intraocular pressure reduction that occurs with topical prostaglandin F2alpha is associated with a reduction of collagens within the uveoscleral outflow pathway.

  6. Regulation of Trib2 by an E2F1-C/EBPα feedback loop in AML cell proliferation.

    LENUS (Irish Health Repository)

    Rishi, Loveena

    2014-04-10

    The loss of regulation of cell proliferation is a key event in leukemic transformation, and the oncogene tribbles (Trib)2 is emerging as a pivotal target of transcription factors in acute leukemias. Deregulation of the transcription factor E2F1, normally repressed by CCAAT enhancer-binding protein α (C\\/EBPα)-p42, occurs in acute myeloid leukemia (AML), resulting in the perturbation of cell cycle and apoptosis, emphasizing its importance in the molecular pathogenesis of AML. Here we show that E2F family members directly regulate Trib2 in leukemic cells and identify a feedback regulatory loop for E2F1, C\\/EBPα, and Trib2 in AML cell proliferation and survival. Further analyses revealed that E2F1-mediated Trib2 expression was repressed by C\\/EBPα-p42, and in normal granulocyte\\/macrophage progenitor cells, we detect C\\/EBPα bound to the Trib2 promoter. Pharmacological inhibition of the cell cycle or Trib2 knockdown resulted in a block in AML cell proliferation. Our work proposes a novel paradigm whereby E2F1 plays a key role in the regulation of Trib2 expression important for AML cell proliferation control. Importantly, we identify the contribution of dysregulated C\\/EBPα and E2F1 to elevated Trib2 expression and leukemic cell survival, which likely contributes to the initiation and maintenance of AML and may have significant implications for normal and malignant hematopoiesis.

  7. New (e,2e) studies of atomic and molecular targets

    Energy Technology Data Exchange (ETDEWEB)

    Casagrande, E M Staicu; Naja, A; Lahmam-Bennani, A [Universite de Paris-Sud XI and CNRS, Laboratoire des Collisions Atomiques et Moleculaires (UMR 8625), Bat. 351, 91405 Orsay Cedex (France); Kheifets, A S [Research School of Physical Science and Engineering, Australian National University, Canberra ACT 0200 (Australia); Madison, D H [Department of Physics, Missouri University of Science and Technology, Rolla, MO 65409-0640 (United States); Joulakian, B [Universite Paul Verlaine-Metz, Laboratoire de Physique Moleculaire et des Collisions (FR 2843), Institut de Physique, 1 rue Arago, 57078 Metz Cedex 3 (France)], E-mail: elena-magdalena.staicu-casagrande@u-psud.fr

    2008-11-01

    We report new coplanar (e,2e) measurements characterised by large energy transfer and close to minimum momentum transfer from the projectile to the target. Ionisation of the two-electron targets He and H{sub 2} is investigated under these particular kinematics. The experimental data are compared with the predictions of the most elaborate theoretical models. The obtained good agreement motivated us to extend our research to the case of more complex targets such as Ar. Comparison with the most elaborate models in the case of multi-electron targets is excellent. Destructive and constructive interference effects in the case of H{sub 2} are observed and discussed.

  8. Arachidonic Acid and Prostaglandins Enhance Potassium-Stimulated Calcium InFlux into Rat Brain Synaptosomes

    Science.gov (United States)

    1990-03-02

    calcium ci 10 100 10~M l0UM 3O"M I Blausten and Uctor. 1975. Leslie. Friedman, Wilcox riMet’al~r 01iM . and FlrI rod. I 9SO( [a~ contro an d drug...releases sesceral types of cell t Barritt. 1981). it i, possible a ra li l o"nic acid troil, lie ph. -phI1o i pi ds ( Brad ford. that secretion. stim ul...cardiosa-,alar Leslie S. W. Friedman MI B . Wilcox R. F. and Elrod S. disease and calcium antagonists. Am J. (’urdio/ 49: Y i Nxw Acute and c~hronic

  9. H2S-induced HCO3- secretion in the rat stomach--involvement of nitric oxide, prostaglandins, and capsaicin-sensitive sensory neurons.

    Science.gov (United States)

    Takeuchi, Koji; Ise, Fumitaka; Takahashi, Kento; Aihara, Eitaro; Hayashi, Shusaku

    2015-04-30

    Hydrogen sulfide (H2S) is known to be an important gaseous mediator that affects various functions under physiological and pathological conditions. We examined the effects of NaHS, a H2S donor, on HCO3(-) secretion in rat stomachs and investigated the mechanism involved in this response. Under urethane anesthesia, rat stomachs were mounted on an ex vivo chamber and perfused with saline. Acid secretion had been inhibited by omeprazole. The secretion of HCO3(-) was measured at pH 7.0 using a pH-stat method and by the addition of 10 mM HCl. NaHS (0.5-10 mM) was perfused in the stomach for 5 min. Indomethacin or L-NAME was administered s.c. before NaHS treatment, while glibenclamide (a KATP channel blocker), ONO-8711 (an EP1 antagonist), or propargylglycine (a cystathionine γ-lyase inhibitor) was given i.p. before. The mucosal perfusion of NaHS dose-dependently increased the secretion of HCO3(-), and this effect was significantly attenuated by indomethacin, L-NAME, and sensory deafferentation, but not by glibenclamide or ONO-8711. The luminal output of nitric oxide, but not the mucosal production of prostaglandin E2, was increased by the perfusion of NaHS. Mucosal acidification stimulated HCO3(-) secretion, and this response was inhibited by sensory deafferentation, indomethacin, L-NAME, and ONO-8711, but not by propargylglycine. These results suggested that H2S increased HCO3(-) secretion in the stomach, and this effect was mediated by capsaicin-sensitive afferent neurons and dependent on nitric oxide and prostaglandins, but not ATP-sensitive K(+) channels. Further study is needed to define the role of endogenous H2S in the mechanism underlying acid-induced gastric HCO3(-) secretion. Copyright © 2014 Elsevier Inc. All rights reserved.

  10. Methanolic extract of Boswellia serrata exhibits anti-cancer activities by targeting microsomal prostaglandin E synthase-1 in human colon cancer cells.

    Science.gov (United States)

    Ranjbarnejad, Tayebeh; Saidijam, Massoud; Moradkhani, Shirin; Najafi, Rezvan

    2017-07-01

    Colorectal cancer (CRC) is the most common cancer. A proper method to reduce mortality of CRC is chemoprevention to prevent initiation and promotion of intestinal tumorgenesis. One of the promising and developing chemopreventive agents is natural compounds found in plants. Frankincense, the resin extract from the Boswellia specious, has been used in traditional and modern medicine for treating various diseases with very minimal side effects. In the current study, we investigated the anti-cancer activity of methanolic extract of Boswellia serrata (B. serrata) on HT-29 human colon cancer cells. HT-29 cells were treated with different concentrations of B. serrata and cell viability was assessed by MTT assay. mRNA expression of microsomal prostaglandin E synthase-1 (mPGES-1), vascular endothelial growth factor (VEGF), C-X-C chemokine receptor type 4 (CXCR4), matrix metalloproteinase-2 (MMP-2), MMP-9 and hypoxia-inducible factor-1 (HIF-1) were examined by quantitative real-time PCR. Apoptosis was evaluated by the proportion of sub-G1 cells. Prostaglandin E2 (PGE2) level and caspase 3 activity were determined by ELISA assay. Tube formation potential and HT-29 cells migration were assessed using three-dimensional vessel formation assay and scratch test. B. serrata extract considerably decreased the expression of mPGES-1, VEGF, CXCR4, MMP-2, MMP-9 and HIF-1. The caspase 3 activity and percent of cells in sub-G1 phase were increased by B. serrata extract. Cell viability, PGE2 generation, in vitro tube formation and cell migration were decreased significantly in B. serrata-treated HT-29 compared to the control group. Our findings suggest that B. serrata extract inhibits proliferation, angiogenesis and migration and induces apoptosis in HT-29 cells by inhibiting of mPGES-1 and decreasing the PGE2 level and its downstream targets. Copyright © 2017 Elsevier Inc. All rights reserved.

  11. CCHCR1 interacts specifically with the E2 protein of human papillomavirus type 16 on a surface overlapping BRD4 binding.

    Directory of Open Access Journals (Sweden)

    Mandy Muller

    Full Text Available The Human Papillomavirus E2 proteins are key regulators of the viral life cycle, whose functions are commonly mediated through protein-protein interactions with the host cell proteome. We identified an interaction between E2 and a cellular protein called CCHCR1, which proved highly specific for the HPV16 genotype, the most prevalent in HPV-associated cancers. Further characterization of the interaction revealed that CCHCR1 binds the N-terminal alpha helices of HPV16 E2 N-terminal domain. On this domain, the CCHCR1 binding interface overlaps that of BRD4, a key mediator of E2 transcriptional activity. Consequently a physical competition occurs between the two proteins for the binding to HPV16 E2, and CCHCR1 interferes with BRD4-mediated enhancement of E2-dependent transcription. In addition, we showed that the interaction with CCHCR1 induced a massive redistribution of HPV16 E2, from a predominantly nuclear to a cytoplasmic localization in dot-like structures, where E2 perfectly co-localizes with CCHCR1. Such a cytoplasmic docking likely interferes with the nuclear functions of HPV16 E2. Upon co-expression of BRD4 and CCHCR1, E2 accumulates both in the nucleus and in the cytoplasm, indicating that for HPV16, both sub-cellular localization and transcriptional functions of E2 may depend on the proportion of both factors within the cell. We provided evidence of a strong induction of the keratinocyte differentiation marker K10 by HPV16 E2, and showed that this activation is compromised by the interaction with CCHCR1. The specific interaction described here could thus impact on the pathogenesis of HPV16. We propose that it could underlie some specific traits of HPV16 infection, such as an enhanced propensity to give rise to lesions evolving toward cancer.

  12. Hepatitis C virus protects human B lymphocytes from Fas-mediated apoptosis via E2-CD81 engagement.

    Directory of Open Access Journals (Sweden)

    Zhihui Chen

    2011-04-01

    Full Text Available HCV infection is often associated with B-cell regulatory control disturbance and delayed appearance of neutralizing antibodies. CD81 is a cellular receptor for HCV and can bind to HCV envelope protein 2 (E2. CD81 also participates to form a B cell costimulatory complex. To investigate whether HCV influences B cell activation and immune function through E2 -CD81 engagement, here, human Burkitt's lymphoma cell line Raji cells and primary human B lymphocytes (PHB were treated with HCV E2 protein and cell culture produced HCV particles (HCVcc, and then the related cell phenotypes were assayed. The results showed that both E2 and HCVcc triggered phosphorylation of IκBα, enhanced the expression of anti-apoptosis Bcl-2 family proteins, and protected Raji cells and PHB cells from Fas-mediated death. In addition, both E2 protein and HCVcc increased the expression of costimulatory molecules CD80, CD86 and CD81 itself, and decreased the expression of complement receptor CD21. The effects were dependent on E2-CD81 interaction on the cell surface, since CD81-silenced Raji cells did not respond to both treatments; and an E2 mutant that lose the CD81 binding activity, could not trigger the responses of both Raji cells and PHB cells. The effects were not associated with HCV replication in cells, for HCV pseudoparticle (HCVpp and HCVcc failed to infect Raji cells. Hence, E2-CD81 engagement may contribute to HCV-associated B cell lymphoproliferative disorders and insufficient neutralizing antibody production.

  13. E2/ER β inhibit ISO-induced cardiac cellular hypertrophy by suppressing Ca2+-calcineurin signaling.

    Science.gov (United States)

    Tsai, Cheng-Yen; Kuo, Wei-Wen; Shibu, Marthandam Asokan; Lin, Yueh-Min; Liu, Chien-Nam; Chen, Yi-Hui; Day, Cecilia-Hsuan; Shen, Chia-Yao; Viswanadha, Vijaya Padma; Huang, Chih-Yang

    2017-01-01

    Cardiovascular incidences are markedly higher in men than in pre-menstrual women. However, this advantage in women declines with aging and therefore can be correlated with the sex hormone 17β-Estradiol (E2) which is reported to protect heart cells by acting though estrogen receptors (ERs). In this study we have determined the effect of E2/ERβ against ISO induced cellular hypertrophy in H9c2 cardiomyoblast cells. The results confirm that ISO induced cardiac-hypertrophy by elevating the levels of hypertrophy associated proteins, ANP and BNP and further by upregulating p-CaMKII, calcineurin, p-GATA4 and NFATc3 which was correlated with a significant enlargement of the H9c2 cardiomyoblast. However, overexpression of ERβ and/or administration of E2 inhibited ISO-induced hypertrophy in H9c2 cells. In addition, E2/ERβ also inhibited ISO-induced NFATc3 translocation, and reduced the protein level of downstream marker, BNP. Furthermore, by testing with the calcineurin inhibitor (CsA), it was confirmed that calcineurin acted as a key mediator for the anti-hypertrophic effect of E2/ERβ. In cells treated with calcium blocker (BATPA), the inhibitory effect of E2/ERβ on ISO-induced Ca2+ influx and hypertrophic effects were totally blocked suggesting that E2/ERβ inhibited calcineurin activity to activate I-1 protein and suppress PP1, then induce PLB protein phosphorylation and activation, resulting in Ca2+ reuptake into sarcoplasmic reticulum through SR Ca2+ cycling modification. In conclusion, E2/ERβ suppresses the Ca2+ influx and calcineurin activity induced by ISO to enhance the PLB protein activity and SR Ca2+ cycling.

  14. RWD Domain as an E2 (Ubc9)-Interaction Module*

    Science.gov (United States)

    Alontaga, Aileen Y.; Ambaye, Nigus D.; Li, Yi-Jia; Vega, Ramir; Chen, Chih-Hong; Bzymek, Krzysztof P.; Williams, John C.; Hu, Weidong; Chen, Yuan

    2015-01-01

    An RWD domain is a well conserved domain found through bioinformatic analysis of the human proteome sequence; however, its function has been unknown. Ubiquitin-like modifications require the catalysis of three enzymes generally known as E1, E2, and E3. We solved the crystal structure of the E2 for the small ubiquitin-like modifiers (SUMO) in complex with an RWD domain and confirmed the structure using solution NMR analysis. The binding surface of RWD on Ubc9 is located near the N terminus of Ubc9 that is known to be involved in noncovalent binding of the proteins in the conjugation machinery, including a domain of E1, SUMO, and an E3 ligase. NMR data indicate that the RWD domain does not bind to SUMO and E1. The interaction between RWD and Ubc9 has a Kd of 32 ± 4 μm. Consistent with the structure and binding affinity and in contrast to a previous report, the RWD domain and RWDD3 have minimal effects on global SUMOylation. The structural and biochemical information presented here forms the basis for further investigation of the functions of RWD-containing proteins. PMID:25918163

  15. RWD Domain as an E2 (Ubc9)-Interaction Module.

    Science.gov (United States)

    Alontaga, Aileen Y; Ambaye, Nigus D; Li, Yi-Jia; Vega, Ramir; Chen, Chih-Hong; Bzymek, Krzysztof P; Williams, John C; Hu, Weidong; Chen, Yuan

    2015-07-03

    An RWD domain is a well conserved domain found through bioinformatic analysis of the human proteome sequence; however, its function has been unknown. Ubiquitin-like modifications require the catalysis of three enzymes generally known as E1, E2, and E3. We solved the crystal structure of the E2 for the small ubiquitin-like modifiers (SUMO) in complex with an RWD domain and confirmed the structure using solution NMR analysis. The binding surface of RWD on Ubc9 is located near the N terminus of Ubc9 that is known to be involved in noncovalent binding of the proteins in the conjugation machinery, including a domain of E1, SUMO, and an E3 ligase. NMR data indicate that the RWD domain does not bind to SUMO and E1. The interaction between RWD and Ubc9 has a Kd of 32 ± 4 μM. Consistent with the structure and binding affinity and in contrast to a previous report, the RWD domain and RWDD3 have minimal effects on global SUMOylation. The structural and biochemical information presented here forms the basis for further investigation of the functions of RWD-containing proteins. © 2015 by The American Society for Biochemistry and Molecular Biology, Inc.

  16. Regulation of Trib2 by an E2F1-C/EBPα feedback loop in AML cell proliferation

    DEFF Research Database (Denmark)

    Rishi, Loveena; Hannon, Maura; Salomè, Mara

    2014-01-01

    The loss of regulation of cell proliferation is a key event in leukemic transformation, and the oncogene tribbles (Trib)2 is emerging as a pivotal target of transcription factors in acute leukemias. Deregulation of the transcription factor E2F1, normally repressed by CCAAT enhancer-binding protein...... α (C/EBPα)-p42, occurs in acute myeloid leukemia (AML), resulting in the perturbation of cell cycle and apoptosis, emphasizing its importance in the molecular pathogenesis of AML. Here we show that E2F family members directly regulate Trib2 in leukemic cells and identify a feedback regulatory loop...

  17. Prostaglandin receptor EP3 regulates cell proliferation and migration with impact on survival of endometrial cancer patients.

    Science.gov (United States)

    Zhu, Junyan; Trillsch, Fabian; Mayr, Doris; Kuhn, Christina; Rahmeh, Martina; Hofmann, Simone; Vogel, Marianne; Mahner, Sven; Jeschke, Udo; von Schönfeldt, Viktoria

    2018-01-02

    Prostaglandin E