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Sample records for prostaglandin f2alpha regulates

  1. Transport of prostaglandin F(2alpha) pulses from the uterus to the ovary at the time of luteolysis in ruminants is regulated by prostaglandin transporter-mediated mechanisms.

    PubMed

    Lee, JeHoon; McCracken, John A; Banu, Sakhila K; Rodriguez, Royce; Nithy, Thamizh K; Arosh, Joe A

    2010-07-01

    In ruminants, prostaglandin F2alpha (PGF(2alpha)) is the uterine luteolytic hormone. During luteolysis, PGF(2alpha) is synthesized and released from the endometrium in a pulsatile pattern. The unique structure of the vascular utero-ovarian plexus (UOP) allows transport of luteolytic PGF(2alpha) pulses directly from the uterus to the ovary, thus bypassing the systemic circulation. However, the underlying molecular mechanism is not known. The objective of the present study was to determine a role for PG transporter protein (PGT) in the compartmental transport of PGF(2alpha) from uterus to ovary through the UOP at the time of luteolysis using the sheep as a ruminant model. [(3)H]PGF(2alpha), with or without a PGT inhibitor, was infused into UOP, and PGF(2alpha) transport and PGT protein expression were determined. Results indicate that PGT protein is expressed in tunica intima, tunica media, and tunica adventitia of the utero-ovarian vein and the ovarian artery of the UOP, and the expression levels are higher on d 10-15 compared with d 3-6 of the estrous cycle. Pharmacological inhibition of PGT prevented transport of exogenous [(3)H]PGF(2alpha) as well as oxytocin-induced endogenous luteolytic PGF(2alpha) pulse up to 80% from uterine venous blood into ovarian arterial blood through the UOP at the time of luteolysis in sheep. Taken together, these results indicate that at the time of luteolysis, transport of PGF(2alpha) from uterus to ovary through the UOP is regulated by PGT-mediated mechanisms. These findings also suggest that impaired PGT-mediated transport of PGF(2alpha) from the utero-ovarian vein into the ovarian artery could adversely influence luteolysis and thus affect fertility in ruminants.

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

    PubMed

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

    2005-01-01

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

  3. Circadian variations of prostaglandin E2 and F2 alpha release in the golden hamster retina.

    PubMed

    de Zavalía, Nuria; Fernandez, Diego C; Sande, Pablo H; Keller Sarmiento, María I; Golombek, Diego A; Rosenstein, Ruth E; Silberman, Dafne M

    2010-02-01

    Circadian variations of prostaglandin E2 and F2alpha release were examined in the golden hamster retina. Both parameters showed significant diurnal variations with maximal values at midnight. When hamsters were placed under constant darkness for 48 h, the differences in prostaglandin release between subjective mid-day and subjective midnight persisted. Western blot analysis showed that cyclooxygenase (COX)-1 levels were significantly higher at midnight than at mid-day, and at subjective midnight than at subjective mid-day, whereas no changes in COX-2 levels were observed among these time points. Immunohistochemical studies indicated the presence of COX-1 and COX-2 in the inner (but not outer) retina. Circadian variations of retinal prostaglandin release were also assessed in suprachiasmatic nuclei (SCN)-lesioned animals. Significant differences in retinal prostaglandin release between subjective mid-day and subjective midnight were observed in SCN-lesioned animals. These results indicate that hamster retinal prostaglandin release is regulated by a retinal circadian clock independent from the SCN. Thus, the present results suggest that the prostaglandin/COX-1 system could be a retinal clock output or part of the retinal clock mechanism.

  4. [Change in the estrous cycle of mice under the effect of prostaglandin F2 alpha].

    PubMed

    Persianinov, L S; Massal'skaia, L M

    1976-01-01

    It was shown that specific reception in female mice to prostaglandine F2alpha maturated in the process of ontogenesis since the vaginal reaction and the weight of the reproductive organs in the immature female animals failed to alter under its effect. In the sexually mature mice prostaglandine F2alpha arrested the course of the estral cycle and caused an untimely occurrence of the next estrus for a more prolonged time than normal, irrespective of the phase of the estral cycle during which it was administered.

  5. [Tafluprost--a novel prostaglandin F2alpha analogue].

    PubMed

    Petrov, S Iu

    2014-01-01

    The review provides a brief history of the evolution of ophthalmic containers: from glass vials to plastic bottles with obligatory preservatives and, finally, to preservative-free polypropylene single-use single-dose tubes. A brief characteristic of benzalkonium chloride, the most commonly used preservative, including mechanisms of its antiseptic activity and ocular toxicity is given. The problem of ocular surface damage, especially in glaucoma patients, due to the long-term use of preserved eye drops, is discussed. Pharmacodynamics of tafluprost, the first commercially available preservative-free single-dose prostaglandin analogue, is described. Operating characteristics of experimental preclinical studies and the first three phases of clinical trials of tafluprost are provided. Post-approval studies of the comparative efficacy and tolerability of the new drug are analyzed and its prospects for clinical use are assessed.

  6. Chain-shortening of prostaglandin F2 alpha by rat liver peroxisomes.

    PubMed

    Diczfalusy, U; Alexson, S E; Pedersen, J I

    1987-05-14

    Liver peroxisomes were isolated from di(2-ethylhexyl)phthalate treated rats by isopycnic sucrose gradient centrifugation of a light mitochondrial fraction. Incubation of prostaglandin F2 alpha with purified peroxisomes resulted in conversion into a more polar product(s). In contrast, incubation with mitochondrial fractions and microsomal fractions under the same conditions did not result in any detectable conversion. The polar material obtained from a preparative incubation was purified by high performance liquid chromatography and characterized by radio-gas chromatography and gas chromatography-mass spectrometry. The structure of the polar compound was shown to be 5,7,11-trihydroxy-tetranorprost-9-enoic acid (tetranor-prostaglandin F1 alpha). Prostaglandin F2 alpha was thus chain-shortened by four carbon atoms. PMID:3472523

  7. Acetylsalicylic acid regulates MMP-2 activity and inhibits colorectal invasion of murine B16F0 melanoma cells in C57BL/6J mice: effects of prostaglandin F(2)alpha.

    PubMed

    Tsai, Chin-Shaw Stella; Luo, Shue-Fen; Ning, Chung-Chu; Lin, Chien-Liang; Jiang, Ming-Chung; Liao, Ching-Fong

    2009-08-01

    Epidemiological studies indicate that acetylsalicylic acid may reduce the risk of mortality due to colon cancers. Metastasis is the major cause of cancer death. Matrix metalloproteinases (MMPs) play important roles in tumor invasion regulation, and prostaglandin F(2)alpha (PGF(2)alpha) is a key stimulator of MMP production. Thus, we investigated whether acetylsalicylic acid regulated MMP activity and the invasion of cancer cells and whether PGF(2)alpha attenuated acetylsalicylic acid-inhibited invasion of cancer cells. Gelatin-based zymography assays showed that acetylsalicylic acid inhibited the MMP-2 activity of B16F0 melanoma cells. Matrigel-based chemoinvasion assays showed that acetylsalicylic acid inhibited the invasion of B16F0 cells. Acetylsalicylic acid can inhibit PGF(2)alpha synthesis and PGF(2)alpha is a key stimulator of MMP-2 production. Our data showed that PGF(2)alpha treatment attenuated the acetylsalicylic acid-inhibited invasion of B16F0 cells. In animal experiments, acetylsalicylic acid reduced colorectal metastasis of B16F0 cells in C57BL/6J mice by 44%. Our results suggest that PGF(2)alpha is a therapeutic target for metastasis inhibition and acetylsalicylic acid may possess anti-metastasis ability.

  8. [Cardiovascular effect of 15(S)-15-methyl-prostaglandin F2alpha].

    PubMed

    Retzke, U; Schwarz, R

    1978-01-01

    The reaction of the cardiovascular system on one intramuscular injection of 250 microgram 15-methyl-prostaglandin F2alpha was examined in 14 normotensive healthy pregnant women between 7th and 11th weeks of gestation with the method of quantitative sphygmometry with unbloody graphic recording of arterial blood pressure and direct electronic determination of velocity of aortic pulse wave. The tests were done in 10 patients in intervals of 5 minutes for one hour and in 4 subjects for 12 hours in intervals of one hour. Systolic blood pressure remains nearly constant, but diastolic blood pressure increases and then decreases significantly. Heart rate decreases significantly. Aortic pulse wave velocity decreases in a characteristic manner. Analogous to the biphasic behaviour of blood pressure cardiac output decreases significantly, but then increases insignificantly. The inverse changes of total peripheral resistance are insignificant. Comparing these reactions with the cardiovascular effects of prostaglandin F2alpha or E2, 15-methyl-prostaglandin F2alpha shows the smallest circulatory alterations.

  9. Effect on prostaglandin F 2 alpha on sperm motility in vitro.

    PubMed

    Grünberger, W; Maier, U; Lunglmayr, G

    1981-01-01

    The effect of prostaglandin F 2 alpha (PGF2 alpha) on sperm motility in ejaculates from 53 subfertile men was investigated. The addition of PGF2 alpha in a concentration of 25 00 ng/ml isotonic salt solution to sperm samples resulted in a highly significant (p less than 0.025) increase in sperm motility; however, only two out of three samples responded in this way, the remainder being unaffected. Mean progressive sperm motility in responders increased by 32.8% of baseline value (determined 2h after liquefaction). In higher concentrations (25 000 ng/ml aliquots), PGF2 alpha was ineffective.

  10. Effect of atenolol treatment on urinary prostaglandins E2 and F2 alpha in essential hypertension.

    PubMed

    Rathaus, M; Magen, A; Rath-Wolfson, L; Shapira, J; Bernheim, J

    1983-12-01

    The urinary excretion of prostaglandins (PG) E2 and F2 alpha was measured by radioimmunoassay in 15 patients with essential hypertension, before and after 2 and 4 weeks of treatment with the selective beta 1-adrenergic blocker, atenolol. Systolic and diastolic blood pressure, pulse rate and plasma renin activity decreased significantly during the treatment. No change was observed in renal function and electrolyte balance. The 24-hour excretion of PGE2 and PGF2 alpha was also unaffected by the antihypertensive treatment. The above findings, in contrast with those previously observed with another beta-blocker, propranolol, suggest that tubular beta-receptors are not involved in the synthesis of PGs. The different hemodynamic effects of the two drugs are the most likely explanation for the different responses in prostaglandin excretion.

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

    SciTech Connect

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

    1985-12-15

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

  12. Prostaglandin F2 alpha-induced response of the bovine ovary, oviduct (uterine tube), and uterus.

    PubMed

    Singh, L P; Sadiku, A; Verma, O P

    1979-12-01

    Tissue strips from the ovary, (uterine tube), and oviduct, and uterus of pregnant and nonpregnant cows were tested for their contractile response to prostaglandin F2 alpha (PGF2 alpha). When 2.1 x 10(-6)M PGF2 alpha was added to the uterine strips, tension of tissues from pregnant cows increased sharply; however, tension in tissues from nonpregnant cows only increased moderately. Similar concentrations failed to elicit any response from oviductal tissues of either group. Unlike the uterus and the oviduct, the ovaries contracted slowly and irregularly. They responded with varying degrees of stimulation; ovaries from pregnant cows with brief and mild stimulation and ovaries from nonpregnant cows with slower and relatively stronger stimulation. Results indicate that the bovine ovary contracts rhythmically and that its sensitivity to PGF2 alpha decreases during pregnancy in contrast to the bovine uterus which becomes increasingly sensitive during pregnancy.

  13. Cardiovascular effects of prostaglandin I2 and prostaglandin F2 alpha in the unanesthetized bullfrog, Rana catesbeiana.

    PubMed

    Robleto, D O; Herman, C A

    1988-04-01

    The cardiovascular effects of prostaglandin (PG)I2 and PGF2 alpha were compared in the unanesthetized American bullfrog (Rana catesbeiana). Control mean arterial pressure (MAP) and heart rate (HR) were 25.7 +/- 1.1 mm Hg and 35.1 +/- 1.1 beats/min, respectively. Intravenous injections of PGI2 decreased MAP and increased HR in a dose-dependent fashion over the range of concentrations tested (0.03, 0.3, 3, and 10 micrograms/kg-body weight [bw]. Neither atropine (1 mg/kg-bw) nor verapamil (1 mg/kg-bw) treatment altered the MAP or HR responses to PGI2 (3 micrograms/kg-bw). However, propranolol (5 mg/kg-bw) significantly blunted the hypotensive effects without affecting the increase in HR. Prostaglandin F2 alpha (tested at 0.3, 3, 30, and 100 micrograms/kg-bw) increased both MAP and HR. Mean arterial pressure increased with concentrations greater than 0.3 microgram/kg-bw and reached peak effects at 30 micrograms/kg-bw. Prostaglandin F2 alpha increased HR at doses greater than 0.3 microgram/kg-bw. Neither the pressor nor positive chronotropic effects of PGF2 alpha (30 micrograms/kg-bw) were affected by atropine or propranolol. However, verapamil significantly attenuated the pressor effects without affecting the increase in HR. These results demonstrate that both prostaglandins have qualitatively similar effects on HR, but opposite effects on MAP. Prostaglandin I2 is a hypotensive prostaglandin, while PGF2 alpha is hypertensive. The pressor effects of PGF2 alpha are partially dependent on calcium influx. The positive chronotropic effects of both prostaglandins are independent of the autonomic nervous system, suggesting a different mechanism of action.

  14. Attenuated cardiovascular effects of prostaglandin I2 and prostaglandin F2 alpha in cold acclimated American bullfrogs, Rana catesbeiana.

    PubMed

    Herman, C A; Robleto, D O; Mata, P L; Lujan, M D

    1986-05-01

    American bullfrogs, Rana catesbeiana respond to prostaglandins with changes in heart rate and blood pressure. These studies compare responses of warm (22 degrees C) and cold acclimated (5 degrees C) bullfrogs to prostaglandins. Gas chromatographic analysis determined equivalent fatty acid profiles in total lipids of heart and artery tissue from warm and cold acclimated animals. Arachidonic acid was the fatty acid precursor found in greatest abundance in both groups. For cardiovascular experiments, bullfrogs were cannulated by using a T-cannula implanted in the right sciatic artery. In warm acclimated bullfrogs, preinfusion systemic arterial pressure (SAP) was 14.7 +/- 0.5 mm Hg, and heart rate was 33.0 +/- 1.7 beats/min. Cold acclimated bullfrogs had SAP values of 8.0 +/- 0.8 mm Hg, and heart rate was 6.9 +/- 0.3 beats/min. Arachidonic and eicosapentaenoic acid infusions (2,000 micrograms/kg body weight [bw]) were hypertensive in cold acclimated and hypotensive in warm acclimated animals. These effects were blocked by indomethacin (4 mg/kg bw). In both warm and cold acclimated bullfrogs, prostaglandin F2 alpha (3-100 micrograms/kg bw) was hypertensive, while prostaglandin I2 (0.03-3 micrograms/kg bw) was hypotensive, with both prostaglandins stimulating a greater absolute response in warm acclimated animals. In addition, both prostaglandins increased heart rate in warm but not in cold acclimated bullfrogs. The results suggest diminished cardiovascular sensitivity to prostaglandins at low environmental temperatures.

  15. Acute ozone exposure increases plasma prostaglandin F2 alpha in ozone-sensitive human subjects

    SciTech Connect

    Schelegle, E.S.; Adams, W.C.; Giri, S.N.; Siefkin, A.D.

    1989-07-01

    Twenty O/sub 3/-sensitive and /sup 2/O O/sub 3/-nonsensitive subjects participated in a study to investigate the effects of disparate O/sub 3/ sensitivity on plasma prostaglandin F2 alpha responses consequent to exposure to ambient O3 concentrations. Subjects were selected from a pool of 75 normal healthy college-aged males who had been previously exposed to 0.35 ppm O3 for 1 h at an exercising VE of 60 L/min. The selection criterion used was the observed decrement in FEV1 after the O/sub 3/ exposure: O/sub 3/-sensitive, FEV1 decrement greater than 24%; O/sub 3/-nonsensitive, FEV1 decrement less than 11%. Each subject was exposed to filtered air and to 0.20 and 0.35 ppm O/sub 3/ for 80 min while exercising at a VE of 50 L/min. These experimental protocols were divided into two 40-min sessions separated by a period of 4 to 10 min. PGF2 alpha, FVC, FEV1, and FEF25-75 were evaluated before, during, and after each protocol. SGaw and Vtg were measured before and after each protocol. Plasma PGF2 alpha was significantly increased in the O/sub 3/-sensitive group during and after the 0.35-ppm O/sub 3/ exposure.

  16. Induction of estrus in cattle by intraovarian injection of prostaglandin F2alpha.

    PubMed

    Rayos, A A; Abalos, J A; Cruz, S F; Kanagawa, H

    1990-09-01

    An effective, reduced dosage (1/10 to 1/20 the systemic dose) method for administering prostaglandin F2alpha in heifers to induce estrus is presented in this study. The PGF2alpha was injected intraovarially in five heifers at a dose of 2 mg and in another five heifers at a dose of 1 mg. Five additional heifers were injected intraovarially with 0.5 ml of distilled water and served as the controls. Regression of the corpus luteum (CL) occurred in all PGF2alpha-treated heifers resulting in marked decline of the peripheral levels of progesterone 24 h after treatment. Estrus was expressed 1 to 3 d later. Regression of the CL, estrus, and decline in the peripheral levels of progesterone were not observed in the control heifers. Conception rates in the heifers given either 2 mg and 1 mg PGF(2alpha) were 60 and 100%, respectively. Seven calves were born at the end of the normal gestation period while one calf was aborted.

  17. Studies on a novel series of acyl ester prodrugs of prostaglandin F2 alpha.

    PubMed Central

    Cheng-Bennett, A; Chan, M F; Chen, G; Gac, T; Garst, M E; Gluchowski, C; Kaplan, L J; Protzman, C E; Roof, M B; Sachs, G

    1994-01-01

    A novel series of prostaglandin F2 alpha (PGF2 alpha) prodrugs, with acyl ester groups at the 9, 11, and 15 positions, was prepared in order to design clinically acceptable prostaglandins for treating glaucoma. Studies involving isolated esterases and ocular tissue homogenates indicated that 9-acyl esters cannot provide a prodrug since PGF2 alpha would not be formed as a product. In contrast, 11-mono, 15-mono, and 11, 15-diesters were converted to PGF2 alpha in ocular tissues and could, therefore, be considered as prodrugs of PGF2 alpha. Carboxylesterase (CE) appeared critically important for the hydrolytic conversion of those PGF2 alpha prodrugs where the 11 or 15-OH group was esterified and such prodrugs were not substrates for acetylcholinesterase (ACHE) or butyrylcholinesterase (BuCHE). The enzymatic hydrolysis of PGF2 alpha-1-isopropyl ester was also investigated for comparative purposes. This PGF2 alpha prodrug was a good substrate for CE, but was also hydrolysed by BuCHE, albeit at a much slower rate. The most striking feature of the enzymatic hydrolysis of PGF2 alpha-1-isopropyl ester in ocular tissue homogenates was that it was much faster than for prodrugs esterified at the 11 and/or 15 positions. In terms of ocular hypotensive activity, all prodrugs which showed detectable conversion to nascent PGF2 alpha were potent ocular hypotensives. Although no separation of ocular hypotensive and ocular surface hyperaemic effects was apparent for PGF2 alpha-1-isopropyl ester, a temporal separation of these effects was apparent for the novel PGF2 alpha ester series. This difference may reflect an unfavourably rapid conversion of PGF2 alpha-1-isopropyl ester in ocular surface tissues compared with anterior segment tissues. PMID:7918269

  18. Change in responsiveness of rabbit corpus luteum to prostaglandin F-2 alpha during pregnancy and pseudopregnancy.

    PubMed

    Marcinkiewicz, J L; Moy, E S; Bahr, J M

    1992-03-01

    Previous studies have suggested that prostaglandin F-2 alpha (PGF-2 alpha) may have a role in luteolysis in rabbits. Rabbits (4-6/group) were given a single injection of saline, or 100, 500 or 2500 micrograms PGF-2 alpha (i.m.) on Day 7, 9, 12 or 15 of pregnancy or pseudopregnancy. Daily blood samples were taken via the marginal ear vein before and for 3 days after the PGF-2 alpha injection. Concentrations of serum progesterone were determined by radioimmunoassay in pseudopregnant rabbits. There were no significant differences between PGF-2 alpha-treated and control rabbits on Days 7 or 9. On Day 12 of pseudopregnancy, progesterone concentration was significantly (P less than 0.05) lower in treated than in control rabbits, the effect being dose dependent. On Day 15 of pseudopregnancy, it was not possible to distinguish between controls and treated groups because luteolysis occurred in all rabbits. In contrast, on Days 7 and 9 of pregnancy, the concentration of progesterone in treated groups was lower than in the control groups (P less than 0.05), the effect being dose dependent. This difference was maintained throughout the sampling period and resulted in termination of pregnancy. By Day 12 of pregnancy, the response to PGF-2 alpha was transient, with a significant decline in progesterone for only 2 days, followed by a return to control concentrations and normal delivery of litters. On Day 15 of pregnancy, no treatment with PGF-2 alpha significantly altered progesterone concentration.(ABSTRACT TRUNCATED AT 250 WORDS)

  19. Matrix metalloproteinase expression and activity following prostaglandin F(2 alpha)-induced luteolysis.

    PubMed

    Ricke, William A; Smith, George W; Smith, Michael F

    2002-03-01

    Luteal tissue contains matrix metalloproteinases (MMPs) that cleave specific components of the extracellular matrix (ECM) and are inhibited by tissue inhibitors of metalloproteinases (TIMPs). We previously reported a decrease in luteal TIMP-1 within 15 min of prostaglandin F(2 alpha) (PGF(2 alpha))-induced luteolysis. An increase in the MMP:TIMP ratio may promote ECM degradation and apoptosis, as observed in other tissues that undergo involution. The objectives of these experiments were to determine whether 1) PGF(2 alpha) affects expression of mRNA encoding fibrillar collagenases (MMP-1 and -13), gelatinases A and B (MMP-2 and -9), membrane type (mt)-1 MMP (MMP-14), stromelysin (MMP-3), and matrilysin (MMP-7), and 2) PGF(2 alpha) increases MMP activity during PGF(2 alpha)-induced luteolysis in sheep. Corpora lutea (n = 3-10/time point) were collected at 0, 15, and 30 min and 1, 2, 4, 6, 12, 24, and 48 h after PGF(2 alpha) administration. Northern blot analysis confirmed the presence of all MMPs except MMP-9. Expression of mRNA for the above MMPs (except MMP-2) increased significantly (P < 0.05) by 30 min, and all MMPs increased significantly (P < 0.05) by 6 h after PGF(2 alpha) administration. Expression of MMP-14 mRNA increased significantly (P < 0.05) by 15 min post-PGF(2 alpha) and remained elevated through 48 h. MMP activity in luteal homogenates (following proenzyme activation and inactivation of inhibitors) was increased significantly (P < 0.05) by 15 min and remained elevated through 48 h post-PGF(2 alpha). MMP activity was localized (in situ zymography) to the pericellular area of various cell types in the 0-h group and was markedly increased by 30 min post-PGF(2 alpha). MMP mRNA expression and activity were significantly increased following PGF(2 alpha) treatment. Increased MMP activity may promote ECM degradation during luteolysis.

  20. Induction of parturition in swine with prostaglandin F(2)alpha, estradiol benzoate and oxytocin.

    PubMed

    Gall, M A; Day, B N

    1987-03-01

    Pregnant sows and gilts were administered either 0, 2.5, 5, 10 or 20 mg prostaglandin F(2)alpha (PGF(2)alpha) intramuscularly on Day 112 or 113 of gestation at 0800 h in an effort to induce parturition. The average interval from PGF(2)alpha injection to farrowing was 55.1 +/- 5.7, 29.4 +/- 3.1, 32.1 +/- 4.6, 27.8 +/- 1.8 and 26.9 +/- 1.1 h for 0, 2.5, 5, 10 and 20 mg, respectively. All PGF(2)alpha treatments increased (P < 0.01) over controls the number of sows farrowing 23 to 33 h after injection. The average gestation length was significantly shorter in treated gilts; however, no detrimental effect on pig performance or pig survivability was observed. A second trial evaluated the effect of a 10-mg dose of PGF(2)alpha on the induction of parturition in sows in order to obtain a majority of sows farrowing within normal working hours (0700 to 1700 h). The interval from injection to farrowing was decreased (P < 0.05) by PGF(2)alpha treatment (66.2 +/- 5.3 vs 28.1 +/- 2.2 h). Fifty-seven percent (P < 0.05) of PGF(2)alpha-treated sows farrowed between 0700 and 1700 h as compared to 13.6% for control sows. A third trial was conducted to examine a sequential treatment of PGF(2)alpha and oxytocin to control the time of parturition more precisely. Sows receiving only 10 mg of PGF(2)alpha farrowed on an average 31.1 +/- 1.4 h after injection. The injection of 40 IU oxytocin 24 to 28 h after PGF(2)alpha decreased (P < 0.05) the interval from PGF(2)alpha to farrowing (28.1 +/- 0.9 h). The addition of oxytocin increased (P < 0.05) the number of sows farrowing within 3 h of injection (33 vs 86% for PGF(2)alpha and PGF(2)alpha + oxytocin treatments, respectively). A fourth trial was designed to determine if the addition of exogenous estradiol benzoate (EB) to a sequential treatment of PGF(2)alpha and oxytocin would improve the predictability and synchronization of the induced parturition. Sows were assigned to receive either saline, 10 mg PGF(2)alpha + 40 IU oxytocin or 10 mg

  1. Estrus synchronization in sheep and goats using combinations of GnRH, progestagen and prostaglandin F2alpha.

    PubMed

    Titi, H H; Kridli, R T; Alnimer, M A

    2010-08-01

    The objective of this experiment was to evaluate the effect of GnRH, progestagen and prostaglandin F(2alpha) on estrus synchronization in sheep and goats. Sixty Awassi ewes and 53 Damascus does were used in the study. The experiment started at the beginning of the breeding season (June/July). The same treatments were applied to sheep and goats as follows: no treatment (CON), 14-day progestagen sponges and 600 IU equine chorionic gonadotropin (S), gonadotropin releasing hormone followed 5 days later by prostaglandin F(2alpha) (GP) and gonadotropin releasing hormone, progestagen sponges for 5 days and prostaglandin F(2alpha) on the day of sponge removal (GSP). None of the ewes in the S group lambed from mating during the induced cycle. A greater lambing rate (p < 0.05) was observed in the GSP group compared with the CON and S groups while the GP group was intermediate. The number of lambs born per lambed ewe was similar among the CON, GP and GSP groups. However, the number of lambs per exposed ewe was greater (p < 0.05) in the GSP than the remaining groups. The induced cycle kidding rate was 77% for all treatments combined. Similar kidding rate were observed among treatments. The numbers of kids born per kidded and exposed doe from mating during the induced estrus were also similar among treatments. Greater numbers of multiple births were observed in the GP and GSP than in the S group. In conclusion, a combination of GnRH, progestagen sponges and PGF(2alpha) can be effective in synchronizing estrus and improving fecundity in sheep and goats. Although the use of GnRH-PGF(2alpha) was effective, the addition of progestagen sponges at the time of GnRH administration appeared to improve reproductive parameters.

  2. Peripheral serum progesterone and luteinizing hormone concentrations of goats during synchronization of estrus and ovulation with prostaglandin F2 alpha.

    PubMed

    Ott, R S; Nelson, D R; Hixon, J E

    1980-09-01

    Prostaglandin F2 alpha (PGF2 alpha) (2 doses, 11 days apart) was given to 20 mixed-breed dairy does to synchronize estrus and ovulation. The dose of PGF2 alpha used was the free-acid equivalent of 8 mg which was divided between 2 injections at 0800 and 1200 hours. At the initiation of treatments, does were from day 0 (estrus) to day 18 of the estrous cycle. Seventeen of the doses exhibited estrus within a mean (+/- SE) interval of 53 +/- 2 hours after the first 0800-hour injection. Peripheral progesterone concentrations determined at daily intervals indicated that PGF2 alpha was luteolytic as early as day 4 of the cycle. Does were in the 8th to 12th days of the cycle at the time of the 2nd treatments with PGF2 alpha. Estrus was observed in all 20 does at 50 +/- 1 hour after the 0800-hour injections. Serum progesterone concentrations confirmed that luteolysis occurred in all of the does. In 19 does, concentrations of luteinizing hormone characteristic of a preovulatory peak were observed 55 +/- 2 hours after the 2nd 0800-hour injection. One doe did not demonstrate a luteinizing hormone peak within the 72-hour period. Laparotomies were performed 6 days after estrus, and ovaries were examined for corpora lutea. The mean number of corpora lutea was 2.0 +/- 1.0. PMID:7192524

  3. Changes in refractoriness of rabbit corpora lutea to a prostaglandin F2 alpha analogue, alfaprostol, during pseudopregnancy.

    PubMed

    Boiti, C; Canali, C; Zerani, M; Gobbetti, A

    1998-07-01

    The responsiveness of rabbit corpus luteum to 200 micrograms of the prostaglandin F2 alpha (PGF2 alpha) analogue, alfaprostol, between Days 3 and 9 of pseudopregnancy was assessed by evaluating the decline in plasma progesterone after treatment with PGF2 alpha in 81 New Zealand White (NZW) rabbits. On Days 3-5, functional luteolysis was not observed. On Days 6, 7, and 8 of pseudopregnancy, the number of rabbits responsive to PGF2 alpha, rose from 38% to 71% and 83%, respectively. In the other cases, the effect of the PGF2 alpha analogue was transient as CL recovered in the following 2 or 3 days. By contrast, on Day 9 luteolysis was effective and persistent in all the animals. In rabbits treated on Day 9, progesterone decreased gradually from 10.6 +/- 0.7 within the first 6 h, but fell to 3.6 +/- 1.5 ng/mL (p < 0.01) 12 h after PGF2 alpha and to 0.2 +/- 0.1 ng/mL (p < 0.01) 24 h later.

  4. Synchronization of lactating dairy cows with prostaglandin F2 alpha: insemination on observed oestrus versus timed artificial insemination.

    PubMed

    Tenhagen, B A; Drillich, M; Heuwieser, W

    2000-12-01

    The effect of two insemination policies after synchronization of oestrus on reproductive performance in two groups of cows was investigated. Oestrus was synchronized by two treatments with prostaglandin F2 alpha (PGF2 alpha) at a 14-day interval. Cows in Group 1 (n = 234) were inseminated twice on appointment 66 and 90 h after the second treatment. Cows in Group 2 (n = 222) were intensively watched for signs of oestrus after the synchronization protocol and inseminated on observed oestrus. Cows with abnormal discharge after synchronization were excluded from breeding and inseminated later during the study period. Service rate within 1 week after synchronization was higher in Group 1 than in Group 2 (89.3 versus 67.1%). Conception rates on first service did not differ between groups (33.2 versus 30.0%). Days to first service and days open were shorter in Group 1 (P < 0.05). The number of cows culled for infertility did not differ between the groups. Endometritis 14-20 days post-partum decreased the percentage of cows pregnant at the end of the study period in both groups but did not have a significant effect on conception rates and days open. It is concluded that additional inseminations required in the timed artificial insemination protocol were economically justified by the reduction in days open in comparison with insemination on observed oestrus after synchronization.

  5. Control of luteal relaxin release by prostaglandin F2 alpha: differences in the sow cycle and pregnancy.

    PubMed

    Bagnell, C A; Baker, N K; McMurtry, J P; Brocht, D M; Lewis, G S

    1990-06-01

    The effect of an in vivo prostaglandin F2 alpha (PGF2 alpha) challenge in pregnant and cyclic sows was compared to determine whether PGF2 alpha-induced release of relaxin (RLX) from the corpus luteum (CL) in late pregnancy is also effective during the cycle. Ovarian venous RLX and progesterone were monitored by radioimmunoassay and RLX localized in the CL by immunohistochemistry. In Day 108 pregnant sows, infusion of PGF2 alpha (100 micrograms) into the ovarian artery resulted in an immediate and sustained rise in ovarian venous RLX with an initial decline in progesterone levels by 30 min which then returned to pretreatment levels. In Day 13 or 15 cyclic sows with functional corpora lutea (i.e., elevated progesterone), RLX was undetectable in ovarian venous blood after 100 micrograms of PGF2 alpha. Administration of PGF2 alpha via either the jugular vein or intramuscular route was also ineffective in releasing RLX from the CL of the cycle. The intensity of RLX immunostaining of the CL was similar in saline and PGF2 alpha-treated sows. These studies indicate that the control of RLX release from the sow CL differs in the estrous cycle and pregnancy.

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

    PubMed Central

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

    1987-01-01

    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 32PO4 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. PMID:3035550

  7. Farrowing induction with a combination of prostaglandin F(2alpha) and a peripherally acting alpha(2)--adrenergic agonist AGN 190851 and a combination of prostaglandin F(2alpha) and oxytocin.

    PubMed

    Yang, P C; Fang, W D; Huang, S Y; Chung, W B; Hsu, W H

    1996-11-01

    We studied the effect of prostaglandin (PG) F(2alpha)-AGN 190851 on farrowing induction and compared it with that of PGF(2alpha)-oxytocin. Eighty crossbred, multiparous sows were randomly assigned to the following 4 treatment groups of 20 sows each: 1) control, saline-saline; 2) PGF(2alpha) (10 mg/sow)-oxytocin (30 IU/sow); 3) PGF(2alpha) (10 mg/sow)-AGN 190851 (0.06 mg/kg); and 4) PGF(2alpha) (10 mg/sow)-AGN 190851 (0.1 mg/kg). Either PGF(2alpha) or saline was administered intramuscularly on Day 111 of gestation at 11:30 h; AGN 190851, oxytocin or saline was administered intramuscularly 20 h after the first injection. The PGF(2alpha)-AGN 190851 (0.1 mg/kg) treated sows had the shortest mean farrowing interval (2.1 +/- 1.6 h, mean +/- SD) compared with the remaining treatment groups (control: 67.1 +/- 26.2 h; PGF(2alpha)-oxytocin: 5.6 +/- 6.7 h; PGF(2alpha)-AGN 190851 [0.06 mg/kg]: 3.0 +/- 2.8 h). Duration of farrowing, litter size, litter weight and interval from weaning to first estrus in sows were not significantly changed by these treatments. The PGF(2alpha)-oxytocin group had a significantly higher stillbirth rate than the control group, whereas the PGF(2alpha)-AGN 190851 (0.1 mg/kg) group had the lowest number of pigs born dead and stillbirth rate among the 4 treatment groups. These results suggested that the PGF(2alpha)-AGN 190851 combination can be used as an alternative method to PGF(2alpha)-oxytocin for synchronizing farrowing.

  8. Release of the lipid peroxidation marker 8-epi-prostaglandin F2 alpha from isolated gill pavement cells.

    PubMed

    Spokas, Eric G; Harshman, Scott; Cohen, Glenn M; Jiang, Chen; Levine, Jaime M; Rodriguez, Ana R; Foglein, Jon; Spur, Bernd W

    2008-07-01

    The aim of the present study was to evaluate oxidative injury in gill pavement cells (GPCs) from fathead minnow (Pimephales promelas) using F2-isoprostane (F2-iP) release as an index of lipid peroxidation. Cells were isolated from pooled gill tissue by collagenase treatment, mechanical sieving, and Percoll density gradient centrifugation. Baseline levels of 8-epi-prostaglandin F2 alpha (8-epi-PGF2 alpha) were measured by incubating GPCs in physiological buffer (10(6) cells/ml) and enzyme immunoassay. After 60 min, the amount of immunoreactive 8-epi-PGF2 alpha (ir8-epi-PGF2 alpha) in control medium ranged from 1,374 to 5,515 pg/ml. Lead nitrate, 0.6 to 120 microM, did not influence ir8-epi-PGF2 alpha release, whereas FeCl3 stimulated release at 500 microM but not at 5 microM. Incubation medium was extracted for acidic lipids and analyzed by liquid chromatography/mass spectrometry/electrospray ionization. A compound in the medium exhibited a retention time on reverse-phase high-performance liquid chromatography nearly identical to that of synthetic 8-epi-PGF2 alpha The mass spectrum taken from the total ion chromatogram from 14.8 to 15.1 min contained a prominent ion at m/z 353, as expected for the molecular ion of 8-epi-PGF2 alpha. Similar results were obtained with tissue subjected to base hydrolysis. Mass spectra of extracted ion chromatograms obtained with gill extracts and authentic standard showed a close correspondence of fragment ions, providing definitive evidence for production and storage of F2-iPs by fish gills. In summary, F2-iP release occurs during lipid peroxidation injury to fish gill epithelium, and its measurement may facilitate aquatic toxicology studies of metallic and nonmetallic contaminants.

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

    SciTech Connect

    Collins, D.A.; Chambers, T.J. )

    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.

  10. Termination of pseudopregnancy by administration of prostaglandin F2alpha and termination of early pregnancy by administration of prostaglandin F2alpha or colchicine or by removal of embryo in mares.

    PubMed

    Kooistra, L H; Ginther, O J

    1976-01-01

    At day 24 of gestation, pregnant mares were allotted to 1 of 5 treatment groups (3 to 5 mares/group): group A--nontreated controls; group B--intraembryonic injection of 4 mg of colchicine on day 24; group C--removal of embryo on day 24; group D--subcutaneous injection of 1.25 mg of prostaglandin F2alpha (PGF2alpha) on day 32; and group E--removal of embryo on day 24 and subcutaneous injection of PGF2alpha on day 32. In all mares treated with colchicine (group B), the fetal bulge was absent within 2 days. The interval from injection of colchicine to onset of estrus was very short (mean, 4 days). These results indicated that treatment with colchicine was lethal to the 24-day embryo, and pseudopregnancy did not occur. Surgical removal of the embryo (group C) resulted in pseudopregnancy characterized by a prolonged interval from treatment to return to estrus (mean, greater than 31 days), prolonged production of progesterone, and prolonged maintenance of tense uterine and cervical tone. The interval from treatment to ovulatory estrus was longer (P less than 0.05) for group C mares than for group B mares. The mean interval from treatment to complete loss of tense tubular uterine tone was not significantly different between group A pregnant controls (28.3 days) and group C pseudopregnant mares (30 days). Treatment of pregnant mares (group D) with a single injection of PGF2alpha on day 32 resulted in loss of pregnancy in 4 of 4 mares within 2 to 5 days, and in all group D mares a large decrease in progesterone concentration occurred on day 33, 34, or 35. Although subsequent reproductive activity was variable, all group D mares rapidly lost the tense uterine and cervical tone characteristic of early pregnancy. These results indicated that a single subcutaneous injection of 1.25 mg of PGF2alpha caused loss of pregnancy, and pseudopregnancy did not occur. Treatment of group E mares, which had been made pseudopregnant by removal of embryo, with 1.25 mg of PGF2alpha resulted in

  11. Timing of ovulation and fertility of heifers after synchronization of oestrus with GnRH and prostaglandin F(2alpha).

    PubMed

    Tenhagen, B-A; Kuchenbuch, S; Heuwieser, W

    2005-02-01

    Synchronization of oestrus and/or ovulation can reduce workload in heifer reproductive management. The objective of this study was to compare two protocols to synchronize oestrus and/or ovulation using GnRH and prostaglandin F(2alpha) (PGF(2alpha)) in dairy heifers concerning their effect on follicular dynamics and reproductive performance. Four trials were carried out. In trial 1, 282 heifers were treated with GnRH and PGF(2alpha) 7 days apart (GP protocol). One group was inseminated on detection of oestrus (IDO 1), and the other group received two timed artificial inseminations (AI) 48 and 72 h after PGF(2alpha) administration (TAI 1). In trial 2, 98 heifers were synchronized with the same GP protocol. Heifers in IDO 2 were treated as in IDO 1, heifers in TAI 2 received two TAI 48 and 78 h after PGF(2alpha) administration. In trial 3, heifers in IDO 3 (n = 71) were again treated as in IDO 1. Heifers in TAI 3 (n = 166) received a second dose of GnRH 48 h after PGF(2alpha) (GPG protocol) and TAI together with this treatment and 24 h later. Trial 4 compared the timing of ovulation after the GP and the GPG protocol, using a subgroup of the heifers from trials 1 to 3. The ovaries of the heifers were scanned via ultrasound at 48, 56, 72, 80, 96 and 104 h after PGF(2alpha) administration. Timing of ovulation and size of the ovulatory follicles were compared between the two groups. In trials 1 to 3, conception rates to first service were between 49 and 66%. They did not differ significantly between IDO and TAI groups within or between trials. Pregnancy rates per synchronization were numerically higher in the TAI groups, but the difference was not significant. Conception rates to breeding on spontaneous oestrus in heifers returning to oestrus were higher than that after synchronized oestrus. In trial 4, more heifers ovulated before the end of the observation period in GPG than in GP (96.5% vs 74.7%; p < 0.001). Overall, ovulatory follicles were smaller in GPG (13.1 +/- 1

  12. Suppression of hepatic prostaglandin F2 alpha in rats by dietary alpha-tocopherol acetate is independent of total hepatic alpha-tocopherol.

    PubMed

    Duitsman, P K; Chen, H W; Cook, L R; Hendrich, S

    1992-09-01

    Groups of eight weanling female F344/N rats were fed semipurified diets that supplied 0, 50, 500, 5000, or 15,000 mg alpha-tocopherol acetate/kg diet, with and without 0.05% phenobarbital (PB) for 9 weeks. Both plasma and hepatic alpha-tocopherol levels, measured by HPLC, strongly correlated with alpha-tocopherol intake (r greater than 0.73, p less than 0.0001). Phenobarbital both depleted hepatic alpha-tocopherol and increased plasma alpha-tocopherol significantly. Although treatment with PB for 9 weeks significantly increased GST activity, PB did not affect hepatic prostaglandin (PG)F2 alpha status, as determined by radioimmunoassay. PGF2 alpha was significantly greater (by 52%) in rats fed no alpha-tocopherol than in rats fed 15,000 mg alpha-tocopherol acetate/kg diet. Hepatic PGF2 alpha status was correlated inversely but weakly with dietary alpha-tocopherol (r = -0.24, p less than 0.05). Hepatic PGF2 alpha status was not correlated with hepatic or plasma alpha-tocopherol status. This finding suggests either that there is a small depletion-resistant subcellular alpha-tocopherol pool which regulates PGF2 alpha production or that alpha-tocopherol alters PGF2 alpha production in vivo by an indirect mechanism.

  13. Comparison of prostaglandin F2alpha, bimatoprost (prostamide), and butaprost (EP2 agonist) on Cyr61 and connective tissue growth factor gene expression.

    PubMed

    Liang, Yanbin; Li, Chen; Guzman, Victor M; Evinger, Albert J; Protzman, Charles E; Krauss, Achim H-P; Woodward, David F

    2003-07-18

    Connective tissue growth factor (CTGF) and Cyr61 (cysteine-rich angiogenic protein 61) are members of the CCN gene family that encode multifunctional, extracellular matrix-associated signaling proteins. Because the mechanism of action of certain anti-glaucoma drugs involves extracellular matrix remodeling of ocular ciliary muscle, with a resultant increase in drainage of aqueous humor from the eye, we compared the effects of three pharmacologically distinct ocular hypotensive agents on Cyr61 and CTGF gene expression. Thus, prostaglandin F2alpha (PGF2alpha) (FP receptor agonist), Butaprost (EP2 receptor agonist), and Bimatoprost (a prostamide) were compared. Using Affymetrix gene chip technology, we first identified that PGF2alpha dramatically up-regulated Cyr61 and CTGF mRNA expression in HEK 293/EBNA cells (hFP-HEK 293/EBNA). Northern blot further confirmed the Cyr61 and CTGF up-regulation is in a dose- and time-dependent manner. PGF2alpha-induced up-regulation of Cyr61 appeared to exclusively involve the Rho pathway, and up-regulation of CTGF was via multiple intracellular pathways. Because prostamide receptors are, to date, defined only at the pharmacological level, Bimatoprost effects on Cyr61 and CTGF were studied in the isolated feline iris sphincter preparation, a tissue highly responsive to prostamides. Both PGF2alpha and Bimatoprost up-regulated Cyr61 mRNA expression in the cat iris tissue. Only PGF2alpha up-regulated CTGF mRNA expression in the cat iris. Therefore, PGF2alpha and Bimatoprost appear to interact with different receptors populations in the cat iris, according to their markedly different effects on CTGF. Activation of prostaglandin EP2 receptors (Gs-coupled) also up-regulated Cyr61 but not CTGF mRNA expression in the isolated cat iris. Similar data were observed in human primary ciliary smooth muscle cells. Thus, despite quite different signal transduction pathways, FP receptor stimulation up-regulates CTGF and Cyr61. The prostamide analog

  14. The effects of prostaglandin F2alpha treatment on peripheral-type benzodiazepine receptors in the ovary and uterus during pseudopregnancy of rats.

    PubMed

    Bar-Ami, Shalom; Bendel, Nachum; Leschiner, Svetlana; Levin, Evgeny; Veenman, Leo; Gavish, Moshe

    2006-02-14

    A previous study by us indicated that peripheral-type benzodiazepine receptor (PBR) density may be increased in the ovaries and uterus of pregnant rats (Weizman R, Dagan E, Snyder SH, Gavish M. Impact of pregnancy and lactation on GABAA receptor and central-type and peripheral-type benzodiazepine receptors. Brain Res 1997;752:7-14). In the present study, the effects of prostaglandin F2alpha (PGF2alpha) on PBR density in the ovary and uterus of pseudopregnant rats were assayed. Pseudopregnancy was induced on day 29 post-partum (PP) by s.c. injection of 50IU pregnant mare serum gonadotropin (PMSG) and 3 days later by s.c. injection of 20IU human chorionic gonadotropin (hCG). PBR ligand binding density was assayed with the specific PBR ligand [3H]PK 11195. A two-fold increase in ovarian PBR density was observed 2 days after hCG administration compared with vehicle control rats and this effect was maintained for 3 weeks. In the uterus, a three-fold increase in PBR density was observed and this increase was maintained for 1 week after hCG administration. Pseudopregnancy did not appear to affect renal PBR density or affinity. Treatment with PGF2alpha, which causes luteolysis, resulted in an approximately 50% reduction of PBR density in the ovaries of pseudopregnant rats at day 53 PP compared to pseudopregnant control rats. Treatment with indomethacin, which prevents the formation of PGF2alpha, caused the PBR density in the uterus of pseudopregnant rats at day 53 PP to be twice as high as in pseudopregnant control rats. All the above treatments did not affect the affinity of [3H]PK 11195 to ovarian and uterine PBR. These data suggest that PBR density in corpora lutea and uterus during pseudopregnancy is regulated by PGF2alpha.

  15. [The influence of intravenous laser therapy on prostaglandin E2 and F2-alpha dynamics and the state of microcirculation in the patients presenting with gastroesophageal reflux disease].

    PubMed

    Burduli, N M; Tadtaeva, D Ia

    2012-01-01

    The objective of the present work was to study the influence of low-frequency laser radiation on the levels of prostaglandins E2 and F2-alpha and characteristics of microcirculation in the patients suffering from gastroesophageal reflux disease (GERD). A total of 112 patients at the age from 19 to 79 years presenting with GERD were examined. 78 of them were given the complete 10-day course of intravenous laser therapy based on a Matriks-VLOK ("Matriks", Russia) therapeutic laser set emitting in the continuous mode at a wavelength of 0.405 mcm with the radiation power 1-11.5 mW at the output of the main lightguide. The characteristics of interest were determined before and after the treatment. It was shown that laser irradiation resulted in the elevation of pro-inflammatory prostaglandin levels and the improvement of parameters of microcirculation. PMID:23373291

  16. In vivo induction of neutrophilia, lymphopenia, and diminution of neutrophil adhesion by stable analogs of prostaglandins E1, E2, and F2 alpha.

    PubMed Central

    Ulich, T. R.; Dakay, E. B.; Williams, J. H.; Ni, R. X.

    1986-01-01

    Stable analogs of prostaglandins E1, E2, and F2 alpha (M-PGE1, DM-PGE2, and M-PGF2 alpha) were found to induce marked changes in circulating white blood cell subsets in Brown-Norway rats after subcutaneous injection. Dose-response studies demonstrated that 1000 micrograms/kg of each prostaglandin induced a maximum neutrophilia in the range of 40-70% of the total white blood cell count (normal, 5-20%) and that as little as 5 micrograms/kg of M-PGE1 induced a significant neutrophilia (P less than 0.05). Kinetic studies demonstrated that the maximum neutrophilia occurred 4-6 hours after injection of each prostaglandin and was not accompanied by the release of morphologically immature neutrophil forms from the bone marrow. Splenectomy slightly diminished the average neutrophilia at 2 hours but not at 4-6 hours after injection, which suggests that release of neutrophils from the spleen partially contributed to the early neutrophilia. Adherence experiments employing whole heparinized blood from rats given prostaglandins 6 hours prior to sacrifice demonstrated that neutrophils exposed to prostaglandins in vivo have diminished adherence to nylon wool columns, which suggests that diminished adherence of the marginated neutrophil pool may contribute to the neutrophilia. The prostaglandin-induced neutrophilia was accompanied not by a significant change in total numbers of circulating white blood cells, but, rather, by a significant decrease in circulating mononuclear white blood cells, including T-helper, T-suppressor, and B cells. The combination of neutrophilia with lymphopenia has classically been attributed to the release of adrenal hormones and suggests 1) that prostaglandins may directly or indirectly cause the release of adrenal hormones, or 2) that adrenal hormones may mediate their effects on circulating white blood cell subsets via prostaglandins, or 3) that prostaglandins activate intracellular messenger systems that are also activated by adrenal hormones. PMID

  17. [Effect of prostaglandins F2 and F2 alpha on the pentosephosate pathway in human blood platelets].

    PubMed

    Makarov, S A; Kudriavtseva, G V; Kolotilova, A I

    1983-01-01

    Rates of glucose-6-phosphate oxidation and formation of sedoheptulose-7-phosphate were increased after 10 min preincubation of human blood platelets with prostaglandins F2 and F2a. When the preincubation was prolonged up to 60 min, the prostaglandins activating effect was manifested only as an increase in sedoheptulose-7-phosphate content. Preincubation of thrombocytes with dibutyryl-cAMP led to an increase in the rate of ribose-5-phosphate consumption as well as of sedoheptulose-7-phosphate formation. Chlorpromazine hydrochloride decreased the rates of glucose-6-phosphate and 6-phosphogluconate oxidation in extracts of human thrombocytes and inhibited the activating effect of prostaglandins on sedoheptulose-7-phosphate formation.

  18. Profiling of Luteal Transcriptome during Prostaglandin F2-Alpha Treatment in Buffalo Cows: Analysis of Signaling Pathways Associated with Luteolysis

    PubMed Central

    Suganthi, Hepziba; Rudraiah, Medhamurthy

    2014-01-01

    In several species including the buffalo cow, prostaglandin (PG) F2α is the key molecule responsible for regression of corpus luteum (CL). Experiments were carried out to characterize gene expression changes in the CL tissue at various time points after administration of luteolytic dose of PGF2α in buffalo cows. Circulating progesterone levels decreased within 1 h of PGF2α treatment and evidence of apoptosis was demonstrable at 18 h post treatment. Microarray analysis indicated expression changes in several of immediate early genes and transcription factors within 3 h of treatment. Also, changes in expression of genes associated with cell to cell signaling, cytokine signaling, steroidogenesis, PG synthesis and apoptosis were observed. Analysis of various components of LH/CGR signaling in CL tissues indicated decreased LH/CGR protein expression, pCREB levels and PKA activity post PGF2α treatment. The novel finding of this study is the down regulation of CYP19A1 gene expression accompanied by decrease in expression of E2 receptors and circulating and intra luteal E2 post PGF2α treatment. Mining of microarray data revealed several differentially expressed E2 responsive genes. Since CYP19A1 gene expression is low in the bovine CL, mining of microarray data of PGF2α-treated macaques, the species with high luteal CYP19A1 expression, showed good correlation between differentially expressed E2 responsive genes between both the species. Taken together, the results of this study suggest that PGF2α interferes with luteotrophic signaling, impairs intra-luteal E2 levels and regulates various signaling pathways before the effects on structural luteolysis are manifest. PMID:25102061

  19. [The level of 8-iso-prostaglandin F2 alpha, 4-hydroxynonenal and malondialdehyde in alcohol dependent men during combined therapy].

    PubMed

    Kopczyńska, Ewa; Lampka, Magdalena; Torliński, Lech; Ziółkowski, Marcin

    2002-01-01

    The aim of the study was the estimation of intensity of lipid peroxidation in alcohol dependent male patients after three months of therapy with naltrexone or tianeptine and the next three months follow-up. 61 males with clinical diagnosis of alcohol dependence (ICD-10) have been examined. The investigated parameters have been determined in blood serum, the 8-iso-prostaglandin F2 alpha by means of immunoenzymatic assay (ELISA) and malondialdehyde with 4-hydroxynonenal by means of colorimetric method. In alcohol dependent men before pharmacotherapy the mean concentration of 8-iso-PGF2 alpha and [MDA + 4-HNE] was higher than the reference interval. Both, after three months of applied drugs and the next three months follow-up, the concentration of studied parameters decreased considerably. The above results show intensification of lipid peroxidation in alcohol abusers and advantageous influence of abstinence from alcohol and treatment of naltrexone or tianeptine on free-radical changes of lipids as well.

  20. Mechanisms of reduced luteal sensitivity to prostaglandin F2alpha during maternal recognition of pregnancy in ewes.

    PubMed

    Costine, Beth A; Inskeep, E Keith; Blemings, Kenneth P; Flores, Jorge A; Wilson, Matthew E

    2007-02-01

    During maternal recognition of pregnancy, the conceptus stimulates endometrial secretion of PGF2alpha and PGE2. However, PGF2alpha is less effective in causing luteal regression in pregnant than in non-pregnant ewes. Experiments were conducted to elucidate mechanisms for reduced luteal sensitivity to PGF2alpha during maternal recognition of pregnancy. Corpora lutea (CL) were collected from pregnant and non-pregnant ewes 0, 4, or 12h following treatment with PGF2alpha on day 12 after estrus. Luteal PTGHS2 mRNA did not differ due to PGF2alpha or pregnancy status. Luteal PTGES mRNA was reduced in both pregnant and non-pregnant ewes after PGF2alpha treatment; while, luteal PTGFS mRNA was reduced 4h after PGF2alpha in pregnant, but not non-pregnant ewes. The result was a greater ratio of PTGES to PTGFS mRNA in pregnant ewes. Luteal mRNA for HPGD did not differ between pregnant and non-pregnant ewes on day 12. Luteal END1 mRNA was reduced in pregnant as compared to non-pregnant ewes prior to PGF2alpha challenge. Luteal END1 mRNA was increased after PGF2alpha in pregnant and non-pregnant ewes; however, ECE1 mRNA was reduced 4h after PGF2alpha in pregnant, but not non-pregnant ewes. The in vitro conversion of PGF2alpha to PGFM was greater in CL of pregnant than non-pregnant ewes at day 14. Luteal conversion of PGF2alpha to PGFM appears to be regulated post-transcriptionally. During maternal recognition of pregnancy, mechanisms of reduced luteal sensitivity to PGF2alpha may include a shift in prostaglandin production to the luteotropin PGE2, a reduction of ECE1 mRNA, and increased catabolism of PGF2alpha. PMID:16524686

  1. Effect of prostaglandin F2 alpha on free radical generation, glutathione content and microsomal oxidase activities in rat liver microsomes induced either by ethanol or acetone.

    PubMed

    Sadovnichy, V; Müller, D; Buko, V

    1997-01-01

    We studied the effect of prostaglandin F2 alpha on parameters related to microsomal metabolism (free radical production and lipid peroxidation, glutathione content and activity of microsomal oxidases) after an induction by ethanol or acetone combined with starvation. Long-term ethanol administration led to a significant increase in lipid peroxide formation and NADPH-dependent chemiluminescence amplified by luminol and lucigenin. At the same time hydrogen peroxide production and NADPH-stimulated lipid peroxidation were enhanced although the effect did not reach the level of statistical significance. The concentration of reduced glutathione (GSH) in the liver was decreased 2-fold, whereas oxidized glutathione (GSSG) content remained unaltered. Ethanol intoxication resulted in an increase in 7-ethoxycoumarin-O-deethylase (ECOD), 7-benzyloxycoumarin-O-deethylase (BCOD) and 7-ethoxy-resorufin-O-deethylase (EROD) activities, whereas 7-pentoxyresorufin-O-deethylase (PROD) and ethylmorphin-N-demethylase (EMND) activities were unaltered. The combination of acetone treatment with starvation resulted in a significant increase in lipid and hydrogen peroxide formation, NADPH-dependent lipid peroxidation and chemiluminescence. GSH and GSSG concentration in the liver dramatically decreased 5- and 3-fold, respectively. The acetone treatment led to significant increase in EROD, ECOD, BCOD, PROD and EMND activities. The treatment of ethanol-intoxicated rats with prostaglandin F2 alpha (PGF2 alpha) exerted more pronounced prooxidant effect on liver than action of alcohol itself. At the same time, PGF2 alpha improved most of parameters changed by acetone treatment combined with starvation, decreasing lipid peroxide and radical formation and enhancing GSH and GSSG contents.

  2. Triphasic effect of prostaglandins E1, E2 and F2alpha on the fluid transport of isolated gall-bladder of guinea-pigs.

    PubMed

    Heintze, K; Leinesser, W; Petersen, K U; Heidenreich, O

    1975-02-01

    Prostaglandins (PGs) F2alpha, E1 and E2 exerted a triphasic influence on the fluid transport of isolated guinea-pig gall-bladders, when applied to the serosal side. PGE1 and PGE2 produced these effects in lower concentrations than F2alpha. Directly after PG addition to the serosal side a short stimulation of fluid transport to between 200 and 400% was observed. The stimulatory effect of PGs was most distinct in gall-bladders from female guinea-pigs, less pronounced in male and nearly absent in pregnant animals. Since PGs increased intraluminal hydrostatic pressure in gall-bladders by contraction of the smooth muscle, experiments were performed in which hydrostatic pressure was increased by different procedures. These included the addition of imidazole (10- minus 2 M), raising of K+ in the bathing solution and an increase in intraluminal pressure by addition of Ringer's solution into the lumen. All three procedures stimulated fluid reabsorption temporarily in the same way as PGs, hence increase of intraluminal pressure is thought to be the reason for the observed temporary stimulation of fluid transport. Direct evidence for this thesis was obtained when the gall-bladder was mounted as a flat sheet over a chamber; in this preparation no stimulation of fluid transport was obtained. The second phase of the PG influence was characterized by a concentration-related inhibition of fluid reabsorption followed by a significant but small reverse of fluid transport (secretion of fluid). When PGs were applied to the mucosal side, only an inhibition of fluid transport was observed, which was much weaker compared to the addition to the serosal side.

  3. Mechanical stimulation of skeletal muscle increases prostaglandin F2(alpha) synthesis and cyclooxygenase activity by a pertussis toxin sensitive mechanism

    NASA Technical Reports Server (NTRS)

    Vandenburgh, Herman H.; Shansky, Janet; Solerssi, Rosa; Chromiak, Joseph

    1992-01-01

    Repetitive mechanical stimulation of differentiated skeletal muscle in tissue culture increases the production of prostaglandin F(sub 2(alpha)), an anabolic stimulator of myofiber growth. Within 4 h of initiating mechanical activity, the activity of cyclooxygenase, a regulatory enzyme in prostaglandin synthesis, was increased 82% (P is less than .005), and this increase was maintained for at least 24 h. Kinetic analysis of the stretch-activated cyclooxygenase indicated a two to three-fold decrease in the enzyme's K(sub m) with no change in V(sub max). The stretch-induced increase in enzymatic activity was not inhibited by cycloheximide, was independent of cellular electrical activity (tetrodotoxin-insensitive), but was prevented by the G protein inhibitor pertussis toxin. Pertussis toxin also inhibited the stretch-induced increases in PGF(sub 2(alpha)) production, and cell growth. It is concluded that stretch of skeletal muscle increases the synthesis of the anabolic modulator PGF(sub 2(alpha)) by a G protein-dependent process which involves activation of cyclooxygenase by a posttranslational mechanism.

  4. Plasma luteinizing hormone and progesterone concentrations in goats with estrous cycles of normal or short duration after prostaglandin F2 alpha administration during diestrus or pregnancy.

    PubMed

    Bretzlaff, K N; Weston, P G; Hixon, J E; Ott, R S

    1988-06-01

    Plasma luteinizing hormone (LH) and progesterone concentrations were compared in does experiencing short-duration estrous cycles and in does with estrous cycles of normal duration. The short-duration estrous cycles were observed immediately after induction of abortion in pregnant does by use of prostaglandin (PG) F2 alpha. Intramuscular administration of 5 mg of PGF2 alpha was accomplished in 8 does that were 52 to 63 days into gestation and in 9 cycling does at 7 to 10 days after estrus. In both groups, the mean plasma concentration of progesterone decreased from a luteal phase concentration immediately before to less than 1 ng/ml by 24 hours after PGF2 alpha administration. Of the 8 does that aborted, 6 experienced short-duration estrous cycles, and 4 of these 6 had an LH surge during the time of blood sample collection. The mean time from PGF2 alpha administration to the LH surge was significantly (P less than 0.05) longer in does with short-duration estrous cycles (71 hours) than that in does with estrous cycles of normal duration (58 hours). The mean area under the LH concentration curve was significantly (P less than 0.005) less for does with short-duration estrous cycles. Short-duration estrous cycles were associated with delayed preovulatory LH surges of reduced magnitude. PMID:3165252

  5. Effect of prostaglandin F(2alpha)- thamsalt and Estrumate (ICI 80996) on plasma progesterone levels in Indian water buffaloes (Bubalus bubalis ).

    PubMed

    Bachlsus, N K; Arora, R C; Prasad, A; Panday, R S

    1980-04-01

    Thirty six buffalo showing normal reproductive cyclas were given a single intramuscular injection of prostaglandin F(2alpha)- thamsalt (PGF(2alpha)) and Estrumate on day 9 or 15 of the estrous cycle in order to induce estrus. In PGF(2alpha) treated animals, plasma progesterone dropped from 2.99+/-0.29 to 0.10 +/- 0.02 ng/ml and from 5.53 +/- 0.53 to 0.09 +/- 0.03 ng/ml (mean +/- SEM) within 72 hours of treatment, on day 9 and 15, respectively. Similarly, the treatment with Estrumate on day 9 or 15 of the cycle reduced the level of proges--terone from 3.02 +/- 0.03 to 0.14 +/- 0.03 ng/ml and from 4.26 +/- 0.47 to 0.21 +/- 0.03 ng/ml, respectively, 72 hours aPter each treatment. It was inferred that both drugs induce estrus in buffalo without any observed residual effect.

  6. Ozone-induced increases in substance P and 8-epi-prostaglandin F2 alpha in the airways of human subjects

    SciTech Connect

    Hazbun, M.E.; Hamilton, R.; Holian, A.; Eschenbacher, W.L. )

    1993-11-01

    We are interested in the mechanisms of ozone-induced lung effects after short-term exposure and the relationship with subsequent pulmonary inflammation and disease. Our hypothesis is that ozone, as a powerful oxidant, will diminish the activity of neutral endopeptidase (NEP) in the airways of humans with resulting increased concentrations of neuropeptides such as substance P (SP). We have exposed seven (two women, five men) healthy, nonsmoking individuals (22 to 30 yr of age) to filtered air and ozone (0.25 ppm) for 1 h in an environmental chamber during heavy exercise. Bronchoscopy with airway lavage (AL) and bronchoalveolar lavage (BAL) was performed immediately after ozone exposure. The lavage samples were analyzed by enzyme immunoassay for SP and 8-epi-prostaglandin F2 alpha (8-epi-PGF2 alpha) (a marker for oxidative free radical reaction) and by radioimmunoassay for complement fragments. FEV1 had declined 12.4 +/- 1.9% (mean +/- SEM) as a result of ozone exposure. The AL concentration for SP and 8-epi-PGF2 alpha and BAL concentration of C3a after ozone exposure were significantly higher than after the filtered air exposure (P < 0.05). There was a significant correlation between SP and 8-epi-PGF2 alpha concentrations in the AL fluid (r2 = 0.89 and P < 0.05). There were no changes in C5a in either compartment or any of the mediators in the plasma samples. These results extend previous results from animal studies suggesting that ozone's mechanism of action is through an oxidative reaction resulting in a decreased activity of NEP in the airways with a subsequent increase in the concentration and activity of SP.

  7. Decreased Cholesterol Uptake and Increased Liver X Receptor-Mediated Cholesterol Efflux Pathways During Prostaglandin F2 Alpha-Induced and Spontaneous Luteolysis in Sheep1

    PubMed Central

    Seto, Nickie L.; Bogan, Randy L.

    2015-01-01

    In nonprimate species, it has been well established that prostaglandin F2 alpha (PGF2alpha) initiates luteolysis. Changes in intracellular cholesterol concentrations caused by modulation of cholesterol uptake and efflux may mediate PGF2alpha-induced luteolysis. These changes in cholesterol efflux and uptake are controlled, in part, by the liver x receptors (LXR) alpha (NR1H3) and beta (NR1H2), nuclear receptors that increase expression of genes necessary for cholesterol efflux or limiting cholesterol uptake. Therefore, we hypothesized that PGF2alpha reduces expression of cholesterol uptake and increases expression of cholesterol efflux genes, mediated in part by enhanced LXR activity. To test this hypothesis, an induced luteolysis model was used whereby ewes were treated during their midluteal phase with saline or PGF2alpha and corpora lutea (CL) collected 12, 24, or 48 h later for determination of mRNA and protein concentrations by quantitative real-time PCR and Western blot analysis, respectively. As a complementary approach, CL undergoing spontaneous luteolysis were compared to midluteal phase CL. The lipoprotein receptors responsible for cholesterol uptake were significantly decreased in both luteolysis models. Expression of the LXR target gene ATP binding cassette subfamily A1 (ABCA1), an important mediator of cholesterol efflux, was significantly increased in both experimental models. Chromatin immunoprecipitation confirmed that PGF2alpha treatment resulted in enhanced NR1H3 and NR1H2 binding to the ABCA1 promoter. Qualitative changes in lipid droplet distribution were also observed following PGF2alpha treatment. These data support the hypothesis that reduced cholesterol uptake and increased efflux mediate luteolysis in sheep, which is partially controlled by PGF2alpha stimulation of LXR activity. PMID:25882703

  8. Apoptosis during spontaneous and prostaglandin F(2alpha)-induced luteal regression in the buffalo cow (Bubalus bubalis): involvement of mitogen-activated protein kinases.

    PubMed

    Yadav, Vijay K; Sudhagar, Ranga R; Medhamurthy, R

    2002-09-01

    The present study was conducted to evaluate whether the corpus luteum (CL) of the water buffalo (Bubalus bubalis) cow undergoes luteal regression by the process of apoptosis and to examine the involvement of mitogen-activated protein (MAP) kinases during prostaglandin (PG) F(2alpha)-induced luteolysis. Sections of CL from late in the estrous cycle, i.e., during spontaneous luteolysis, stained for 4',6'-diamidino-2-phenylindole revealed increased numbers of condensed nuclei, indicating cell death by apoptosis, which was confirmed further by the occurrence of pronounced oligonucleosome formation. For morphological and biochemical characterization during PGF(2alpha)-induced apoptosis, CL were collected at 0, 4, 12, and 18 h after injection of 750 micro g of Tiaprost, a synthetic analogue of PGF(2alpha), to midestrous buffalo cows. Serum progesterone concentrations fell within 4 h and decreased (P < 0.05) maximally by 18 h. Concomitant decreases (P < 0.05) in the levels of steroidogenic acute regulatory mRNA and protein were observed in CL during 12-18 h, with the more profound effect on mRNA levels. Quantitative analysis of the genomic DNA showed a >5-fold increase (P < 0.05) in the low molecular weight DNA fragments by 18 h postinjection. Immunoblot analysis of CL tissue lysates showed increased (P < 0.05) levels of phospho-Jun N-terminal kinase (JNK) 1 (4- to 14-fold during 4-18 h) and phospho-p38 (2- to 4-fold at 18 h). Immunohistochemical evaluation of CL sections revealed an increased nuclear localization of phospho-JNK after treatment. These findings demonstrate that the CL of the buffalo cow undergoes cell death by the process of apoptosis both during spontaneous and PGF(2alpha)-induced luteolysis and that MAP kinases are involved during PGF(2alpha)-mediated apoptosis in the CL.

  9. Effects of a single administration of prostaglandin F2alpha, or a combination of prostaglandin F2alpha and prostaglandin E2, or placebo on fertility variables in dairy cows 3–5 weeks post partum, a randomized, double-blind clinical trial

    PubMed Central

    Hirsbrunner, Gaby; Burkhardt, Heinz W; Steiner, Adrian

    2006-01-01

    Background Delayed uterine involution has negative effects on the fertility of cows; use of prostaglandin F2alpha alone as a single treatment has not been shown to consistently improve fertility. Combined administration of PGF2alpha and PGE2 increased uterine pressure in healthy cows. We hypothesized, that the combination of both prostaglandins would accelerate uterine involution and have, therefore, a positive effect on fertility variables. In commercial dairy farming, the benefit of a single post partum combined prostaglandin treatment should be demonstrated. Methods 383 cows from commercial dairy farms were included in this study. Uterine size and secretion were evaluated at treatment 21–35 days post partum and 14 days later. Cows were randomly allocated to one of three treatment groups: PGF2alpha and PGE2, PGF2alpha or placebo. For every animal participating in the study, the following reproduction variables were recorded: Interval from calving to first insemination, days open, number of artificial inseminations (AI) to conception; subsequent treatment of uterus, subsequent treatment of ovaries. Plasma progesterone level at time of treatment was used as a covariable. For continuous measurements, analysis of variance was performed. Fisher's exact test for categorical non-ordered data and exact Kruskal-Wallis test for ordered data were used; pairwise group comparisons with Bonferroni adjustment of significance level were performed. Results There was no significant difference among treatment groups in uterine size. Furthermore, there was no significant difference among treatments concerning days open, number of AI, and subsequent treatment of uterus and ovaries. Days from calving to first insemination tended to be shorter for cows with low progesterone level given PGF2alpha and PGE2 in combination than for the placebo-group (P = 0.024). Conclusion The results of this study indicate that the administration of PGF2alpha or a combination of PGF2alpha and PGE2 21 to

  10. Prostaglandin F2 alpha-induced calcium transient in ovine large luteal cells: II. Modulation of the transient and resting cytosolic free calcium alters progesterone secretion.

    PubMed

    Wegner, J A; Martinez-Zaguilan, R; Gillies, R J; Hoyer, P B

    1991-02-01

    A previous study demonstrated that prostaglandin F2 alpha (PGF2 alpha) stimulates a transient increase in cytosolic free Ca2+ levels [( Ca2+]i) in ovine large luteal cells. In the present study, the magnitude of the PGF2 alpha (0.5 microM)-induced calcium transient in Hanks' medium (87 +/- 2 nM increase above resting levels) was reduced (P less than 0.05) but not completely eliminated in fura-2 loaded large luteal cells incubated in Ca2(+)-free or phosphate- and carbonate-free medium (10 +/- 1 nM, 32 +/- 6 nM, above resting levels; respectively). Preincubation for 2 min with 1 mM LaCl3 (calcium antagonist) eliminated the PGF2 alpha-induced calcium transient. The inhibitory effect of PGF2 alpha on secretion of progesterone was reduced in Ca2(+)-free medium or medium plus LaCl3. Resting [Ca2+]i levels and basal secretion of progesterone were both reduced (P less than 0.05) in large cells incubated in Ca2(+)-free medium (27 +/- 4 nM; 70 +/- 6% control, respectively) or with 5 microM 5,5'-dimethyl bis-(O-aminophenoxy)ethane-N,N,N'N'-tetraacetic acid (40 +/- 2 nM; 49 +/- 1% control; respectively). In addition, secretion of progesterone was inhibited (P less than 0.05) by conditions that increased (P less than 0.05) [Ca2+]i; that is LaCl3 ([Ca2+]i, 120 +/- 17 nM; progesterone, 82 +/- 8% control) and PGF2 alpha ([Ca2+]i, 102 +/- 10 nM; progesterone, 82 +/- 3% control). In small luteal cells, resting [Ca2+]i levels and secretion of progesterone were reduced by incubation in Ca2(+)-free Hanks ([Ca2+]i, 28 +/- 2 nM; progesterone, 71 +/- 6% control), however, neither LaCl3 nor PGF2 alpha increased [Ca2+]i levels or inhibited secretion of progesterone. The findings presented here provide evidence that extracellular as well as intracellular calcium contribute to the PGF2 alpha-induced [Ca2+]i transient in large cells. Furthermore, whereas an adequate level of [Ca2+]i is required to support progesterone production in both small and large cells, optimal progesterone production in

  11. Synchronization of estrus and artificial insemination in replacement beef heifers using gonadotropin-releasing hormone, prostaglandin F2alpha, and progesterone.

    PubMed

    Lamb, G C; Larson, J E; Geary, T W; Stevenson, J S; Johnson, S K; Day, M L; Ansotegui, R P; Kesler, D J; DeJarnette, J M; Landblom, D G

    2006-11-01

    We evaluated whether a fixed-time AI (TAI) protocol could yield pregnancy rates similar to a protocol requiring detection of estrus, or detection of estrus and AI plus a clean-up TAI for heifers not detected in estrus, and whether adding an injection of GnRH at controlled internal drug release (CIDR) insertion would enhance fertility in CIDR-based protocols. Estrus in 2,075 replacement beef heifers at 12 locations was synchronized, and AI was preceded by 1 of 4 treatments arranged as a 2 x 2 factorial design: 1) Estrus detection + TAI (ETAI) (n = 516): CIDR for 7 d plus 25 mg of prostaglandin F2alpha (PG) at CIDR insert removal, followed by detection of estrus for 72 h and AI for 84 h after PG (heifers not detected in estrus by 84 h received 100 microg of GnRH and TAI); 2) G+ETAI (n = 503): ETAI plus 100 microg GnRH at CIDR insertion; 3) Fixed-time AI (FTAI) (n = 525): CIDR for 7 d plus 25 mg of PG at CIDR removal, followed in 60 h by a second injection of GnRH and TAI; 4) G+FTAI (n = 531): FTAI plus 100 microg of GnRH at CIDR insertion. Blood samples were collected (d -17 and -7, relative to PG) to determine ovarian status. For heifers in ETAI and G+ETAI treatments, a minimum of twice daily observations for estrus began on d 0 and continued for at least 72 h. Inseminations were performed according to the a.m.-p.m. rule. Pregnancy was diagnosed by transrectal ultrasonography. The percentage of heifers exhibiting ovarian cyclic activity at the initiation of treatments was 89%. Pregnancy rates among locations across treatments ranged from 38 to 74%. Pregnancy rates were 54.7, 57.5, 49.3, and 53.1% for ETAI, G+ETAI, FTAI, and G+FTAI treatments, respectively. Although pregnancy rates were similar among treatments, a tendency (P = 0.065) occurred for pregnancy rates in the G+ETAI treatment to be greater than in the FTAI treatment. We concluded that the G+FTAI protocol yielded pregnancy rates similar to protocols that combine estrus detection and TAI. Further, the G

  12. Effect of Decreasing Intraluteal Progesterone on Sensitivity of the Early Porcine Corpus Luteum to the Luteolytic Actions of Prostaglandin F2alpha1

    PubMed Central

    Diaz, Francisco J.; Luo, Wenxiang; Wiltbank, Milo C.

    2010-01-01

    Prostaglandin F2alpha (PGF) causes luteolysis of the pig corpus luteum (CL) only after Day 12 of the estrous cycle. Recent evidence indicates that progesterone (P4) may protect the CL from cell death. The present study tested the hypothesis that acute inhibition of P4 by treatment with epostane (EPO; 3betaHSD inhibitor) in CL lacking luteolytic capacity (Day 9 CL) will allow PGF to induce responses associated with luteolysis. Multiple PGF-induced responses were evaluated, including genes involved in production of PGF and estradiol-17beta, apoptosis (caspase 3), and transcription (FOSB). These responses are associated with PGF-induced luteolysis and do not normally occur in CL lacking luteolytic capacity. Animals on Day 7 after estrus were divided into four groups: 1) control (C), 2) PGF, 3) EPO, and 4) PGF plus EPO (PGF+EPO). Treatment with EPO (10 mg/kg) or vehicle was given every 12 h for 36 h. Treatment with PGF (25 mg) or vehicle was given at 38 h, and CL were collected from all animals at 48 h. Some CL from each animal were frozen in liquid nitrogen for mRNA and protein analysis. Remaining CL were incubated in media for 2 h for determination of P4 and PGF production. EPO dramatically decreased production of P4 by luteal tissue (ng/mg tissue) by 90% and 95% in EPO and PGF+EPO groups, respectively, compared to C (P < 0.01). Low production of PGF by luteal tissue was found in C, PGF, and EPO groups; however, treatment with PGF+EPO dramatically increased (782%) luteal PGF production. Similar to intraluteal PGF production, increased mRNA for cyclooxygenase 2 (PTGS2) and phospholipase A2 (group IB; PLA2G1B) was found in the PGF+EPO, but not in the EPO or PGF, group. Aromatase (CYP19A1) mRNA was not induced by PGF or EPO; however, PGF+EPO caused a more than 40-fold increase in CYP19A1 mRNA (P < 0.01). CASP3 mRNA was increased (P < 0.01) by EPO (3.4-fold) and by PGF (2.7-fold) but was most dramatically increased by PGF+EPO (5.3-fold), whereas caspase activity was only

  13. Cloning of a buffalo (Bubalus bubalis) prostaglandin F(2alpha) receptor: changes in its expression and concentration in the buffalo cow corpus luteum.

    PubMed

    Verma-Kumar, Shalu; Srinivas, S V; Muraly, P; Yadav, Vijay K; Medhamurthy, R

    2004-06-01

    Acting primarily through its specific G protein-coupled receptor termed FPr, prostaglandin (PG) F(2alpha) induces regression of the corpus luteum (CL) at the end of a non-fertile oestrous cycle. This study was aimed at cloning a full-length cDNA for FPr and determining its expression and protein concentrations during different stages of CL development in the water buffalo. Serum progesterone and StAR expression were determined to establish temporal relationships between indices of steroidogenesis and changes in FPr expression at different stages of CL development. In contrast to the dairy cow, the stage IV CL (day 20 of the oestrous cycle) did not appear to be functionally regressed in the buffalo. Molecular cloning of a cDNA encoding the buffalo FPr yielded a full length 2193 bp FPr cDNA containing a single open reading frame encoding a 362 amino acid protein with seven putative membrane-spanning domains. The deduced buffalo FPr amino acid sequence possesses a high degree of identity with the other mammalian homologues. Steady state concentration of buffalo FPr transcript increased (P > 0.05) from stage I to stage II/III, and declined at 18 h post PGF(2alpha) injection. The FPr concentration expressed as fmol/microg of plasma membrane protein showed an increase (P > 0.05) from stage I (1.98 +/- 0.10), through stage II/III (2.42 +/- 0.48) to stage IV (2.77 +/- 0.18). High affinity FPr was observed in stage I (K(d) 4.86 nmol) and stage II/III (K(d) 6.28 nmol) while low affinity FPr (K(d) 19.44 nmol) was observed in stage IV. In conclusion, we have cloned a full length FPr cDNA from buffalo cow CL and observed that FPr mRNA expression, receptor number and affinity did not vary significantly (P > 0.05) within the luteal phase of the oestrous cycle.

  14. Evidence for human thromboxane receptor heterogeneity using a novel series of 9,11-cyclic carbonate derivatives of prostaglandin F2 alpha.

    PubMed Central

    Krauss, A. H.; Woodward, D. F.; Gibson, L. L.; Protzman, C. E.; Williams, L. S.; Burk, R. M.; Gac, T. S.; Roof, M. B.; Abbas, F.; Marshall, K.; Senior, J.

    1996-01-01

    1. The pharmacological activity of a novel series of 9,11-cyclic carbonate derivatives of prostaglandin F2 alpha (PGF2 alpha) was investigated in various isolated smooth muscle preparations possessing different prostanoid receptor subtypes as well as in human platelets. Since subdivision of thromboxane (TP-) receptors into vascular/smooth muscle and platelet subtypes is a controversial subject, our studies included a human smooth muscle preparation (myometrium) in addition to the widely used rat aorta and human platelets as TP-receptor preparations. 2. Two members of that series, AGN191976 and AGN192093 were found to be highly potent and selective thromboxane-mimetics. AGN191976 and AGN192093 contracted isolated tissues of the rat thoracic aorta with EC50 values of 0.32 +/- 0.08 and 1.30 +/- 0.53 nM, respectively. Both agonists were at least 10 times more potent than the benchmark TP-agonist, U-46619, in this preparation, whilst being at least 500 times less potent at other prostanoid receptors (DP, EP1, EP3, FP, IP) in vitro. 3. In human myometrial strips from pregnant and non-pregnant donors, both AGN191976 and AGN192093 were potent contractile agonists. The rank order of potency in myometrium of AGN191976 > AGN192093 > U-46619 correlated well with that in the rat aorta. In human platelet-rich plasma (PRP), however, AGN191976 had potent proaggregatory activity (EC50 = 16.3 +/- 1.4 nM), which is a TP-receptor-mediated event, whereas AGN192093 was a much weaker agonist (EC50 = 37.9 +/- 2.0 microM). AGN192093 did not behave as an antagonist in the platelets, since it did not antagonize platelet aggregation induced by ADP, arachidonic acid, U-46619 or AGN191976. In human washed platelets, the activity profile of AGN191976 (EC50 = 4.15 +/- 0.52 nM) and AGN192093 (no aggregation up to 10 microM) was similar to that obtained in PRP. 4. The involvement of TP-receptors was verified with the potent TP-antagonist, SQ29548. SQ29548 (0.1 microM in myometrium; 1 microM in

  15. Differential gene expression in the bovine corpus luteum during transition from early phase to midphase and its potential role in acquisition of luteolytic sensitivity to prostaglandin F2 alpha.

    PubMed

    Goravanahally, Madhusudan P; Salem, Mohamed; Yao, Jianbo; Inskeep, E Keith; Flores, Jorge A

    2009-05-01

    Prostaglandin F2 alpha (PGF(2alpha)) brings about regression of the bovine corpus luteum (CL). This luteolytic property of PGF(2alpha) is used in beef and dairy cattle to synchronize estrus. A limitation of this protocol is insensitivity of the early CL to luteolytic actions of PGF(2alpha). The mechanisms underlying this differential luteal sensitivity are poorly understood. The developing CL has a maximum number of PGF(2alpha) receptors; therefore, differences in signaling events may be responsible for luteal insensitivity. Hence, differential gene expression at two developmental stages of CL, Day 4 (D-4) and D-10 after estrus, might account for differences in signal transduction pathways associated with luteal sensitivity. This possibility was examined in these studies. Microarray analysis (n = 3 cows per stage) identified 167 genes that were differentially expressed (P < 0.05). These were categorized into genes involved in protein biosynthesis and modification (18.5%), transcription regulation and DNA biosynthesis (18.5%), miscellaneous (17.0%), cell signaling (12.0%), steroidogenesis and metabolism (10.2%), extracellular matrix and cytoskeletal proteins (9.5%), unknown functions (6.0%), protein degradation (5.3%), and antioxidant property (3.0%). Real-time PCR confirmed the differential expression of nine selected genes, including tyrosine 3-monooxygenase/tryptophan 5-monooxygense activation protein zeta polypeptide (YWHAZ) and regulator of G protein signaling 2 24-kDa (RGS2), observed in microarray. Furthermore, the in vivo effect of exogenous PGF(2alpha) (n = 3 cows per stage) on selected genes that were found to be differentially expressed during this developmental transition was examined. PGF(2alpha) increased the expression of a guanine nucleotide-binding protein (G protein) beta polypeptide 1 (GNB1) in D-4 CL and calcium/calmodulin-dependent kinase kinase 2 beta (CAMKK2) in D-10 CL. Therefore, GNB1, CAMKK2, YWHAZ, and RGS2 are candidate genes that may

  16. Maternal recognition of pregnancy in swine. II. Plasma concentrations of progesterone and 13,14-dihydro-15-keto-prostaglandin F2 alpha during the estrous cycle and during short and long pseudopregnancy in gilts.

    PubMed

    Pusateri, A E; Wilson, M E; Diekman, M A

    1996-09-01

    Two experiments were conducted to determine plasma progesterone (P4) and 13,14-dihydro-15-keto-prostaglandin F2 alpha (PGFM) concentrations in unmated gilts induced to have either short pseudopregnancy (SPP) or long pseudopregnancy (LPP). In experiment 1, estradiol-17 beta (E2) was injected on different combinations of days between Days 11 and 16 of the estrous cycle. For gilts induced to exhibit SPP, the interestrous interval averaged 27.0 +/- 0.4 days compared to the control interval of 20.0 +/- 0.4 days. In experiment 2, E2 injections were given on Days 12 and 13 or on Days 12 through 25. Interestrous intervals in SPP and nonpseudopregnant gilts were 25.6 +/- 0.2 and 19.9 +/- 0.6 days, respectively. Four of six gilts treated with E2 on Days 12-25 were induced to have LPP lasting more than 100 days. In both experiments, plasma P4 declined to baseline approximately 3 days before posttreatment estrus, regardless of type of pseudopregnancy induced. Plasma PGFM peaked 4-6 days before posttreatment estrus in gilts displaying each type of response. In gilts exhibiting LPP, plasma PGFM concentrations tended to increase steadily during pseudopregnancy. These data suggest that the mechanisms of luteolysis during the estrous cycle of unmated gilts and during estrogen-induced SPP and LPP may be similar. The present results suggest that luteal persistence during SPP and LPP may be due to delayed peak release of prostaglandin F2 alpha by the uterus.

  17. Prostaglandin E2 and F2 alpha inhibit growth of human gastric carcinoma cell line KATO III with simultaneous stimulation of cyclic AMP production.

    PubMed

    Nakamura, A; Chiba, T; Yamatani, T; Yamaguchi, A; Inui, T; Morishita, T; Kadowaki, S; Fujita, T

    1989-01-01

    The effects of prostaglandins (PGs) on the growth of human gastric carcinoma cell line KATO III were investigated. PGE2 as well as PGF2 alpha significantly and dose-dependently inhibited the growth of this gastric carcinoma cell line (PGE2 greater than PGF2 alpha). This inhibition of cell growth by the PGs was associated with the increase in cyclic AMP production (PGE2 greater than PGF2 alpha), whereas inositol-phospholipid turnover was not affected by either PGE2 or PGF2 alpha as assessed by the formation of 3H-inositol phosphates. Furthermore, the proliferation of these gastric carcinoma cells was also suppressed by the administration of forskolin as well as of dibutyryl cyclic AMP. These results suggest that PGE2 and PGF2 alpha inhibit the growth of cultured human gastric carcinoma cells KATO III via stimulation of cyclic AMP production. PMID:2536452

  18. Effects of exogenous estradiol-17 beta on luteinizing hormone, progesterone, and estradiol-17 beta concentrations before and after prostaglandin F2 alpha-induced termination of pregnancy and pseudopregnancy in gilts.

    PubMed

    Smith, C A; Almond, G W; Esbenshade, K L

    1992-02-01

    This study evaluated the influence of exogenous estradiol-17 beta (E2) administration on LH concentrations and the number of animals returning to estrus after the termination of pregnancy or pseudopregnancy in gilts. Gilts were mated (pregnant; n = 11) on the 1st d of estrus or received 5 mg of estradiol valerate i.m. at d 11 to 15 after the onset of estrus (pseudopregnant; n = 9). Gilts were treated with prostaglandin F2 alpha (PGF2 alpha, 15 and 10 mg) at 12-h intervals on d 44 of pregnancy or pseudopregnancy. The day of abortion or luteolysis (progesterone less than .2 ng/mL) was considered d 0. Six pregnant and four pseudopregnant gilts received s.c. an E2 capsule (24 mg of E2) on d -20 and additional E2 capsules on d -13 and -6. The E2 capsules were removed on the day after PGF2 alpha administration. Blood samples were collected at 12-h intervals from d -21 to -3, at 6-h intervals from d -2 to 21 or the onset of estrus, and at 15-min intervals for 8 h on d -2, 1, 4, 7, 10, 14, and 18. After each 8-h sampling period, gilts were treated i.v. with GnRH at .5 micrograms/kg of BW and blood samples collected at 10-min intervals for 3 h. A greater (P less than .05) proportion of sham-treated gilts than of E2-treated gilts exhibited a preovulatory-like LH surge after abortion/luteolysis. It was evident that E2 supplementation before luteolysis reduced the ability of pregnant and pseudopregnant gilts to return to estrus.

  19. Influence of maternal and service-sire breed on serum progesterone and estrogen before calving and plasma 13,14-dihydro-15-keto-prostaglandin F2 alpha after calving.

    PubMed

    Lammoglia, M A; Holloway, J W; Lewis, A W; Neuendorff, D A; Randel, R D

    1995-04-01

    Effects of breed of service sire and cow on birth weight and prepartum and postpartum endocrine function were studied in multiparous Brahman (n = 20) and Angus (n = 20) cows bred to Brahman or Angus bulls. Before calving, blood samples were collected on d 34 to 28, 27 to 21, 20 to 14, and 13 to 7, and after calving, samples were collected from d 0 to 7. Progesterone (P4), estrogen (E2), and 13,14-dihydro-15-keto-prostaglandin F2 alpha (PGFM) were quantified with RIA. Calves born to Brahman were smaller (P < .05) than calves born to Angus cows. Prepartum concentrations of P4 were greater in Angus cows and decreased more rapidly near parturition than in Brahman cows (breed of dam x period; P < .03). Cows bearing bull calves had greater concentrations of P4 on d 20 to 14 before calving than cows bearing heifer calves (sex of calf x period; P < .04). Prepartum E2 was influenced (P < .05) by the breed of dam x breed of sire x period interaction. The ratio of P4:E2 tended to decrease more in Angus than in Brahman cows near parturition (breed of dam x period; P < .09). Postpartum PGFM tended to be influenced (P < .08) by breed of dam x breed of sire; from d 3 to 5, Brahman cows bred to Angus bulls tended (P < .08) to have greater PGFM than Brahman cows bred to Brahman bulls or than Angus cows bred to Brahman or Angus bulls.2+ f1p4 PMID:7628961

  20. Irradiation of human skin by short wavelength ultraviolet radiation (100--290 nm) (u.v.C): increased concentrations of arachidonic acid and prostaglandines E2 and F2alpha.

    PubMed

    Camp, R D; Greaves, M W; Hensby, C N; Plummer, N A; Warin, A P

    1978-08-01

    1. Human abdominal skin was irradiated with six times the minimal erythema dose of ultraviolet C (100--290 nm) radiation. Erythema appeared at 3 h, was of moderate degree by 6 h and was maximal at 12--24 h. It was reduced at 48 h and by 72 h had disappeared. 2. A suction bulla technique was used for the recovery of exudate from normal and inflamed skin at 6, 18, 24 and 48 h after irradiation. 3. Prostaglandin-like activity, estimated by bioassay, showed maximum increase at 18 h, when erythema was also maximum. PGF 2alpha, measured by both radioimmunoassay and by combined gas-liquid chromatography--gas spectrometry, followed a similar time course then fell to normal, or near normal, levels at 48 h. 4. Prostaglandin E2 and arachidonic acid concentrations, measured by gas chromatography--mass spectrometry, were maximally raised at 18--24 h. At 48 h, when some erythema was still present, though reduced, prostaglandin E2 concentrations were still raised above control values. 5. The results provide direct evidence in support of the view that the erythma following irradiation of human skin by u.v.C involves activation of arachidonic acid metabolism. However, the relationship between the erythema and increased prostaglandin activity is not fully understood.

  1. Enzymatic formation of prostamide F2alpha from anandamide involves a newly identified intermediate metabolite, prostamide H2.

    PubMed

    Yang, Wu; Ni, Jinsong; Woodward, David F; Tang-Liu, Diane D-S; Ling, Kah-Hiing John

    2005-12-01

    Prostaglandin F2alpha 1-ethanolamide (prostamide F2alpha) is a potent ocular hypotensive agent in animals and represents a new class of fatty acid amide compounds. Accumulated evidence indicated that anandamide, an endogenous bioactive ligand for cannabinoid receptors, may serve as a common substrate to produce all prostamides, including prostamide F2alpha. After incubation of anandamide with cyclooxygenase 2 (COX-2), the reaction mixture was profiled by HPLC and an intermediate metabolite was discovered and characterized as a cyclic endoperoxide ethanolamide using HPLC-tandem mass spectrometry. Formation of prostamide F2alpha was also demonstrated when the intermediate metabolite was isolated and incubated with prostaglandin F synthase (PGF synthase). These results suggest that the biosynthesis of prostamide F2alpha proceeds in two consecutive steps: oxidation of anandamide to form an endoperoxide intermediate by COX-2, and reduction of the endoperoxide intermediate to form prostamide F2alpha by PGF synthase. This endoperoxide ethanolamide intermediate has been proposed as prostamide H2. PMID:16150817

  2. Prostaglandin synthesis and catabolism in the gastric mucosa: studies in normal rabbits and rabbits immunized with prostaglandin E2

    SciTech Connect

    Redfern, J.S.

    1988-09-01

    Antral and fundic mucosal homogenates obtained from prostaglandin E2-immunized rabbits converted 14C-arachidonic acid to prostaglandin E2, 6-keto prostaglandin F1 alpha, prostaglandin F2 alpha, and prostaglandin D2. Percentage conversion of 14C-arachidonic acid to these prostaglandin products was not significantly different in prostaglandin E2-immunized rabbits compared with control rabbits (thyroglobulin-immunized and unimmunized rabbits combined). Synthesis of 6-keto prostaglandin F1 alpha, prostaglandin E2 and 13,14-dihydro 15-keto prostaglandin E2 from endogenous arachidonic acid after vortex mixing fundic mucosal homogenates was similar in prostaglandin E2 immunized rabbits and control rabbits. Both in prostaglandin E2-immunized rabbits and controls, 3H-prostaglandin E2 was catabolized extensively by the fundic mucosa, whereas 3H-6-keto prostaglandin F1 alpha, 3H-prostaglandin F2 alpha, and 3H-prostaglandin D2 were not catabolized to any appreciable extent. The rate of catabolism of PGs was not significantly different in prostaglandin E2-immunized rabbits and control rabbits, with the exception of prostaglandin F2 alpha which was catabolized slightly more rapidly in prostaglandin E2-immunized rabbits. These results indicate that development of gastric ulcers in prostaglandin E2-immunized rabbits is not associated with an alteration in the capacity of the gastric mucosa to synthesize or catabolize prostaglandins.

  3. Prostaglandins and the regulation of parturition in mares.

    PubMed

    Ousey, J C; Fowden, A L

    2012-02-01

    Prostaglandins play an essential role during the perinatal period in the mare. Prostaglandin concentrations are low for the majority of pregnancy due to the regulatory action of progestagens on those enzymes responsible for metabolism of prostaglandins. Towards term, prostaglandin concentrations gradually increase, closely associated with upregulation of the fetal hypothalamo-pituitary-adrenal axis, stimulation of the prostaglandin synthesising enzyme PGHS-2 and changes in the ratio of progestagens and oestrogens. Recent evidence in the mare indicates that proinflammatory cytokines are key mediators of prostaglandin synthesis both at term parturition in healthy mares and at preterm parturition associated with placental infection. Prostaglandin concentrations rise substantially during active labour and decline after birth, associated with delivery of the placenta. During induced labour, prostaglandin concentrations are variable depending on the proximity to spontaneous parturition at term. Once the proinflammatory endocrine cascade is initiated, it is difficult to prevent active labour by administration of drugs that reduce prostaglandin concentrations in peripheral plasma. Further work is needed to establish the inter-relationships between prostaglandin production and other endocrine changes associated with labour at term and preterm in the mare.

  4. Prostaglandins temporally regulate cytoplasmic actin bundle formation during Drosophila oogenesis.

    PubMed

    Spracklen, Andrew J; Kelpsch, Daniel J; Chen, Xiang; Spracklen, Cassandra N; Tootle, Tina L

    2014-02-01

    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.

  5. [Effect of prostaglandin E2 and F2 alpha on steroid biosynthesis in rat ovary (author's transl)].

    PubMed

    Takahashi, M; Aizawa, Y

    1979-01-01

    Conversion in vitro of pregnenolone to progesterone by the ovaries from immature rats after treatment of PMS and HCG was inhibited by addition of PGE2 (1.4 X 10(-7)M) or PGF2 alpha (1.4 X 10(-7)M). Result of conversion in vitro of pregnenolone to progesterone and estradiol-17 beta by ovary of adult rat in estrus showed that the progesterone biosynthesis in the ovary was inhibited by PGF2 alpha (1.4 X 10(-7)M) but the releasing rate of progesterone from the ovary into the medium increased by about 1.25 fold. Progesterone in the medium decreased dramatically following incubation. Estradiol-17 beta in the ovarian tissue and in the medium did not differ from the control rate with addition of PGF2 alpha. When the effect of PGF2 alpha (1.4 X 10(-7)M) in vitro on the conversion of testosterone to estrone and estradiol-17 beta by the ovary from adult rat in estrus was studied, we found that the releasing rate of estrone from the ovary into the medium was increased by addition of PGF2 alpha; the rate was significantly different from control level after addition of PGF2 alpha 30 min of incubation (p less than 0.01). Thus a minute amount of PGE2 and PGF2 alpha influences steroid biosynthesis in the rat ovary.

  6. [Influence of time of initiation of a prostaglandin F2alpha protocol in dairy cows with puerperal endometritis].

    PubMed

    Falkenberg, U; Heuwieser, W

    2005-07-01

    A field trial was conducted to elucidate the effect of the time of initiation of a repeated PGF2alpha-application in a 14 day interval for treatment of endometritis in dairy cows. On a commercial dairy farm in Brandenburg, Germany, a total of 494 dairy cows were examined by rectal palpation and adspection for signs of endometritis (vaginal discharge, enlarged uterus) between day 20 to 26 post partum (dpp). We performed two further examinations by rectal palpation and external adspection to monitor the puerperal phase (34.-40. dpp, 55.-61. dpp). All cows with symptoms of an endometritis were treated with PGF2alpha (0.15 mg R-Cloprostenol, Preloban, Intervet Deutschland GmbH Unterschleissheim) twice in a 14-day interval. In the group "Early" (n = 146) the first injection of Cloprostenol was administered at time of the 1st examination. In the group "Late" (n = 129) an identical treatment was administered in cows with endometritis, however it was started 14 days later (34.-40. dpp). The incidence of endometritis was 57.7% in the group "Early" and 53.5% in the group "Late" at the first time of examination. The 1st service conception rates for treated cows were 34% in the group "Early" vs. 37% in the group "Late". In the group "Early" differences were found in days open between treated cows with endometritis and untreated controls without symptoms of endometritis (99.1 d vs. 110.8 d, p > 0.05). In the group "Late", days open for treated (106.8 d) and untreated cows (108.0 d) were similar. The severity of endometritis influenced the percentage of cows pregnant at 200 dpp. Regarding cows with a severe endometritis (E2 and E3) the percentage of pregnant cows 200 dpp was higher in the group treated early (E2: 78.4%; E3: 80.0%) than in the group with the late initiation of the treatment (E2: 68.6%; E3: 54.5%, p < 0.05). Cows with a moderate endometritis (E1) had a similar percentage of pregnant cows (200 dpp) as the untreated cows without endometritis. It is concluded that application of PGF2alpha in the 4th and 6th week post partum in a 14 day interval in cases of severe endometritis is more effective than the application of the same treatment two weeks later. PMID:16124698

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

    PubMed

    Kellner, R G; Van der Kraak, G

    1992-04-01

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

  8. Enhancement of scleral macromolecular permeability with prostaglandins.

    PubMed Central

    Weinreb, R N

    2001-01-01

    PURPOSE: It is proposed that the sclera is a metabolically active and pharmacologically responsive tissue. These studies were undertaken to determine whether prostaglandin exposure can enhance scleral permeability to high-molecular-weight substances. METHODS: Topical prostaglandin F2 alpha (PGF2 alpha) was administered to monkeys to determine if this altered the amount of scleral matrix metalloproteinases (MMPs). Experiments also were performed to determine whether the prostaglandin F (FP) receptor and gene transcripts are expressed in normal human sclera. Permeability of organ-cultured human sclera following prostaglandin exposure then was studied and the amount of MMP released into the medium measured. Finally, the permeability of human sclera to basic fibroblast growth factor (FGF-2) was determined following prostaglandin exposure. RESULTS: Topical prostaglandin administration that reduced scleral collagen also increased scleral MMP-1, MMP-2, and MMP-3 by 63 +/- 35%, 267 +/- 210%, and 729 +/- 500%, respectively. FP receptor protein was localized in scleral fibroblasts, and FP receptor gene transcript was identified in sclera. Exposure to prostaglandin F2 alpha, 17-phenyltrinor, PGF2 alpha, or latanoprost acid increased scleral permeability by up to 124%, 183%, or 213%, respectively. In these cultures, MMP-1, MMP-2, and MMP-3 were increased by up to 37%, 267%, and 96%, respectively. Finally, transscleral absorption of FGF-2 was increased by up to 126% with scleral exposure to latanoprost. CONCLUSIONS: These studies demonstrate that the sclera is metabolically active and pharmacologically responsive to prostaglandins. Further, they demonstrate the feasibility of cotreatment with prostaglandin to enhance transscleral delivery of peptides, such as growth factors and high-molecular-weight substances, to the posterior segment of the eye. PMID:11797317

  9. [Effect of thrombin and prostaglandins E and F on various indices of carbohydrate metabolism in human platelets].

    PubMed

    Makarov, S A; Kudriavtseva, G V; Kolotilova, A I

    1985-01-01

    After incubation of intact thrombocytes with prostaglandins E2 and F2 alpha stimulation of glucose-6-phosphate dehydrogenase and glutathione reductase activities as well as an increase in the rate of sedoheptulose-7-phosphate accumulation were found. Thrombin inhibited the glucose-6-phosphate dehydrogenase activity by 30% in these thrombocytes. Addition of thrombin, following the incubation of thrombocytes with prostaglandins, removed the activating effect of the prostaglandins on the pentosephosphate pathway reactions, inhibited glutathione reductase and lactate dehydrogenase.

  10. [The inhibition of prostaglandin induced uterine contractions by diazoxide in vitro (author's transl)].

    PubMed

    Schneider-Affeld, F; Rüttgers, H; Hter, J; Kubli, F

    1977-02-01

    The tocolytic efficiency of Diazoxide, a benzothiadiazine derivative with pronounced musculotropic action, was tested on the isolated uteri of non-gravid and gravid rats. Regular uterine contractions were induced by the prostaglandines E2 and F2 alpha. Their amplitude and frequency could be suppressed totally or subtotally. Contraction intervals lasted 4--22 min. The basal tone was reduced in most cases.

  11. Evidence for selective regulation of the phosphorylation of myocyte proteins by isoproterenol and prostaglandin E1.

    PubMed

    Hayes, J S; Bowling, N; King, K L; Boder, G B

    1982-01-12

    Both isoproterenol and prostaglandin E1 increased the activation state of cyclic AMP-dependent protein kinase in cultured myocytes; however, only isoproterenol enhanced phosphorylase activity and contractile state. Following the incubation of intact myocytes with 32PO3-(4), 32 phosphoproteins were resolved from total cellular proteins by electrophoresis in sodium dodecyl sulfate polyacrylamide gels followed by autoradiography. Isoproterenol stimulated 32PO3-(4) incorporation into 16 proteins, including 2 phosphoproteins not observed under control conditions. By contrast, prostaglandin E1 neither caused a measurable change in the protein phosphorylation pattern nor interfered with isoproterenol's capacity to do so. Isoproterenol stimulated myocyte protein phosphorylation in either the presence or absence of extracellular Ca2+. The results suggest that the regulation of protein phosphorylation following adenylate cyclase stimulation is: (1) an agonist-specific process and not due solely to a random accumulation of intracellular cycle AMP and activation of protein kinase; (2) the Ca2+ mobilization component of beta-receptor activation does not account for the paradoxical effects of isoproterenol and prostaglandin E1; (3) activation of cyclic AMP-dependent protein kinase does not always result in an enhancement of protein phosphorylation.

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

    PubMed Central

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

    2015-01-01

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

  13. Effect of altrenogest and Lutalyse on parturition control, plasma progesterone, unconjugated estrogen and 13,14-dihydro-15-keto-prostaglandin F2 alpha in sows.

    PubMed

    Guthrie, H D; Meckley, P E; Young, E P; Hartsock, T G

    1987-07-01

    To investigate control of parturition time, 154 sows farrowing 220 litters at three locations were treated with altrenogest and Lutalyse (PG). The four treatment groups were: 1) no treatment (control group); 2) an im injection of 15 mg of PG at 1000 on d 111, 112 or 113 of gestation (d 0 = first day of estrus and gestation); 3) altrenogest (20 mg X sow-1 X d-1) fed twice daily for 4 d starting on d 109, 110 or 111; and 4) altrenogest and an injection of PG at 1000 on the day after the last feeding of altrenogest. Control sows at the University of Delaware (UD), University of Maryland (UM) and USDA, Beltsville Agricultural Research Center (BARC) had mean gestation lengths of 113.5, 114.2 and 115.7 d and live pigs/litter were 10.5, 11.0 and 7.4, respectively. Altrenogest started by d 110 prevented unscheduled early farrowing and increased (P less than .01) gestation length by 1.7 and 1.1 d, respectively, at UD and UM, but had not effect at BARC. The time from PG to parturition was 24.3, 22.6 and 34.4 h, respectively, at UD, UM and BARC. More sows at UD and UM farrowed between 0700 and 1700 on the expected day of parturition after injection of PG (59.3%) than with no PG (20.7%; P less than .05). The high incidence of small litters (less than six pigs) from sows inseminated with frozen semen at BARC resulted in negative correlations of live pigs/litter with gestation length (r = -.533, P = .0001) and with time from PG injection to birth of first pig (r = -.425, P = .017); these correlations were not significant at UD and UM where only natural service was used.(ABSTRACT TRUNCATED AT 250 WORDS)

  14. Induction of oestrus in Saanen goats at early breeding season by intravaginal progesterone sponges (MAP) or by prostaglandin F(2)alpha injections. Effect on different age groups.

    PubMed

    Alaçam, E; Oszar, S; Kiliçoglu, C; Güven, B; Izgür, H; Tekeli, T; Glatzel, P

    1985-09-01

    Twenty-one maiden and 29 pluriparous milking Ankara Saanen goats received either two i.m. injections of PGF(2)alpha (n=25) or intravaginal MAP sponges (n=25) early in November at the start of the breeding season. About twice as many pluriparous goats as maiden goats exhibited estrus after either treatment (87% vs. 47%). Breeding after this induced estrus caused pregnancies in 62% of the pluriparous goats, but only in 24% of the maiden animals. Maximal concentrations of progesterone were reached 11 days after the start of the MAP treatment. Progesterone declined to basal levels two to four days after sponge withdrawal. A significant slower progesterone increase also resulting in lower maximal concentrations could be observed in maiden goats. Luteolysis was evident in all animals within 24 h after PGF(2)alpha injection. Nine goats (six maiden and three pluriparous) did not exhibit Heat after the second injection and showed only a slow increase of progesterone. It seems that noncyclic animals are less sensitive to MAP treatment than to the first PGF(2)alpha injection. Goats at the beginning of the breeding season may react after a premature interruption of corpus luteum function (after second PGF(2)alpha injection) with delayed or inadequate follicular function. PMID:16726081

  15. Technical note: use of slow-release estradiol and prostaglandin F2alpha to induce pseudopregnancy and control estrus in gilts.

    PubMed

    Cushman, R A; Davis, P E; Boonyaprakob, U; Hedgpeth, V S; Burns, P J; Britt, J H

    1999-11-01

    We determined whether a single injection of slow-release estradiol-17beta (SRE2) would induce pseudopregnancy in gilts and whether PGF2alpha would regress the corpora lutea (CL) of pseudopregnancy. Crossbred gilts (n = 40) were induced to ovulate by treatment with 400 IU of hCG + 200 IU of eCG (PG600, Intervet, Millsboro, DE) given at 180 d of age (d = 0). On d 14, gilts were injected i.m. with one of five doses (n = 8 gilts/dose) of SRE2 (0, 12.5, 25, 50, or 100 mg). Blood samples were collected before SRE2 and twice weekly until d 73 to monitor serum progesterone (P4) and estradiol (E2). On d 59, gilts received (i.m.) 10 mg of PGF2alpha (Lutalyse, Pharmacia Upjohn, Kalamazoo, MI) and were checked for estrus for 7 d. On d 62, mammary development was scored (0 = no development; 1 = some development; 2 = teat and gland development) by a neutral observer. Treatment with SRE2 increased (P < .05) peak E2 concentrations, duration of luteal function, and mammary gland score. There were no differences (chi-square, P > .05) among doses of SRE2 in the percentage of pseudopregnant gilts that showed luteolysis after PGF2alpha. We conclude that a single injection of SRE2 can induce pseudopregnancy and that the CL can be regressed with PGF2alpha, providing a simple method for controlling estrus in gilts.

  16. Efficacy of induction of luteolysis in superovulated cows is dependent on time of prostaglandin F2alpha analog treatment: effects on plasma progesterone and luteinizing hormone profiles.

    PubMed

    Viana, J H M; Vargas, M S B; Siqueira, L G B; Camargo, L S A; Figueiredo, A C S; Fernandes, C A C; Palhao, M P

    2016-09-01

    The objectives were to (1) evaluate the effectiveness of induction of luteolysis in superovulated (SOV) cows at two distinct time points after embryo flushing; and (2) compare the pattern of LH release after treatment with PGF in cows with single vs. multiple ovulations. In the first experiment, Holstein cows were SOV with 400 IU of FSH following standard procedures. Uterine flushing for embryo recovery was performed 7 days after artificial insemination (Day 0), and cows were randomly allocated into two groups to receive PGF (0.5-mg sodium cloprostenol, intramascular) either immediately after flushing (Day 7 group, N = 19) or 4 days later (Day 11 group, N = 20). Time of luteolysis was determined on the basis of plasma progesterone (P4) concentrations. There was no difference (P > 0.05) in plasma P4 before treatment between Day 7 and Day 11 groups. A decline in plasma P4 was observed 48 hours after PGF treatment in both the groups (P < 0.0001). In Day 11 cows, P4 continued to decrease thereafter, whereas Day 7 animals had no further reduction in plasma P4. Luteolysis (P4 < 1 ng/mL) occurred in all Day 11 cows. In the Day 7 group, however, luteolysis failure was observed for 11 of 19 cows (57.9%). In cows without luteolysis, plasma P4 increased after the initial PGF-induced decline. The second experiment compared luteolysis in (SOV, N = 6) vs. non-SOV (control, N = 8) cows. Both groups received a single PGF treatment on Day 11 after estrus, and luteolysis was monitored daily by ovarian ultrasonography and plasma P4 measurements. In addition, plasma LH was measured in blood samples taken every 20 minutes for 1 hour during five consecutive days after treatment. A similar percentage of reduction in P4 was observed in both groups 24 hours after treatment; however, SOV cows only reached plasma P4 values similar (P > 0.05) to controls 96 hours after treatment. There was no difference in initial LH values between SOV and controls (P > 0.05). The slower decrease in plasma P4 in the SOV group prevented an increase in LH for up to 96 hours after luteolysis induction, whereas LH values increased (P < 0.05) in controls 24 hours after treatment. In conclusion, (1) luteolysis may fail or be incomplete when PGF treatment is given on the day of uterine flushing (Day 7) in SOV cows; (2) induction of luteolysis 4 days later (Day 11) is effective, but the initial high-plasma P4 concentrations result in a slower slope of P4 decline to basal levels, and consequently, delayed increase in LH pulses. PMID:27118386

  17. Effect of prostaglandin F2alpha at the time of AI on progesterone levels and pregnancy rate in synchronized Italian Mediterranean buffaloes.

    PubMed

    Neglia, G; Natale, A; Esposito, G; Salzillo, F; Adinolfi, L; Campanile, G; Francillo, M; Zicarelli, L

    2008-05-01

    The aims of this study were to evaluate the effects of an intravenous or intramuscular PGF2alpha analogue administration on the day of estrus on progesterone concentration and pregnancy rate in buffaloes undergoing artificial insemination (AI). To this end, two experiments were carried out. The first study was performed on 72 Mediterranean buffaloes synchronized by the Ovsynch-TAI Program. On the day of estrus only animals considered in heat were divided into four groups: Groups IVC and IMC received, respectively, an intravenous or intramuscular injection of cloprostenol (0.524 mg), whereas control Groups IVS and IMS received the same injections of saline. Milk samples were collected daily from each animal to assess progesterone concentration in the whey by RIA method. In addition on alternate days, buffaloes underwent transrectal ultrasound analysis. The second study was carried out on 385 buffaloes synchronized by the Ovsynch-TAI Program. On the day of AI, animals were divided in four groups, as described in experiment 1. Pregnancy rate was evaluated either on day 26 or day 45 and embryonic mortality rate was recorded. Statistical analysis was performed by ANOVA and chi2 test. A higher (P<0.05) progesterone concentration was recorded on day 11 (Day 0=estrus day) in Groups IVC and IMC compared to Groups IVS and IMS (351.6+/-129.7 and 355.8+/-112.2 pg ml(-1) vs. 239.8+/-81.1 and 243.6+/-90.5 pg ml(-1), respectively). Furthermore, a larger CL was recorded on the same day in treated vs. control groups (1.25+/-0.15 and 1.27+/-0.17 cm, respectively, in Groups IVC and IMC vs. 1.08+/-0.14 and 1.05+/-0.13 cm in IVS and IMS). In the second study, a higher pregnancy rate was observed in treated (IVC+IMC) vs. control (IVS+IMS) groups (46.7% vs. 30.7%; P<0.01), while no differences were recorded between treated groups. From these data, it can be concluded that either intravenous or intramuscular administration of PGF2alpha at the time of AI can enhance progesterone levels and pregnancy rate in buffaloes. PMID:18346780

  18. Prostaglandin F2alpha stimulates the Raf/MEK1/mitogen-activated protein kinase signaling cascade in bovine luteal cells.

    PubMed

    Chen, D B; Westfall, S D; Fong, H W; Roberson, M S; Davis, J S

    1998-09-01

    Upon binding to its G protein-coupled transmembrane receptors, the actions of PGF2alpha on the corpus luteum are initiated by the phospholipase C/diacylglycerol-inositol 1,4,5-trisphosphate (InsP3)/Ca2+-protein kinase C (PKC) pathway. However, little is known about the downstream intracellular signaling events that can lead to transcriptional activation in response to PGF2alpha. The present study was conducted to examine the involvement of the mitogen-activated protein kinase (MAPK) signaling cascade in the corpus luteum. Three isoforms of the Raf family of oncoprotein kinases (A-Raf, B-Raf, and Raf-1 or c-Raf) were detected in bovine luteal cells. Raf-1 and B-Raf, but not A-Raf, were activated by PGF2alpha (1 microM) and the pharmacological PKC activator phorbol myristate acetate (PMA, 20 nM). Kinetic analysis revealed that PGF2alpha rapidly and transiently activated Raf-1. In vitro protein kinase assays demonstrated that activation of Raf-1 and B-Raf resulted in the phosphorylation and activation of MAPK kinase (MEK1), which subsequently phosphorylated p42mapk. As determined by hyperphosphorylation, tyrosine phosphorylation, and enzymatic activity, p42mapk and p44mapk were rapidly and transiently activated by both PGF2alpha (1 microM) and PMA (20 nM). Additionally, both PGF2alpha (1 microM) and PMA (20 nM) stimulated phosphorylation of Raf-1, MEK1, and p42mapk in 32P-labeled cells. Our data demonstrate that PGF2alpha activates the Raf/MEK1/p42/44mapk signaling cascade in bovine luteal cells and that the actions of PGF2alpha are mimicked by the PKC activator PMA. Activation of the Raf/MEK1/MAPK signaling cascade by PGF2alpha in luteal cells provides a mechanism to transduce signals initiated by PGF2alpha receptors on the cell surface into the nucleus. Activation of the Raf/MEK1/MAPK signaling cascade may be associated with transcriptional activation of luteal genes possessing activator protein-1-binding sites.

  19. Up-regulation of cyclooxygenase-2 by product-prostaglandin E2

    NASA Technical Reports Server (NTRS)

    Tjandrawinata, R. R.; Hughes-Fulford, M.

    1997-01-01

    The development of prostate cancer has been linked to high level of dietary fat intake. Our laboratory investigates the connection between cancer cell growth and fatty acid products. Studying human prostatic carcinoma PC-3 cells, we found that prostaglandin E2 (PGE2) increased cell growth and up-regulated the gene expression of its own synthesizing enzyme, cyclooxygenase-2 (COX-2). PGE2 increased COX-2 mRNA expression dose-dependently with the highest levels of stimulation seen at the 3-hour period following PGE2 addition. The NSAID flurbiprofen (5 microM), in the presence of exogenous PGE2, inhibited the up-regulation of COX-2 mRNA and cell growth. These data suggest that the levels of local intracellular PGE2 play a major role in the growth of prostate cancer cells through an activation of COX-2 gene expression.

  20. Distinct Roles of Central and Peripheral Prostaglandin E2 and EP Subtypes in Blood Pressure Regulation

    PubMed Central

    Yang, Tianxin; Du, Yaomin

    2012-01-01

    Prostaglandin E2 (PGE2) is a major prostanoid with a wide variety of biological activities. PGE2 can influence blood pressure (BP) both positively and negatively. In particular, centrally administered PGE2 induces hypertension whereas systemic administration of PGE2 produces a hypotensive effect. These physiologically opposing effects are generated by the existence of multiple EP receptors, namely EP1–4, which are G protein-coupled receptors with distinct signaling properties. This review highlights the distinct roles of PGE2 in BP regulation and the involvement of specific EP receptor subtypes. American Journal of Hypertension, advance online publication 14 June 2012; doi:10.1038/ajh.2012.67 PMID:22695507

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

    SciTech Connect

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

    2008-03-14

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

  2. Prostaglandin E{sub 2} regulates melanocyte dendrite formation through activation of PKC{zeta}

    SciTech Connect

    Scott, Glynis Fricke, Alex; Fender, Anne; McClelland, Lindy; Jacobs, Stacey

    2007-11-01

    Prostaglandins are lipid signaling intermediates released by keratinocytes in response to ultraviolet irradiation (UVR) in the skin. The main prostaglandin released following UVR is PGE{sub 2}, a ligand for 4 related G-protein-coupled receptors (EP{sub 1}, EP{sub 2}, EP{sub 3} and EP{sub 4}). Our previous work established that PGE{sub 2} stimulates melanocyte dendrite formation through activation of the EP{sub 1} and EP{sub 3} receptors. The purpose of the present report is to define the signaling intermediates involved in EP{sub 1}- and EP{sub 3}-dependent dendrite formation in human melanocytes. We recently showed that activation of the atypical PKC{zeta} isoform stimulates melanocyte dendricity in response to treatment with lysophosphatidylcholine. We therefore examined the potential contribution of PKC{zeta} activation on EP{sub 1}- and EP{sub 3}-dependent dendrite formation in melanocytes. Stimulation of the EP{sub 1} and EP{sub 3} receptors by selective agonists activated PKC{zeta}, and inhibition of PKC{zeta} activation abrogated EP{sub 1}- and EP{sub 3}-receptor-mediated melanocyte dendricity. Because of the importance of Rho-GTP binding proteins in the regulation of melanocyte dendricity, we also examined the effect of EP{sub 1} and EP{sub 3} receptor activation on Rac and Rho activity. Neither Rac nor Rho was activated upon treatment with EP{sub 1,3}-receptor agonists. We show that melanocytes express only the EP{sub 3A1} isoform, but not the EP{sub 3B} receptor isoform, previously associated with Rho activation, consistent with a lack of Rho stimulation by EP{sub 3} agonists. Our data suggest that PKC{zeta} activation plays a predominant role in regulation of PGE{sub 2}-dependent melanocyte dendricity.

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

    PubMed

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

    2004-05-01

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

  4. Intracrine prostaglandin E(2) signalling regulates hypoxia-inducible factor-1α expression through retinoic acid receptor-β.

    PubMed

    Fernández-Martínez, Ana B; Jiménez, María I Arenas; Manzano, Victoria Moreno; Lucio-Cazaña, Francisco J

    2012-12-01

    We have previously found in human renal proximal tubular HK-2 cells that hypoxia- and all-trans retinoic acid-induced hypoxia-inducible factor-1α up-regulation is accompanied by retinoic acid receptor-β up-regulation. Here we first investigated whether hypoxia-inducible factor-1α expression is dependent on retinoic acid receptor-β and our results confirmed it since (i) hypoxia-inducible factor-1α-inducing agents hypoxia, hypoxia-mimetic agent desferrioxamine, all-trans retinoic acid and interleukin-1β increased retinoic acid receptor-β expression, (ii) hypoxia-inducible factor-1α up-regulation was prevented by retinoic acid receptor-β antagonist LE-135 or siRNA retinoic acid receptor-β and (iii) there was direct binding of retinoic acid receptor-β to the retinoic acid response element in hypoxia-inducible factor-1α promoter upon treatment with all-trans retinoic acid and 16,16-dimethyl-prostaglandin E(2). Since intracellular prostaglandin E(2) mediates hypoxia-inducible factor-1α up-regulation in normoxia in HK-2 cells, we next investigated and confirmed, its role in the up-regulation of retinoic acid receptor-β in normoxia by hypoxia-inducible factor-1α-inducing agents all-trans retinoic acid, interleukin-1β and 16,16-dimethyl-prostaglandin E(2) by inhibiting cyclooxygenases, prostaglandin influx transporter or EP receptors. Interestingly, the hypoxia-induced increase in retinoic acid receptor-β expression and accumulation of hypoxia-inducible factor-1α was also blocked by the inhibitors tested. This is the first time, to our knowledge, that retinoic acid receptor-β signalling is involved in the control of the expression of transcription factor hypoxia-inducible factor-1α in both normoxia and hypoxia and that retinoic acid receptor-β expression is found to be strictly regulated by intracellular prostaglandin E(2). Given the relevance of hypoxia-inducible factor-1α in the kidney in terms of tumorigenesis, progressive renal failure, production

  5. Regulation of cytoplasmic calcium: interactions between prostaglandins, prostacyclin, thromboxane A2, zinc, copper and taurine.

    PubMed

    Horrobin, D F; Manku, M S; Cunnane, S; Karmazyn, M; Morgan, R O; Ally, A I; Karmall, R A

    1978-02-01

    The regulation of cytoplasmic calcium is a key process in nerve tissue. Using a smooth muscle model we have shown that prostaglandin (PG) E2 probably regulates entry from extracellular fluid, whereas the release from intracellular stores depends on the interplay between thromboxane (TX) A2, PGEI and prostacyclin. Hormones and other agents interact with this system in the following ways: vasopressin, angiotensin and inositol mobilize arachidonic acid from membrane phospholipids and increase synthesis of PGE2 and TXA2, cortisol blocks this action. Prolactin and zinc mobilize dihomo-gamma-linolenic acid and increase synthesis of PGEI. These effects can be blocked by cortisol, lithium and taurine, three agents which on their own have no effect on basal PG production. Epileptogenic agents like penicillin and picrotoxin also stimulate PG synthesis, while diphenylhydantoin is a PG antagonist and diazepam is a TXA2 antagonist. The effects of all these agents occur at concentrations which are physiological in the case of the natural ones, and readily attained in human plasma in the case of the drgus. In view of recent evidence that calcium may be important in demyelination and considering the established role it plays in nerve conduction and synaptic transmission, we suggest that these observations may be of significance in understanding Friedreich's ataxia.

  6. Prostaglandin E2 regulates Th17 cell differentiation and function through cyclic AMP and EP2/EP4 receptor signaling.

    PubMed

    Boniface, Katia; Bak-Jensen, Kristian S; Li, Ying; Blumenschein, Wendy M; McGeachy, Mandy J; McClanahan, Terrill K; McKenzie, Brent S; Kastelein, Robert A; Cua, Daniel J; de Waal Malefyt, René

    2009-03-16

    Prostaglandins, particularly prostaglandin E2 (PGE2), play an important role during inflammation. This is exemplified by the clinical use of cyclooxygenase 2 inhibitors, which interfere with PGE2 synthesis, as effective antiinflammatory drugs. Here, we show that PGE2 directly promotes differentiation and proinflammatory functions of human and murine IL-17-producing T helper (Th17) cells. In human purified naive T cells, PGE2 acts via prostaglandin receptor EP2- and EP4-mediated signaling and cyclic AMP pathways to up-regulate IL-23 and IL-1 receptor expression. Furthermore, PGE2 synergizes with IL-1beta and IL-23 to drive retinoic acid receptor-related orphan receptor (ROR)-gammat, IL-17, IL-17F, CCL20, and CCR6 expression, which is consistent with the reported Th17 phenotype. While enhancing Th17 cytokine expression mainly through EP2, PGE2 differentially regulates interferon (IFN)-gamma production and inhibits production of the antiinflammatory cytokine IL-10 in Th17 cells predominantly through EP4. Furthermore, PGE2 is required for IL-17 production in the presence of antigen-presenting cells. Hence, the combination of inflammatory cytokines and noncytokine immunomodulators, such as PGE2, during differentiation and activation determines the ultimate phenotype of Th17 cells. These findings, together with the altered IL-12/IL-23 balance induced by PGE2 in dendritic cells, further highlight the crucial role of the inflammatory microenvironment in Th17 cell development and regulation.

  7. Flow-induced prostaglandin E2 release regulates Na and K transport in the collecting duct.

    PubMed

    Flores, Daniel; Liu, Yu; Liu, Wen; Satlin, Lisa M; Rohatgi, Rajeev

    2012-09-01

    Fluid shear stress (FSS) is a critical regulator of cation transport in the collecting duct (CD). High-dietary sodium (Na) consumption increases urine flow, Na excretion, and prostaglandin E(2) (PGE(2)) excretion. We hypothesize that increases in FSS elicited by increasing tubular flow rate induce the release of PGE(2) from renal epithelial cells into the extracellular compartment and regulate ion transport. Media retrieved from CD cells exposed to physiologic levels of FSS reveal several fold higher concentration of PGE(2) compared with static controls. Treatment of CD cells with either cyclooxygenase-1 (COX-1) or COX-2 inhibitors during exposure to FSS limited the increase in PGE(2) concentration to an equal extent, suggesting COX-1 and COX-2 contribute equally to FSS-induced PGE(2) release. Cytosolic phospholipase A2 (cPLA2), the principal enzyme that generates the COX substrate arachidonic acid, is regulated by mitogen-activated protein-kinase-dependent phosphorylation and intracellular Ca(2+) concentration ([Ca(2+)](i)), both signaling processes, of which, are activated by FSS. Inhibition of the ERK and p38 pathways reduced PGE(2) release by 53.3 ± 8.4 and 32.6 ± 11.3%, respectively, while antagonizing the JNK pathway had no effect. In addition, chelation of [Ca(2+)](i) limited the FSS-mediated increase in PGE(2) concentration by 47.5 ± 7.5% of that observed in untreated sheared cells. Sheared cells expressed greater phospho-cPLA2 protein abundance than static cells; however, COX-2 protein expression was unaffected (P = 0.064) by FSS. In microperfused CDs, COX inhibition enhanced flow-stimulated Na reabsorption and abolished flow-stimulated potassium (K) secretion, but did not affect ion transport at a slow flow rate, implicating that high tubular flow activates autocrine/paracrine PGE(2) release and, in turn, regulates flow-stimulated cation transport. In conclusion, FSS activates cPLA2 to generate PGE(2) that regulates flow-mediated Na and K transport in

  8. Regulation of renal proximal tubule Na-K-ATPase by prostaglandins.

    PubMed

    Herman, Maryann B; Rajkhowa, Trivikram; Cutuli, Facundo; Springate, James E; Taub, Mary

    2010-05-01

    Prostaglandins (PGs) play a number of roles in the kidney, including regulation of salt and water reabsorption. In this report, evidence was obtained for stimulatory effects of PGs on Na-K-ATPase in primary cultures of rabbit renal proximal tubule (RPT) cells. The results of our real-time PCR studies indicate that in primary RPTs the effects of PGE(2), the major renal PG, are mediated by four classes of PGE (EP) receptors. The role of these EP receptors in the regulation of Na-K-ATPase was examined at the transcriptional level. Na-K-ATPase consists of a catalytic α-subunit encoded by the ATP1A1 gene, as well as a β-subunit encoded by the ATP1B1 gene. Transient transfection studies conducted with pHβ1-1141 Luc, a human ATP1B1 promoter/luciferase construct, indicate that both PGE(1) and PGE(2) are stimulatory. The evidence for the involvement of both the cAMP and Ca(2+) signaling pathways includes the inhibitory effects of the myristolylated PKA inhibitor PKI, the adenylate cyclase (AC) inhibitor SQ22536, and the PKC inhibitors Gö 6976 and Ro-32-0432 on the PGE(1) stimulation. Other effectors that similarly act through cAMP and PKC were also stimulatory to transcription, including norepinephrine and dopamine. In addition to its effects on transcription, a chronic incubation with PGE(1) was observed to result in an increase in Na-K-ATPase mRNA levels as well as an increase in Na-K-ATPase activity. An acute stimulatory effect of PGE(1) on Na-K-ATPase was observed and was associated with an increase in the level of Na-K-ATPase in the basolateral membrane.

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

    PubMed Central

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

    2013-01-01

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

  10. Regulation of Calcium Channels and Exocytosis in Mouse Adrenal Chromaffin Cells by Prostaglandin EP3 Receptors

    PubMed Central

    Jewell, Mark L.; Breyer, Richard M.

    2011-01-01

    Prostaglandin (PG) E2 controls numerous physiological functions through a family of cognate G protein-coupled receptors (EP1–EP4). Targeting specific EP receptors might be therapeutically useful and reduce side effects associated with nonsteroidal anti-inflammatory drugs and selective cyclooxygenase-2 inhibitors that block prostanoid synthesis. Systemic immune challenge and inflammatory cytokines have been shown to increase expression of the synthetic enzymes for PGE2 in the adrenal gland. Catecholamines and other hormones, released from adrenal chromaffin cells in response to Ca2+ influx through voltage-gated Ca2+ channels, play central roles in homeostatic function and the coordinated stress response. However, long-term elevation of circulating catecholamines contributes to the pathogenesis of hypertension and heart failure. Here, we investigated the EP receptor(s) and cellular mechanisms by which PGE2 might modulate chromaffin cell function. PGE2 did not alter resting intracellular [Ca2+] or the peak amplitude of nicotinic acetylcholine receptor currents, but it did inhibit CaV2 voltage-gated Ca2+ channel currents (ICa). This inhibition was voltage-dependent and mediated by pertussis toxin-sensitive G proteins, consistent with a direct Gβγ subunit-mediated mechanism common to other Gi/o-coupled receptors. mRNA for all four EP receptors was detected, but using selective pharmacological tools and EP receptor knockout mice, we demonstrated that EP3 receptors mediate the inhibition of ICa. Finally, changes in membrane capacitance showed that Ca2+-dependent exocytosis was reduced in parallel with ICa. To our knowledge, this is the first study of EP receptor signaling in mouse chromaffin cells and identifies a molecular mechanism for paracrine regulation of neuroendocrine function by PGE2. PMID:21383044

  11. Role of nitric oxide and prostaglandins in the regulation of blood pressure in conscious rats.

    PubMed

    Inglés, A C; Ruiz, F J; Salom, M G; Quesada, T; Carbonell, L F

    1995-06-01

    The present study was designed to investigate the possible role of endothelium-derived vasodilators, nitric oxide and prostaglandins, in the regulation of blood pressure during the presence and absence of the major pressor systems. Conscious rats were infused with a cocktail of inhibitors of the sympathetic nervous system, renin-angiotensin system, and V1 vascular receptor to vasopressin (achieved with hexamethonium, captopril, phentolamine, propranolol, and the V1 vasopressin (AVP) antagonist des-(CH2)5Tyr(Me)-AVP). The cocktail of vasoconstrictor inhibitors induced a marked fall of mean arterial pressure (MAP) from 109 +/- 2 to 52 +/- 2 mmHg (1 mmHg = 133.3 Pa) (n = 24). In animals with blockade, the specific inhibitor of nitric oxide synthesis, NG-nitro-L-arginine methyl ester (L-NAME), induced a significant increase of MAP from 51 +/- 1 to 84 +/- 2 mmHg (n = 6). In the presence of indomethacin, a cyclooxygenase inhibitor, the pressor response to L-NAME was from 52 +/- 2 to 126 +/- 4 mmHg (n = 6). Neither indomethacin (n = 6) nor vehicle (n = 6) alone altered MAP. In intact animals without blockade, L-NAME caused a similar increase of MAP when it was injected alone (from 107 +/- 3 to 144 +/- 4 mmHg, n = 7) or with indomethacin (from 113 +/- 3 to 144 +/- 3, n = 6). Indomethacin alone (n = 8) did not change MAP. In conclusion, in the absence of the major pressor systems, the pressor effect of the inhibition of the production of endogenous nitric oxide and vasodilator prostanoid synthesis appears to be synergistic. These results suggest that these two endogenous vasodilators are involved in the maintenance of blood pressure.

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

    PubMed Central

    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

  13. The effect of prostaglandins on experimental storage disease in rats.

    PubMed Central

    Joh, K.; Riede, U. N.; Zahradnik, H. P.

    1990-01-01

    The aim of this study was to investigate the effect of prostaglandins (PGs) on the release of lysosomes into the extracellular space in experimentally-induced storage disease in rats. The generalized phospholipidosis was induced by oral administration of chlorphentermine to Wistar rats. PG-E2 or PG-F2 alpha (50 micrograms/100 g) was injected intravenously into rats with phospholipidosis. Control rats were injected with the same amount of saline. Twenty-four hours later, extracellular and intracellular lysosomes were analysed morphometrically in electromicrographs of the liver, kidney, myocardium, skeletal muscle, aorta and cervix uteri, having been stained with acid-phosphatase. The morphometric parameters used were the numerical density of lysosomes per unit volume and the volume density of lysosomes per unit volume. The results show that, in comparison with the controls, a volumetric increase of extracellular lysosomes and a volumetric decrease of intracellular lysosomes were achieved by PG-E2 or PG-F2 alpha administration in several organs, but not in the myocardium or skeletal muscles. The effect of PG-F2 alpha was greater than that of PG-E2 in the liver and kidney, while the effect of PG-E2 was greater than that of PG-F2 alpha in the aorta and cervix uteri. These results indicate that PGs influence the discharge of storage lysosomes in bipolar epithelial cells in the liver and kidney, and also influence the release of non-storing lysosomes in apolar mesenchymal cells in the aorta and cervix uteri. Images Fig. 1 Fig. 2 Fig. 4 Fig. 5 Fig. 6 PMID:2331405

  14. Influence of prostaglandins and thyrotropin releasing hormone (TRH) on hormone secretion and growth in wether lambs.

    PubMed

    Davis, S L; Anfinson, M S; Klindt, J; Ohlson, D L

    1977-06-01

    A series of experiments were conducted in ewes and whether (castrate male) lambs to evaluate the influence of prostaglandins on secretion of anabolic hormones and to determine if repeated injections of prostaglandin (PG) F2alpha would chronically influence the secretion of these hormones and perhaps growth rate as well. A single intravenous injection of PGA1 and PGB1 (100 microgram/kg) exerted no significant (P greater than .10) influence on plasma concentrations of prolactin (PRL), growth hormone (GH) or thyrotropin (TSH) in ewes. PGA1, but not PGB1, stimulated an increase in the plasma concentration of insulin. Infusion of PGF2alpha for 5.5 hr into ewes resulted in increased (P less than .05) plasma concentrations of both GH and ARL while TSH and insulin were not significantly influenced. Prostaglandin F2alpha, when injected subcutaneously into wether lambs (10 mg twice weekly) stimulated (P less than .05) plasma GH concentrations after the first injection, but not after 3 weeks of treatment. Changes in plasma PRL or TSH were not observed consistently in the lambs treated chronically with PGF2alpha or TRH. Prostaglandin F2alpha, in the present studies, and PGE1 in previously reported studies (1-3), has been demonstrated to be stimulatory to the secretion of PRL and GH. In contrast, PGA1 and PGB1, which lack an 11-hydroxyl group, failed to influence the secretion of either PRL or GH. It would, therefore, appear that the 11-hydroxyl group is a structural requirement for prostaglandins to influence the secretion of these two hormones in sheep. Treatment with thyrotropin releasing hormone (TRH), alone or in combination with PGF 2alpha, significantly (P less than .05) increased growth rate (average daily gains) while PGF2alpha did not, despite the fact that both compounds exerted similar effects on plasma GH.

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

    PubMed Central

    Wang, Xiaowei; Shaw, Dana K.; Hammond, Holly L.; Sutterwala, Fayyaz S.; Rayamajhi, Manira; Shirey, Kari Ann; Perkins, Darren J.; Bonventre, Joseph V.; Velayutham, Thangam S.; Evans, Sean M.; Rodino, Kyle G.; VieBrock, Lauren; Scanlon, Karen M.; Carbonetti, Nicholas H.; Carlyon, Jason A.; Miao, Edward A.; McBride, Jere W.; Kotsyfakis, Michail

    2016-01-01

    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. PMID:27482714

  16. Prostaglandin E2 regulates renal cell carcinoma invasion through the EP4 receptor-Rap GTPase signal transduction pathway.

    PubMed

    Wu, Juanjuan; Zhang, Yushan; Frilot, Nicole; Kim, Jae I; Kim, Wan-Ju; Daaka, Yehia

    2011-09-30

    Prognosis for patients with early stage kidney cancer has improved, but the treatment options for patients with locally advanced disease and metastasis remain few. Understanding the molecular mechanisms that regulate invasion and metastasis is critical for developing successful therapies to treat these patients. Proinflammatory prostaglandin E(2) plays an important role in cancer initiation and progression via activation of cognate EP receptors that belong to the superfamily of G protein-coupled receptors. Here we report that prostaglandin E(2) promotes renal cancer cell invasion through a signal transduction pathway that encompasses EP4 and small GTPase Rap. Inactivation of Rap signaling with Rap1GAP, like inhibition of EP4 signaling with ligand antagonist or knockdown with shRNA, reduces the kidney cancer cell invasion. Human kidney cells evidence increased EP4 and decreased Rap1GAP expression levels in the malignant compared with benign samples. These results support the idea that targeted inhibition of EP4 signaling and restoration of Rap1GAP expression constitute a new strategy to control kidney cancer progression.

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

    PubMed

    Wang, Xiaowei; Shaw, Dana K; Hammond, Holly L; Sutterwala, Fayyaz S; Rayamajhi, Manira; Shirey, Kari Ann; Perkins, Darren J; Bonventre, Joseph V; Velayutham, Thangam S; Evans, Sean M; Rodino, Kyle G; VieBrock, Lauren; Scanlon, Karen M; Carbonetti, Nicholas H; Carlyon, Jason A; Miao, Edward A; McBride, Jere W; Kotsyfakis, Michail; Pedra, Joao H F

    2016-08-01

    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. PMID:27482714

  18. Goiter formation following prostaglandin administration in rats.

    PubMed Central

    Lupulescu, A.

    1976-01-01

    Prostaglandins (PGE1 and PGE2) induced a hyperplastic microfollicular goiter with a high radioiodine (131I) thyroid uptake, increased endocytosis, a heavy autoradiographic (125I) reaction, and a moderate increase of thyroid hormones (T4, T3), thyroxine-binding globulin (TGB), and thyrotropin (TSH) concentrations in adult rats. Ultrastructurally, both prostaglandins (E1 and E2) markedly stimulated the thyroid cell activity and increased the number of pseudopodia, the size of colloid and dense granule populations, and the number of polysomes. Conversely, a hypofunction of thyroid glands with low radioiodine (131I) thyroid uptake, a decreased autoradiographic (125I) reaction, and a moderate decrease in T4, T3, TGB, and TSH concentrations were observed following prostaglandin F 2alpha. Ultrastructurally, a decrease in size of the colloid and dense granule population and the number of degenerative mitochondria occurred infollicular cells. An intense hyperplasia of parafollicular (C) cells, with abundant population of characteristic dense granules, could be seen in PGF 2alpha-treated rats. A marked decrease of radioiodine (131I) uptake, endocytosis, and autoradiographic (125I) reaction and a sharp decline in T4, T3, and TBG were observed in hypophysectomized and chronically prostaglandin-treated rats. Light and electron microscopy revealed signs of an advanced thyroid hypofunction with flat cuboidal cells, reduced microvilli, scarce endoplasmic reticulum, and few dense droplets. The present findings demonstrate that the chronic administration of prostaglandins exerts significant effects of thyroid gland and goiter formation (goitrogenesis), radioiodine metabolism, and hormone synthesis, and that these effects are mediated by TSH secretion. Images Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 Figure 7 Figure 8 Figure 9 Figure 10 PMID:970439

  19. [Possible significance of prostaglandins in the pathogenesis of Crohn's disease].

    PubMed

    Schmidt, E; Bruch, H P; Walter, K

    1977-04-01

    Prostaglandins (E1, E2, F2alpha) produce and intensify peristaltic contractions in the healthy human intestinal muscle system according to dosage (threshold I-10(-4) microng/ml--maximum effective concentration 1 microng/ml). By subsequent introduction of adrenaline, the intestinal muscle system activated by prostaglandines can be completely relaxed again. Intestinal muscles from patients with Crohn's disease show a marked deviation from this behaviour: 1. The intestinal muscle system is extremely sensitive to prostagladins: maximum concentrations are already reached by about a thousand times smaller concentration than in the intestines. 2. The dose of adrenaline does not lead to dialtion, which is usual, but to contraction of the muscle system. These changes in the contractility of the intestine can explain some components of the clinical symptomatology of Crohn's disease.

  20. Aldo Keto Reductase 1B7 and Prostaglandin F2α Are Regulators of Adrenal Endocrine Functions

    PubMed Central

    Lambert-Langlais, Sarah; Volat, Fanny; Manin, Michèle; Coudoré, François; Val, Pierre; Sahut-Barnola, Isabelle; Ragazzon, Bruno; Louiset, Estelle; Delarue, Catherine; Lefebvre, Hervé; Urade, Yoshihiro; Martinez, Antoine

    2009-01-01

    Prostaglandin F2α (PGF2α), represses ovarian steroidogenesis and initiates parturition in mammals but its impact on adrenal gland is unknown. Prostaglandins biosynthesis depends on the sequential action of upstream cyclooxygenases (COX) and terminal synthases but no PGF2α synthases (PGFS) were functionally identified in mammalian cells. In vitro, the most efficient mammalian PGFS belong to aldo-keto reductase 1B (AKR1B) family. The adrenal gland is a major site of AKR1B expression in both human (AKR1B1) and mouse (AKR1B3, AKR1B7). Thus, we examined the PGF2α biosynthetic pathway and its functional impact on both cortical and medullary zones. Both compartments produced PGF2α but expressed different biosynthetic isozymes. In chromaffin cells, PGF2α secretion appeared constitutive and correlated to continuous expression of COX1 and AKR1B3. In steroidogenic cells, PGF2α secretion was stimulated by adrenocorticotropic hormone (ACTH) and correlated to ACTH-responsiveness of both COX2 and AKR1B7/B1. The pivotal role of AKR1B7 in ACTH-induced PGF2α release and functional coupling with COX2 was demonstrated using over- and down-expression in cell lines. PGF2α receptor was only detected in chromaffin cells, making medulla the primary target of PGF2α action. By comparing PGF2α-responsiveness of isolated cells and whole adrenal cultures, we demonstrated that PGF2α repressed glucocorticoid secretion by an indirect mechanism involving a decrease in catecholamine release which in turn decreased adrenal steroidogenesis. PGF2α may be regarded as a negative autocrine/paracrine regulator within a novel intra-adrenal feedback loop. The coordinated cell-specific regulation of COX2 and AKR1B7 ensures the generation of this stress-induced corticostatic signal. PMID:19809495

  1. Parturition and recruitment of macrophages in cervix of mice lacking the prostaglandin F receptor.

    PubMed

    Yellon, Steven M; Ebner, Charlotte A; Sugimoto, Yukihiko

    2008-03-01

    Parturition does not occur in transgenic mice lacking the prostaglandin F receptor (Ptgfr(-/-)) because luteolysis is forestalled and progesterone production persists. Ovariectomy of pregnant Ptgfr(-/-) mice leads to a decline in circulating progesterone and delivery of live pups. The objective of the present study was to test the hypothesis that immigration of macrophages and increased innervation of the cervix of Ptgfr(-/-) mice was associated with ripening and parturition. The cervix of pregnant Ptgfr(-/-) mice was studied on Days 15-21 after breeding; additional groups were ovariectomized on Day 19 of pregnancy, and the cervix obtained on Day 20 of pregnancy before birth or the next day at about 24 h after birth. On Days 18-19 of pregnancy, macrophage numbers and nerve fiber density increased more than 3-fold compared with findings in nonpregnant or Day 15 or 21 pregnant Ptgfr(-/-) mice. The magnitude and time course of these changes were comparable to those found in wild-type controls that delivered on Day 19 after breeding. Thus, the mechanism regulating macrophage immigration, innervation, and cervical remodeling in Ptgfr(-/-) mice with delayed parturition is similar to wild-type controls that deliver at term. By contrast, ovariectomy forestalled the decrease in cervical macrophages in Ptgfr(-/-) mice. By Day 21 after breeding, macrophage numbers more than double those after ovariectomy, relative to those found in pregnant Ptgfr(-/-) mice, whereas nerve fiber density was the same regardless of birth. Density of collagen structure in these mice directly matched macrophage traffic in the cervix. The findings indicate that the prostaglandin F(2alpha) receptor and progesterone withdrawal are a necessary part of the final common pathway for ripening of the cervix and the process of parturition.

  2. Oestradiol and prostaglandin F2α regulate sexual displays in females of a sex-role reversed fish

    PubMed Central

    Gonçalves, David; Costa, Silvia Santos; Teles, Magda C.; Silva, Helena; Inglês, Mafalda; Oliveira, Rui F.

    2014-01-01

    The mechanisms regulating sexual behaviours in female vertebrates are still poorly understood, mainly because in most species sexual displays in females are more subtle and less frequent than displays in males. In a sex-role reversed population of a teleost fish, the peacock blenny Salaria pavo, an external fertilizer, females are the courting sex and their sexual displays are conspicuous and unambiguous. We took advantage of this to investigate the role of ovarian-synthesized hormones in the induction of sexual displays in females. In particular, the effects of the sex steroids oestradiol (E2) and testosterone (T) and of the prostaglandin F2α (PGF2α) were tested. Females were ovariectomized and their sexual behaviour tested 7 days (sex steroids and PGF2α) and 14 days (sex steroids) after ovariectomy by presenting females to an established nesting male. Ovariectomy reduced the expression of sexual behaviours, although a significant proportion of females still courted the male 14 days after the ovary removal. Administration of PGF2α to ovariectomized females recovered the frequency of approaches to the male's nest and of courtship displays towards the nesting male. However, E2 also had a positive effect on sexual behaviour, particularly on the frequency of approaches to the male's nest. T administration failed to recover sexual behaviours in ovariectomized females. These results suggest that the increase in E2 levels postulated to occur during the breeding season facilitates female mate-searching and assessment behaviours, whereas PGF2α acts as a short-latency endogenous signal informing the brain that oocytes are mature and ready to be spawned. In the light of these results, the classical view for female fishes, that sex steroids maintain sexual behaviour in internal fertilizers and that prostaglandins activate spawning behaviours in external fertilizers, needs to be reviewed. PMID:24452030

  3. Oestradiol and prostaglandin F2α regulate sexual displays in females of a sex-role reversed fish.

    PubMed

    Gonçalves, David; Costa, Silvia Santos; Teles, Magda C; Silva, Helena; Inglês, Mafalda; Oliveira, Rui F

    2014-03-01

    The mechanisms regulating sexual behaviours in female vertebrates are still poorly understood, mainly because in most species sexual displays in females are more subtle and less frequent than displays in males. In a sex-role reversed population of a teleost fish, the peacock blenny Salaria pavo, an external fertilizer, females are the courting sex and their sexual displays are conspicuous and unambiguous. We took advantage of this to investigate the role of ovarian-synthesized hormones in the induction of sexual displays in females. In particular, the effects of the sex steroids oestradiol (E2) and testosterone (T) and of the prostaglandin F2α (PGF2α) were tested. Females were ovariectomized and their sexual behaviour tested 7 days (sex steroids and PGF2α) and 14 days (sex steroids) after ovariectomy by presenting females to an established nesting male. Ovariectomy reduced the expression of sexual behaviours, although a significant proportion of females still courted the male 14 days after the ovary removal. Administration of PGF2α to ovariectomized females recovered the frequency of approaches to the male's nest and of courtship displays towards the nesting male. However, E2 also had a positive effect on sexual behaviour, particularly on the frequency of approaches to the male's nest. T administration failed to recover sexual behaviours in ovariectomized females. These results suggest that the increase in E2 levels postulated to occur during the breeding season facilitates female mate-searching and assessment behaviours, whereas PGF2α acts as a short-latency endogenous signal informing the brain that oocytes are mature and ready to be spawned. In the light of these results, the classical view for female fishes, that sex steroids maintain sexual behaviour in internal fertilizers and that prostaglandins activate spawning behaviours in external fertilizers, needs to be reviewed. PMID:24452030

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

    PubMed Central

    Dubocovich, M L; Langer, S Z

    1975-01-01

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

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

    PubMed

    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.

  6. Regulation of prostaglandin E{sub 2} synthesis after brain irradiation

    SciTech Connect

    Moore, Amy H.; Olschowka, John A.; Williams, Jacqueline P.; Okunieff, Paul; O'Banion, M. Kerry . E-mail: kerry_obanion@urmc.rochester.edu

    2005-05-01

    Purpose: A local tissue reaction, termed neuroinflammation, occurs after irradiation of brain tissue. Previous work suggested that cyclooxygenase (COX)-2 activity was important for changes in gene expression associated with neuroinflammation as well as increased prostaglandin E{sub 2} (PGE{sub 2}) levels seen after radiation treatment. Methods and materials: To begin to determine the contributions of other enzymes involved in PGE{sub 2} production, we examined protein levels of COX-1 and COX-2 as well as 2 PGE synthases (membrane and cytosolic PGES) 4 h after 35 Gy single dose irradiation to the brains of C3HeN mice. We also evaluated the effects of specific COX inhibitors on PGE{sub 2} production and PGES expression. Results: As expected, COX-2 expression increased after radiation exposure. Brain irradiation also increased tissue protein levels for both PGES isoforms. Specific COX-2 inhibition with NS398 lowered brain PGE{sub 2} levels by about 60%. Surprisingly, COX-1 inhibition with SC560 completely prevented the elevation of PGE{sub 2} seen after irradiation. Interestingly, NS398 reduced the membrane-associated PGES isoform, whereas SC560 treatment lowered cytosolic isoform levels below those seen in unirradiated controls. Conclusions: Taken together, these data indicate that both cyclooxygenases contribute to PGE{sub 2} production in irradiated brain and reveal dependence of PGES isoforms expression on specific cyclooxygenase activities.

  7. Novel Roles for Hypoxia and Prostaglandin E2 in the Regulation of IL-8 During Endometrial Repair

    PubMed Central

    Maybin, Jacqueline A.; Hirani, Nikhil; Jabbour, Henry N.; Critchley, Hilary O.D.

    2011-01-01

    The endometrium has a remarkable capacity for efficient repair; however, factors involved remain undefined. Premenstrual progesterone withdrawal leads to increased prostaglandin (PG) production and local hypoxia. Here we determined human endometrial expression of interleukin-8 (IL-8) and the roles of PGE2 and hypoxia in its regulation. Endometrial biopsy specimens (n = 51) were collected. Endometrial cells and explants were exposed to 100 nmol/L of PGE2 or 0.5% O2. The endometrial IL-8 concentration peaked during menstruation (P < 0.001) and had a significant proangiogenic effect. IL-8 was increased by PGE2 and hypoxia in secretory but not proliferative explants, which suggests that exposure to progesterone is essential. In vitro progesterone withdrawal induced significant IL-8 up-regulation in proliferative explants primed with progestins, but only in the presence of hypoxia. Epithelial cells treated simultaneously with PGE2 and hypoxia demonstrated synergistic increases in IL-8. Inhibition of HIF-1 by short hairpin RNA abolished hypoxic IL-8 induction, and inhibition of NF-κB by an adenoviral dominant negative inhibitor decreased PGE2-induced IL-8 expression (P > 0.05). Increased menstrual IL-8 is consistent with a role in repair. Progesterone withdrawal, hypoxia, and PGE2 regulate endometrial IL-8 by acting via HIF-1 and NF-κB. Hence, progesterone withdrawal may activate two distinct pathways to initiate endometrial repair. PMID:21356375

  8. Biosynthesis and degradation of canine placental prostaglandins: prepartum changes in expression and function of prostaglandin F2α-synthase (PGFS, AKR1C3) and 15-hydroxyprostaglandin dehydrogenase (HPGD).

    PubMed

    Gram, Aykut; Büchler, Urs; Boos, Alois; Hoffmann, Bernd; Kowalewski, Mariusz P

    2013-07-01

    There is no distinct explanation of the mechanism for the prepartal prostaglandin F2alpha (PGF2alpha) increase in pregnant dogs. Although the PGF2alpha-synthase (PGFS [AKR1C3]) mRNA expression and localization profiles have been previously investigated in canine utero/placental compartments, the availability and biochemical activity of the PGFS (AKR1C3) protein remain unknown. In order to better understand the regulation of canine uterine PGF2alpha availability and eventual prepartum release in luteolytic amounts in dogs, canine-specific PGFS (AKR1C3) and 15-hydroxyprostaglandin dehydrogenase (HPGD) antibodies were generated and used to characterize the expression, cellular localization, and biochemical properties of PGFS (AKR1C3) and HPGD in the utero/placental compartments and corpus luteum throughout pregnancy and at prepartum luteolysis. PGFS (AKR1C3) expression was weak or absent in luteal samples. Uterine PGFS (AKR1C3) was up-regulated postimplantation and declined prepartum. The utero/placental expression of PGFS (AKR1C3) was identified in the superficial uterine glands throughout gestation and in the trophoblast cells within the feto-maternal contact zone during placentation, suggesting a possible role for PGFS (AKR1C3) in the trophoblast invasion. Utero-placental HPGD was up-regulated until postimplantation, lower at midgestation, and greatly suppressed at prepartum. Expression was routinely identified in the endometrial surface and glandular epithelia, and positive signals were also observed in the trophoblast cells at the feto-maternal contact zone. The biochemical activity of recombinant PGFS (AKR1C3) and HPGD was confirmed after its expression in a heterologous system. The colocalization of HPGD with PGFS (AKR1C3) expression suggests a modulatory role for HPGD as a gatekeeper of the supply of prostaglandin in the pregnant canine uterus.

  9. Biosynthesis and degradation of canine placental prostaglandins: prepartum changes in expression and function of prostaglandin F2α-synthase (PGFS, AKR1C3) and 15-hydroxyprostaglandin dehydrogenase (HPGD).

    PubMed

    Gram, Aykut; Büchler, Urs; Boos, Alois; Hoffmann, Bernd; Kowalewski, Mariusz P

    2013-07-01

    There is no distinct explanation of the mechanism for the prepartal prostaglandin F2alpha (PGF2alpha) increase in pregnant dogs. Although the PGF2alpha-synthase (PGFS [AKR1C3]) mRNA expression and localization profiles have been previously investigated in canine utero/placental compartments, the availability and biochemical activity of the PGFS (AKR1C3) protein remain unknown. In order to better understand the regulation of canine uterine PGF2alpha availability and eventual prepartum release in luteolytic amounts in dogs, canine-specific PGFS (AKR1C3) and 15-hydroxyprostaglandin dehydrogenase (HPGD) antibodies were generated and used to characterize the expression, cellular localization, and biochemical properties of PGFS (AKR1C3) and HPGD in the utero/placental compartments and corpus luteum throughout pregnancy and at prepartum luteolysis. PGFS (AKR1C3) expression was weak or absent in luteal samples. Uterine PGFS (AKR1C3) was up-regulated postimplantation and declined prepartum. The utero/placental expression of PGFS (AKR1C3) was identified in the superficial uterine glands throughout gestation and in the trophoblast cells within the feto-maternal contact zone during placentation, suggesting a possible role for PGFS (AKR1C3) in the trophoblast invasion. Utero-placental HPGD was up-regulated until postimplantation, lower at midgestation, and greatly suppressed at prepartum. Expression was routinely identified in the endometrial surface and glandular epithelia, and positive signals were also observed in the trophoblast cells at the feto-maternal contact zone. The biochemical activity of recombinant PGFS (AKR1C3) and HPGD was confirmed after its expression in a heterologous system. The colocalization of HPGD with PGFS (AKR1C3) expression suggests a modulatory role for HPGD as a gatekeeper of the supply of prostaglandin in the pregnant canine uterus. PMID:23677986

  10. Dietary n-3 polyunsaturated fatty acids alter the expression of genes involved in prostaglandin biosynthesis in the bovine uterus.

    PubMed

    Coyne, G S; Kenny, D A; Childs, S; Sreenan, J M; Waters, S M

    2008-09-15

    Nutrition plays a critical role in the regulation of cow fertility. There is emerging evidence that dietary long chain n-3 polyunsaturated fatty acids (LC n-3 PUFA) may act as specific regulators of some reproductive processes. In vitro studies suggest that the n-3 PUFAs, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) may play pivotal roles by suppressing the synthesis of uterine prostaglandin F(2alpha) (PGF(2alpha)) which is centrally involved in the control of the bovine oestrous cycle and in early embryo survival. The objective of the current study was to determine the effect of dietary inclusion of n-3 PUFA on uterine endometrial mRNA expression of key genes regulating PGF(2alpha) biosynthesis. Beef heifers were fed either a low (CON; n=10) or high (HIGH PUFA; n=10) n-3 PUFA diet for 45 days and endometrial tissues were harvested following slaughter. Following analysis, tissues within each dietary group were ranked on the basis of their PUFA concentrations and the highest (n=7) and lowest (n=7) within each of HIGH PUFA and CON, respectively, were used in gene expression studies. Endometrial n-3 PUFA concentrations were more than two-fold higher (P<0.05) and EPA concentrations alone more than seven-fold higher (P<0.01) in the HIGH PUFA than the CON group. Endometrial concentrations of arachidonic acid, were lower (P<0.001) in the tissues from HIGH PUFA than those from the CON group. Total RNA was isolated from all endometrial tissues and real-time reverse transcription (RT) PCR conducted to compare the relative expression of 11 genes with known involvement in uterine biosynthesis of 2-series prostaglandins. Expression of mRNA for prostaglandin E synthase (PGES) and peroxisome proliferator-activated receptors, PPAR alpha and delta was increased (P<0.05) while mRNA expression of phospholipase A(2) (PLA(2)) was decreased (P=0.06) in the HIGH PUFA endometrial tissues. Expression of genes coding for the oxytocin receptor (OTR), phospholipase C (PLC

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

    SciTech Connect

    Karlinsky, J.B.; Goldstein, R.H. )

    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.

  12. Regulation of prostaglandin production by nitric oxide; an in vivo analysis.

    PubMed Central

    Salvemini, D; Settle, S L; Masferrer, J L; Seibert, K; Currie, M G; Needleman, P

    1995-01-01

    1. Endotoxin E. Coli lipopolysaccharide (LPS)-treatment in conscious, restrained rats increased plasma and urinary prostaglandin (PG) and nitric oxide (NO) production. Inducible cyclo-oxygenase (COX-2) and nitric oxide synthase (iNOS) expression accounted for the LPS-induced PG and NO release since the glucocorticoid, dexamethasone inhibited both effects. Thus, LPS (4 mg kg-1) increased the plasma levels of nitrite/nitrate from 14 +/- 1 to 84 +/- 7 microM within 3 h and this rise was inhibited to 35 +/- 1 microM by dexamethasone. Levels of 6-keto PGF1 alpha in the plasma were below the detection limit of the assay (< 0.2 ng ml-1). However, 3 h after the injection of LPS these levels rose to 2.6 +/- 0.2 ng ml-1 and to 0.7 +/- 0.01 ng ml-1 after LPS in rats that received dexamethasone. 2. The induced enzymes were inhibited in vivo with selective COX and NOS inhibitors. Furthermore, NOS inhibitors, that did not affect COX activity in vitro markedly suppressed PG production in the LPS-treated animals. For instance, the LPS-induced increased in plasma nitrite/nitrate and 6-keto PGF1 alpha at 3 h was decreased to 18 +/- 2 microM and 0.5 +/- 0.02 ng ml-1, 23 +/- 1 microM and 0.7 +/- 0.01 ng ml-1, 29 +/- 2 microM and 1 +/- 0.01 ng ml-1 in rats treated with LPS in the presence of the NOS inhibitors NG-monomethyl-L-arginine, NG-nitro arginine methyl ester and aminoguanidine, respectively.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:7542531

  13. Estrogen receptors regulate the estrous behavior induced by progestins, peptides, and prostaglandin E2.

    PubMed

    Lima-Hernández, F J; Gómora-Arrati, P; García-Juárez, M; Blaustein, J D; Etgen, A M; Beyer, C; González-Flores, O

    2014-07-01

    The role of classical estrogen receptors (ERs) in priming female reproductive behavior has been studied previously; however, the participation of this receptor during activation of estrous behavior has not been extensively studied. The purpose of this work was to test the possibility that the facilitation of lordosis behavior in estrogen-primed rats by progesterone (P) and its 5α- and 5β-reduced metabolites, gonadotropin-releasing hormone (GnRH), leptin, prostaglandin E2 (PGE2) and vagino-cervical stimulation (VCS) involves interactions with classical ERs by using the selective ER modulator, tamoxifen. To further assess the role of ERs, we also explored the effects of the pure ER antagonist, ICI182780 (ICI), on estrous behavior induced by P and GnRH. Ovariectomized, estrogen-primed rats (5μg estradiol benzoate 40h earlier) were injected intraventricularly with the above-mentioned compounds, or they received VCS. All compounds and VCS effectively facilitated estrous behavior when tested at 60, 120 or 240min after infusion or application of VCS. Intraventricular infusion of tamoxifen (5μg), 30min before, significantly attenuated estrous behaviors induced in estradiol-primed rats by P, most of its 5α- and 5β-reduced metabolites, GnRH, and PGE2, but not by VCS. Although there was a trend for reduction, tamoxifen did not significantly decrease lordosis in females treated with 5β-pregnan-3,20-dione. ICI also inhibited lordosis behavior induced by P and GnRH at some testing intervals. These results suggest that activation of classical ERs participates in the triggering effects on estrous behavior induced by agents with different chemical structures that do not bind directly to ERs.

  14. Regulation by resveratrol of prostaglandin E2-stimulated osteoprotegerin synthesis in osteoblasts.

    PubMed

    Yamamoto, Naohiro; Tokuda, Haruhiko; Kuroyanagi, Gen; Mizutani, Jun; Matsushima-Nishiwaki, Rie; Kondo, Akira; Kozawa, Osamu; Otsuka, Takanobu

    2014-11-01

    Resveratrol is a natural polyphenol found in red grape skins, berries and red wine. Accumulating evidence suggests that resveratrol has various beneficial effects on the human body. In the present study, we investigated the effects of prostaglandin E(2) (PGE(2)) on osteoprotegerin (OPG) synthesis and the effects of resveratrol on OPG synthesis in osteoblast-like MC3T3-E1 cells. PGE(2) significantly stimulated both the release of OPG and the mRNA expression levels of OPG, as shown by OPG assay and real-time RT-PCR, respectively. Resveratrol markedly suppressed the release and the mRNA levels of OPG induced by PGE(2). On the contrary, SRT1720, an activator of sirtuin 1 (SIRT1), hardly affected the PGE(2)-induced release of OPG. PD98059 [a specific inhibitor of the upstream kinase that activates p44/p42 mitogen-activated protein (MAP) kinase], SB203580 (a specific inhibitor of p38 MAP kinase) and SP600125 [a specific inhibitor of stress-activated protein kinase/c-Jun N-terminal kinase (SAPK/JNK)], reduced the PGE(2)-induced release of OPG. Resveratrol attenuated the PGE(2)-induced phosphorylation of p44/p42 MAP kinase, p38 MAP kinase and SAPK/JNK. However, SRT1720 failed to affect the phosphorylation of p44/p42 MAP kinase, p38 MAP kinase and SAPK/JNK induced by PGE(2). These results strongly suggest that resveratrol reduces PGE(2)-stimulated OPG synthesis through the inhibition of p44/p42 MAP kinase, p38 MAP kinase and SAPK/JNK in osteoblasts, and that these suppressive effects are independent of the activation of SIRT1.

  15. Estrus synchronization and fertility behavior in Black Bengal goats following either progesterone or prostaglandin treatment.

    PubMed

    Ishwar, A K; Pandey, J N

    1990-11-01

    Thirty-six Black Bengal female goats were in the study. They were divided into three groups of 12 goats each. Group I served as the control, Group II was treated with progesterone, Group III was administered prostaglandin F2alpha. There was 100% estrus synchronization in the PGF2alpha treated group and 90% in the progesterone treated group. The total number of kids produced in the PGF2 alpha treated group was 15 followed by 12 in the progesterone - treated group and 6 in the control group. The gestation length was found to be similar in all three groups. PMID:16726900

  16. Prostaglandin E2 receptor subtype 2 regulation of scavenger receptor CD36 modulates microglial Aβ42 phagocytosis.

    PubMed

    Li, Xianwu; Melief, Erica; Postupna, Nadia; Montine, Kathleen S; Keene, C Dirk; Montine, Thomas J

    2015-01-01

    Recent studies underline the potential relevance of microglial innate immune activation in Alzheimer disease. Primary mouse microglia that lack prostaglandin E2 receptor subtype 2 (EP2) show decreased innate immune-mediated neurotoxicity and increased amyloid β (Aβ) peptide phagocytosis, features that were replicated in vivo. Here, we tested the hypothesis that scavenger receptor CD36 is an effector of EP2-regulated Aβ phagocytosis. CD36 expression was 143-fold greater in mouse primary microglia than in primary astrocytes. Three different means of suppressing EP2 signaling increased and an agonist of EP2 decreased CD36 expression in primary wild-type microglia. Activation of Toll-like receptor (TLR) 3, TLR4, and TLR7, but not TLR2 or TLR9, reduced primary microglial CD36 transcription and cell surface CD36 protein and reduced Aβ42 phagocytosis as well. At each step, the effects of innate immune activation on CD36 were reversed by at least 50% by an EP2 antagonist, and this partial rescue of microglia Aβ42 phagocytosis was largely mediated by CD36 activity. Finally, we showed in hippocampus of wild-type mice that innate immune activation suppressed CD36 expression by an EP2-dependent mechanism. Taken together with results of others that found brain clearance of Aβ peptides and behavioral improvements mediated by CD36 in mice, regulation of CD36-mediated Aβ phagocytosis by suppression of EP2 signaling may provide a new approach to suppressing some aspects of Alzheimer disease pathogenesis.

  17. Ovarian, hormonal, and reproductive events associated with synchronization of ovulation and timed appointment breeding of Bos indicus-influenced cattle using intravaginal progesterone, gonadotropin-releasing hormone, and prostaglandin F2alpha.

    PubMed

    Saldarriaga, J P; Cooper, D A; Cartmill, J A; Zuluaga, J F; Stanko, R L; Williams, G L

    2007-01-01

    The objectives of this study were to 1) compare cumulative pregnancy rates in a traditional management (TM) scheme with those using a synchronization of ovulation protocol (CO-Synch + CIDR) for timed AI (TAI) in Bos indicus-influenced cattle; 2) evaluate ovarian and hormonal events associated with CO-Synch + CIDR and CO-Synch without CIDR; and 3) determine estrual and ovulatory distributions in cattle synchronized with Select-Synch + CIDR. The CO-Synch + CIDR regimen included insertion of a controlled internal drug-releasing device (CIDR) and an injection of GnRH (GnRH-1) on d 0, removal of the CIDR and injection of PGF2alpha (PGF) on d 7, and injection of GnRH (GnRH-2) and TAI 48 h later. For Exp. 1, predominantly Brahman x Hereford (F1) and Brangus females (n = 335) were stratified by BCS, parity, and day postpartum (parous females) before random assignment to CO-Synch + CIDR or TM. To maximize the number of observations related to TAI conception rate (n = 266), an additional 96 females in which TM controls were not available for comparison also received CO-Synch + CIDR. Conception rates to TAI averaged 39 +/- 3% and were not affected by location, year, parity, AI sire, or AI technician. Cumulative pregnancy rates were greater (P < 0.05) at 30 and 60 d of the breeding season in CO-Synch + CIDR (74.1 and 95.9%) compared with TM (61.8 and 89.7%). In Exp. 2, postpartum Brahman x Hereford (F1) cows (n = 100) were stratified as in Exp. 1 and divided into 4 replicates of 25. Within each replicate, approximately one-half (12 to 13) received CO-Synch + CIDR, and the other half received CO-Synch only (no CIDR). No differences were observed between treatments, and the data were pooled. Percentages of cows ovulating to GnRH-1, developing a synchronized follicular wave, exhibiting luteal regression to PGF, and ovulating to GnRH-2 were 40 +/- 5, 60 +/- 5, 93 +/- 2, and 72 +/- 4%, respectively. In Exp. 3, primiparous Brahman x Hereford, (F1) heifers (n = 32) and pluriparous cows (n = 18) received the Select Synch + CIDR synchronization regimen (no GnRH-2 or TAI). Mean intervals from CIDR removal to estrus and ovulation, and from estrus to ovulation were 70 +/- 2.9, 99 +/- 2.8, and 29 +/- 2.2 h, respectively. These results indicate that the relatively low TAI conception rate observed with CO-Synch + CIDR in these studies was attributable primarily to failure of 40% of the cattle to develop a synchronized follicular wave after GnRH-1 and also to inappropriate timing of TAI/GnRH-2.

  18. Ovarian, hormonal, and reproductive events associated with synchronization of ovulation and timed appointment breeding of Bos indicus-influenced cattle using intravaginal progesterone, gonadotropin-releasing hormone, and prostaglandin F2alpha.

    PubMed

    Saldarriaga, J P; Cooper, D A; Cartmill, J A; Zuluaga, J F; Stanko, R L; Williams, G L

    2007-01-01

    The objectives of this study were to 1) compare cumulative pregnancy rates in a traditional management (TM) scheme with those using a synchronization of ovulation protocol (CO-Synch + CIDR) for timed AI (TAI) in Bos indicus-influenced cattle; 2) evaluate ovarian and hormonal events associated with CO-Synch + CIDR and CO-Synch without CIDR; and 3) determine estrual and ovulatory distributions in cattle synchronized with Select-Synch + CIDR. The CO-Synch + CIDR regimen included insertion of a controlled internal drug-releasing device (CIDR) and an injection of GnRH (GnRH-1) on d 0, removal of the CIDR and injection of PGF2alpha (PGF) on d 7, and injection of GnRH (GnRH-2) and TAI 48 h later. For Exp. 1, predominantly Brahman x Hereford (F1) and Brangus females (n = 335) were stratified by BCS, parity, and day postpartum (parous females) before random assignment to CO-Synch + CIDR or TM. To maximize the number of observations related to TAI conception rate (n = 266), an additional 96 females in which TM controls were not available for comparison also received CO-Synch + CIDR. Conception rates to TAI averaged 39 +/- 3% and were not affected by location, year, parity, AI sire, or AI technician. Cumulative pregnancy rates were greater (P < 0.05) at 30 and 60 d of the breeding season in CO-Synch + CIDR (74.1 and 95.9%) compared with TM (61.8 and 89.7%). In Exp. 2, postpartum Brahman x Hereford (F1) cows (n = 100) were stratified as in Exp. 1 and divided into 4 replicates of 25. Within each replicate, approximately one-half (12 to 13) received CO-Synch + CIDR, and the other half received CO-Synch only (no CIDR). No differences were observed between treatments, and the data were pooled. Percentages of cows ovulating to GnRH-1, developing a synchronized follicular wave, exhibiting luteal regression to PGF, and ovulating to GnRH-2 were 40 +/- 5, 60 +/- 5, 93 +/- 2, and 72 +/- 4%, respectively. In Exp. 3, primiparous Brahman x Hereford, (F1) heifers (n = 32) and pluriparous cows (n = 18) received the Select Synch + CIDR synchronization regimen (no GnRH-2 or TAI). Mean intervals from CIDR removal to estrus and ovulation, and from estrus to ovulation were 70 +/- 2.9, 99 +/- 2.8, and 29 +/- 2.2 h, respectively. These results indicate that the relatively low TAI conception rate observed with CO-Synch + CIDR in these studies was attributable primarily to failure of 40% of the cattle to develop a synchronized follicular wave after GnRH-1 and also to inappropriate timing of TAI/GnRH-2. PMID:17179551

  19. Prostaglandins from Cytosolic Phospholipase A2α/Cyclooxygenase-1 Pathway and Mitogen-activated Protein Kinases Regulate Gene Expression in Candida albicans-infected Macrophages.

    PubMed

    Yun, Bogeon; Lee, HeeJung; Jayaraja, Sabarirajan; Suram, Saritha; Murphy, Robert C; Leslie, Christina C

    2016-03-25

    In Candida albicans-infected resident peritoneal macrophages, activation of group IVA cytosolic phospholipase A2(cPLA2α) by calcium- and mitogen-activated protein kinases triggers the rapid production of prostaglandins I2 and E2 through cyclooxygenase (COX)-1 and regulates gene expression by increasing cAMP. InC. albicans-infected cPLA2α(-/-)or COX-1(-/-)macrophages, expression ofI l10,Nr4a2, and Ptgs2 was lower, and expression ofTnfα was higher, than in wild type macrophages. Expression was reconstituted with 8-bromo-cAMP, the PKA activator 6-benzoyl-cAMP, and agonists for prostaglandin receptors IP, EP2, and EP4 in infected but not uninfected cPLA2α(-/-)or COX-1(-/-)macrophages. InC. albicans-infected cPLA2α(+/+)macrophages, COX-2 expression was blocked by IP, EP2, and EP4 receptor antagonists, indicating a role for both prostaglandin I2 and E2 Activation of ERKs and p38, but not JNKs, by C. albicansacted synergistically with prostaglandins to induce expression of Il10,Nr4a2, and Ptgs2. Tnfα expression required activation of ERKs and p38 but was suppressed by cAMP. Results using cAMP analogues that activate PKA or Epacs suggested that cAMP regulates gene expression through PKA. However, phosphorylation of cAMP-response element-binding protein (CREB), the cAMP-regulated transcription factor involved inIl10,Nr4a2,Ptgs2, andTnfα expression, was not mediated by cAMP/PKA because it was similar inC. albicans-infected wild type and cPLA2α(-/-)or COX-1(-/-)macrophages. CREB phosphorylation was blocked by p38 inhibitors and induced by the p38 activator anisomycin but not by the PKA activator 6-benzoyl-cAMP. Therefore, MAPK activation inC. albicans-infected macrophages plays a dual role by promoting the cPLA2α/prostaglandin/cAMP/PKA pathway and CREB phosphorylation that coordinately regulate immediate early gene expression.

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

    PubMed

    Zimmer, K M; Karmazyn, M

    1997-11-01

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

  1. Prostaglandin E2 regulation of amnion cell vascular endothelial growth factor expression: relationship with intramembranous absorption rate in fetal sheep.

    PubMed

    Cheung, Cecilia Y; Beardall, Michael K; Anderson, Debra F; Brace, Robert A

    2014-08-01

    We hypothesized that prostaglandin E2 (PGE2) stimulates amniotic fluid transport across the amnion by upregulating vascular endothelial growth factor (VEGF) expression in amnion cells and that amniotic PGE2 concentration correlates positively with intramembranous (IM) absorption rate in fetal sheep. The effects of PGE2 at a range of concentrations on VEGF 164 and caveolin-1 gene expressions were analyzed in cultured ovine amnion cells. IM absorption rate, amniotic fluid (AF) volume, and PGE2 concentration in AF were determined in late-gestation fetal sheep during control conditions, isovolumic fetal urine replacement (low IM absorption rate), or intra-amniotic fluid infusion (high IM absorption rate). In ovine amnion cells, PGE2 induced dose- and time-dependent increases in VEGF 164 mRNA levels and reduced caveolin-1 mRNA and protein levels. VEGF receptor blockade abolished the caveolin-1 response, while minimally affecting the VEGF response to PGE2. In sheep fetuses, urine replacement reduced amniotic PGE2 concentration by 58%, decreased IM absorption rate by half, and doubled AF volume (P < 0.01). Intra-amniotic fluid infusion increased IM absorption rate and AF volume (P < 0.01), while amniotic PGE2 concentration was unchanged. Neither IM absorption rate nor AF volume correlated with amniotic PGE2 concentration under each experimental condition. Although PGE2 at micromolar concentrations induced dose-dependent responses in VEGF and caveolin-1 gene expression in cultured amnion cells consistent with a role of PGE2 in activating VEGF to mediate AF transport across the amnion, amniotic PGE2 at physiological nanomolar concentrations does not appear to regulate IM absorption rate or AF volume.

  2. Prostaglandin E2 Via Steroidogenic Factor-1 Coordinately Regulates Transcription of Steroidogenic Genes Necessary for Estrogen Synthesis in Endometriosis

    PubMed Central

    Attar, Erkut; Tokunaga, Hideki; Imir, Gonca; Yilmaz, M. Bertan; Redwine, David; Putman, Michael; Gurates, Bilgin; Attar, Rukset; Yaegashi, Nobuo; Hales, Dale B.; Bulun, Serdar E.

    2009-01-01

    Context: Products of at least five specific steroidogenic genes, including steroidogenic acute regulatory protein (StAR), which facilitates the entry of cytosolic cholesterol into the mitochondrion, side chain cleavage P450 enzyme, 3β-hydroxysteroid-dehydrogenase-2, 17-hydroxylase/17-20-lyase, and aromatase, which catalyzes the final step, are necessary for the conversion of cholesterol to estrogen. Expression and biological activity of StAR and aromatase were previously demonstrated in endometriosis but not in normal endometrium. Prostaglandin E2 (PGE2) induces aromatase expression via the transcriptional factor steroidogenic factor-1 (SF1) in endometriosis, which is opposed by chicken-ovalbumin upstream-transcription factor (COUP-TF) and Wilms’ tumor-1 (WT1) in endometrium. Objective: The aim of the study was to demonstrate a complete steroidogenic pathway leading to estrogen biosynthesis in endometriotic cells and the transcriptional mechanisms that regulate basal and PGE2-stimulated estrogen production in endometriotic cells and endometrium. Results: Compared with normal endometrial tissues, mRNA levels of StAR, side chain cleavage P450, 3β-hydroxysteroid-dehydrogenase-2, 17-hydroxylase/17-20-lyase, aromatase, and SF1 were significantly higher in endometriotic tissues. PGE2 induced the expression of all steroidogenic genes; production of progesterone, estrone, and estradiol; and StAR promoter activity in endometriotic cells. Overexpression of SF1 induced, whereas COUP-TFII or WT1 suppressed, StAR promoter activity. PGE2 induced coordinate binding of SF1 to StAR and aromatase promoters but decreased COUP-TFII binding in endometriotic cells. COUP-TFII or WT1 binding to both promoters was significantly higher in endometrial compared with endometriotic cells. Conclusion: Endometriotic cells contain the full complement of steroidogenic genes for de novo synthesis of estradiol from cholesterol, which is stimulated by PGE2 via enhanced binding of SF1 to promoters

  3. Prostaglandin E2 EP3 receptor regulates cyclooxygenase-2 expression in the kidney

    PubMed Central

    Quiroz-Munoz, Mariana; Cuevas, Catherina A.; Cespedes, Carlos; Ferreri, Nicholas R.

    2012-01-01

    Cyclooxygenase-2 (COX-2) is constitutively expressed and highly regulated in the thick ascending limb (TAL). As COX-2 inhibitors (Coxibs) increase COX-2 expression, we tested the hypothesis that a negative feedback mechanism involving PGE2 EP3 receptors regulates COX-2 expression in the TAL. Sprague-Dawley rats were treated with a Coxib [celecoxib (20 mg·kg−1·day−1) or rofecoxib (10 mg·kg−1·day−1)], with or without sulprostone (20 μg·kg−1·day−1). Sulprostone was given using two protocols, namely, previous to Coxib treatment (prevention effect; Sulp7-Coxib5 group) and 5 days after initiation of Coxib treatment (regression effect; Coxib10-Sulp5 group). Immunohistochemical and morphometric analysis revealed that the stained area for COX-2-positive TAL cells (μm2/field) increased in Coxib-treated rats (Sham: 412 ± 56.3, Coxib: 794 ± 153.3). The Coxib effect was inhibited when sulprostone was used in either the prevention (285 ± 56.9) or regression (345 ± 51.1) protocols. Western blot analysis revealed a 2.1 ± 0.3-fold increase in COX-2 protein expression in the Coxib-treated group, an effect abolished by sulprostone using either the prevention (1.2 ± 0.3-fold) or regression (0.6 ± 0.4-fold vs. control, P < 0.05) protocols. Similarly, the 6.4 ± 0.6-fold increase in COX-2 mRNA abundance induced by Coxibs (P < 0.05) was inhibited by sulprostone; prevention: 0.9 ± 0.3-fold (P < 0.05) and regression: 0.6 ± 0.1 (P < 0.05). Administration of a selective EP3 receptor antagonist, L-798106, also increased the area for COX-2-stained cells, COX-2 mRNA accumulation, and protein expression in the TAL. Collectively, the data suggest that COX-2 levels are regulated by a novel negative feedback loop mediated by PGE2 acting on its EP3 receptor in the TAL. PMID:22622465

  4. Regulation of human cutaneous circulation evaluated by laser Doppler flowmetry, iontophoresis, and spectral analysis: importance of nitric oxide and prostaglandines.

    PubMed

    Kvandal, Per; Stefanovska, Aneta; Veber, Mitja; Kvernmo, Hebe Désirée; Kvermmo, Hebe Désirée; Kirkebøen, Knut Arvid

    2003-05-01

    Nitric oxide (NO) and prostaglandines (PGs) are important in regulation of vascular tone and blood flow. Their contribution in human cutaneous circulation is still uncertain. We inhibited NO synthesis by infusing N(G)-monomethyl-L-arginine (L-NMMA) in the brachial artery (16 micromol/min for 5 min) and reversed it by intraarterial infusion of L-arginine (40 micromol/min for 7.5 min). PG synthesis was inhibited by the cyclooxygenase inhibitor aspirin (600 mg over 5 min intravenously). Basal cutaneous perfusion and perfusion responses during iontophoresis with the endothelium-dependent vasodilator acetylcholine (ACh) and the endothelium-independent vasodilator sodium nitroprusside (SNP) were recorded by laser Doppler flowmetry (LDF). We performed wavelet transforms of the measured signals. Mean spectral amplitude within the frequency interval from 0.0095 to 1.6 Hz and mean and normalized amplitudes of five intervals around 1, 0.3, 0.1, 0.04, and 0.01 Hz were analysed. The oscillations with frequencies around 1, 0.3, 0.1, and 0.04 Hz are influenced by the heartbeat, the respiration, the intrinsic myogenic activity of vascular smooth muscle, and the neurogenic activity of the vessel wall, respectively. We have previously shown that the oscillation with a frequency around 0.01 Hz is modulated by the vascular endothelium. L-NMMA reduced mean value of the LDF signal by approximately 20% (P = 0.0067). This reduction was reversed by L-arginine. Mean value of the LDF signals during ACh and SNP iontophoresis did not change after infusion of L-NMMA. Aspirin did not affect mean value of the LDF signal or the LDF signal during ACh or SNP iontophoresis. Before interventions the only significant difference between the effects of ACh and SNP was observed in the frequency around 0.01 Hz, where ACh increased normalized amplitude to a greater extent than SNP. L-NMMA abolished this difference, whereas it reappeared after infusion of L-arginine (P = 0.0084). Aspirin did not affect this

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

    PubMed

    Brown, R C; Poole, A

    1984-10-01

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

  6. Reduction of cervical resistance by prostaglandin suppositories prior to dilatation for induced abortion.

    PubMed

    Dingfelder, J R; Brenner, W E; Hendricks, C H; Staurovsky, L G

    1975-05-01

    Several recent reports citing increased rates of prematurity among women who have had induced first-trimester abortion suggest that forceful cervical dilatation may result in cervical incompetence in future pregnancy. There appear to be conflicting clinical impressions regarding the effectiveness on cervical softening and the reduction of cervical resistance produced by various prostaglandins. The development of the Electronic Force Monitor which is capable of precise measurement of the forces encountered in overcoming resistance during dilatation provided objective evidence with which to evaluate the effects of vaginally administered prostaglandin E2 and F2alpha suppositories. Suppositories were administered 3 hours prior to cervical dilatation, after which suction curettage was performed. Compared to the nonmedicated control group, patients receiving PGF2alpha suppositories exhibited greatly reduced cervical resistance, in some cases permitting direct introduction of the suction curette without need for any preliminary dilatation. Those patients receiving PGE2 suppositories showed an intermediate degree of cervical softening.

  7. 15-Deoxy-delta 12,14-prostaglandin J2 biphasically regulates the proliferation of mouse hippocampal neural progenitor cells by modulating the redox state.

    PubMed

    Katura, Takashi; Moriya, Takahiro; Nakahata, Norimichi

    2010-04-01

    The activity of neural progenitor cells (NPCs) is regulated by various humoral factors. Although prostaglandin (PG) D(2) is known to mediate various physiological brain functions such as sleep, its actions on NPCs have not been fully understood. In the process of investigating the effects of PGD(2) on NPCs, we found that 15-deoxy-Delta(12,14)-prostaglandin J(2) (15d-PGJ(2)), an endogenous metabolite of PGD(2), exhibits a novel regulation of the proliferation of NPCs derived from mouse hippocampus. 15d-PGJ(2) showed biphasic effects on epidermal growth factor-induced proliferation of NPCs; facilitation at low concentrations ( approximately 0.3 muM) and suppression at higher concentrations (0.5-10 microM) in vitro. 2-Chloro-5-nitrobenzanilide (GW9662), an inhibitor of peroxisome proliferator-activated receptor gamma, known to be a molecular target for 15d-PGJ(2), failed to abolish the effects of 15d-PGJ(2). 9,10-dihydro-15d-PGJ(2) (CAY10410), a structural analog of 15d-PGJ(2) lacking the electrophilic carbon in the cyclopentenone ring, did not show 15d-PGJ(2)-like actions. Treatment with 15d-PGJ(2) increased the levels of reactive oxygen species and decreased endogenous GSH levels. Furthermore, supplementation with a membrane-permeable analog of glutathione, GSH ethyl ester (2 mM), diminished the biphasic effects of 15d-PGJ(2). Finally, cell division in the dentate gyrus of postnatal mice was increased by injection of low-dose (1 ng i.c.v.) 15d-PGJ(2) and suppressed by high-dose (30 ng) 15d-PGJ(2). These results suggest that 15d-PGJ(2) regulates the proliferation of NPCs via its electrophilic nature, which enables covalent binding to molecules such as GSH. PMID:20086036

  8. MicroRNA 21 is a homeostatic regulator of macrophage polarization and prevents prostaglandin E2-mediated M2 generation.

    PubMed

    Wang, Zhuo; Brandt, Stephanie; Medeiros, Alexandra; Wang, Soujuan; Wu, Hao; Dent, Alexander; Serezani, C Henrique

    2015-01-01

    Macrophages dictate both initiation and resolution of inflammation. During acute inflammation classically activated macrophages (M1) predominate, and during the resolution phase alternative macrophages (M2) are dominant. The molecular mechanisms involved in macrophage polarization are understudied. MicroRNAs are differentially expressed in M1 and M2 macrophages that influence macrophage polarization. We identified a role of miR-21 in macrophage polarization, and found that cross-talk between miR-21 and the lipid mediator prostaglandin E2 (PGE2) is a determining factor in macrophage polarization. miR-21 inhibition impairs expression of M2 signature genes but not M1 genes. PGE2 and its downstream effectors PKA and Epac inhibit miR-21 expression and enhance expression of M2 genes, and this effect is more pronounced in miR-21-/- cells. Among potential targets involved in macrophage polarization, we found that STAT3 and SOCS1 were enhanced in miR-21-/- cells and further enhanced by PGE2. We found that STAT3 was a direct target of miR-21 in macrophages. Silencing the STAT3 gene abolished PGE2-mediated expression of M2 genes in miR-21-/- macrophages. These data shed light on the molecular brakes involved in homeostatic macrophage polarization and suggest new therapeutic strategies to prevent inflammatory responses.

  9. Selenoprotein-dependent Up-regulation of Hematopoietic Prostaglandin D2 Synthase in Macrophages Is Mediated through the Activation of Peroxisome Proliferator-activated Receptor (PPAR) γ*

    PubMed Central

    Gandhi, Ujjawal H.; Kaushal, Naveen; Ravindra, Kodihalli C.; Hegde, Shailaja; Nelson, Shakira M.; Narayan, Vivek; Vunta, Hema; Paulson, Robert F.; Prabhu, K. Sandeep

    2011-01-01

    The plasticity of macrophages is evident from their dual role in inflammation and resolution of inflammation that are accompanied by changes in the transcriptome and metabolome. Along these lines, we have previously demonstrated that the micronutrient selenium increases macrophage production of arachidonic acid (AA)-derived anti-inflammatory 15-deoxy-Δ12,14-prostaglandin J2 (15d-PGJ2) and decreases the proinflammatory PGE2. Here, we hypothesized that selenium modulated the metabolism of AA by a differential regulation of various prostaglandin (PG) synthases favoring the production of PGD2 metabolites, Δ12-PGJ2 and 15d-PGJ2. A dose-dependent increase in the expression of hematopoietic-PGD2 synthase (H-PGDS) by selenium and a corresponding increase in Δ12-PGJ2 and 15d-PGJ2 in RAW264.7 macrophages and primary bone marrow-derived macrophages was observed. Studies with organic non-bioavailable forms of selenium and the genetic manipulation of cellular selenium incorporation machinery indicated that selenoproteins were necessary for H-PGDS expression and 15d-PGJ2 production. Treatment of selenium-deficient macrophages with rosiglitazone, a peroxisome proliferator-activated receptor γ ligand, up-regulated H-PGDS. Furthermore, electrophoretic mobility shift assays indicated the presence of an active peroxisome proliferator-activated receptor-response element in murine Hpgds promoter suggesting a positive feedback mechanism of H-PGDS expression. Alternatively, the expression of nuclear factor-κB-dependent thromboxane synthase and microsomal PGE2 synthase was down-regulated by selenium. Using a Friend virus infection model of murine leukemia, the onset of leukemia was observed only in selenium-deficient and indomethacin-treated selenium-supplemented mice but not in the selenium-supplemented group or those treated with 15d-PGJ2. These results suggest the importance of selenium in the shunting of AA metabolism toward the production of PGD2 metabolites, which may have

  10. Crypt stem cell survival in the mouse intestinal epithelium is regulated by prostaglandins synthesized through cyclooxygenase-1.

    PubMed Central

    Cohn, S M; Schloemann, S; Tessner, T; Seibert, K; Stenson, W F

    1997-01-01

    Prostaglandins (PGs) are important mediators of epithelial integrity and function in the gastrointestinal tract. Relatively little is known, however, about the mechanism by which PGs affect stem cells in the intestine during normal epithelial turnover, or during wound repair. PGs are synthesized from arachidonate by either of two cyclooxygenases, cyclooxygenase-1 (Cox-1) or cyclooxygenase-2 (Cox-2), which are present in a wide variety of mamalian cells. Cox-1 is thought to be a constitutively expressed enzyme, and the expression of Cox-2 is inducible by cytokines or other stimuli in a variety of cell types. We investigated the role of PGs in mouse intestinal stem cell survival and proliferation following radiation injury. The number of surviving crypt stem cells was determined 3.5 d after irradiation by the microcolony assay. Radiation injury induced a dose-dependent decrease in the number of surviving crypts. Indomethacin, an inhibitor of Cox-1 and Cox-2, further reduced the number of surviving crypts in irradiated mice. The indomethacin dose response for inhibition of PGE2 production and reduction of crypt survival were similar. DimethylPGE2 reversed the indomethacin-induced decrease in crypt survival. Selective Cox-2 inhibitors had no effect on crypt survival. PGE2, Cox-1 mRNA, and Cox-1 protein levels all increase in the 3 d after irradiation. Immunohistochemistry for Cox-1 demonstrated localization in epithelial cells of the crypt in the unirradiated mouse, and in the regenerating crypt epithelium in the irradiated mouse. We conclude that radiation injury results in increased Cox-1 levels in crypt stem cells and their progeny, and that PGE2 produced through Cox-1 promotes crypt stem cell survival and proliferation. PMID:9077547

  11. Prostaglandin F2α-F-prostanoid receptor regulates CXCL8 expression in endometrial adenocarcinoma cells via the calcium–calcineurin–NFAT pathway

    PubMed Central

    Sales, Kurt J.; Maldonado-Pérez, David; Grant, Vivien; Catalano, Rob D.; Wilson, Martin R.; Brown, Pamela; Williams, Alistair R.W.; Anderson, Richard A.; Thompson, E. Aubrey; Jabbour, Henry N.

    2009-01-01

    Pro-inflammatory mediators, like prostaglandin (PG) and chemokines, promote tumourigenesis by enhancing cell proliferation, migration of immune cells and recruitment of blood vessels. Recently we showed elevated expression of the chemokine (C-X-C motif) receptor 2 (CXCR2) in endometrial adenocarcinomas localized to neutrophils and neoplastic epithelial and vascular cells. Furthermore we found that PGF2α-F-prostanoid (FP) receptor regulates the expression of the CXCR2 ligand CXCL1, to promote neutrophil chemotaxis in endometrial adenocarcinomas. In the present study we identified another CXCR2 ligand, CXCL8 as a target for PGF2α-FP receptor signalling which enhances epithelial cell proliferation in endometrial adenocarcinoma cells in vitro and in nude mice in vivo. We found that PGF2α-FP receptor interaction induces CXCL8 expression in endometrial adenocarcinoma cells via the protein kinase C–calcium–calcineurin–NFAT signaling pathway. Promoter analysis revealed that CXCL8 transcriptional activation by PGF2α signaling is mediated by cooperative interactions between the AP1 and NFAT binding sites. Furthermore, PGF2α via the FP receptor induced the expression of the regulator of calcineurin 1 isoform 4 (RCAN1-4) via the calcineurin/NFAT pathway in a reciprocal manner to CXCL8. Using an adenovirus to overexpress RCAN1-4, we found that RCAN1-4 is a negative regulator of CXCL8 expression in endometrial adenocarcinoma cells. Taken together our data have elucidated the molecular and cellular mechanism whereby PGF2α regulates CXCL8 expression via the FP receptor in endometrial adenocarcinomas and have highlighted RCAN1-4 as a negative regulator of CXCL8 expression which may be exploited therapeutically to inhibit CXCL8-mediated tumour development. PMID:19819266

  12. Changes in the prostaglandin levels in alcohol toxicity: effect of curcumin and N-acetylcysteine.

    PubMed

    Rajakrishnan, V; Jayadeep, A; Arun, O S; Sudhakaran, P R; Menon, V P

    2000-10-01

    The present study was undertaken to evaluate the potential role of curcumin, the antioxidant principal from Curcuma longa Linn., and the sulphur-containing amino acid N-acetylcysteine against ethanol-induced changes in the levels of prostanoids. Biochemical assessment of liver damage was done by measuring the activities of serum enzymes (i.e., aspartate transaminase and alkaline phosphatase), which were significantly increased in rats fed ethanol, whereas the elevated levels of these enzymes were decreased after curcumin and N-acetylcysteine treatment to rats fed ethanol. We observed a significant increase in the levels of prostaglandins E(1), E(2), F(2alpha), and D(2) in liver, kidney, and brain. Administration of curcumin and N-acetylcysteine was shown to decrease the level of these prostanoids in the tissue studied. PMID:11120449

  13. Gene transcription of TLR2, TLR4, LPS ligands and prostaglandin synthesis enzymes are up-regulated in canine uteri with cystic endometrial hyperplasia-pyometra complex.

    PubMed

    Silva, E; Leitão, S; Henriques, S; Kowalewski, M P; Hoffmann, B; Ferreira-Dias, G; da Costa, L Lopes; Mateus, L

    2010-01-01

    Escherichia coli (E. coli) is the most frequent bacterium isolated in cases of cystic endometrial hyperplasia-pyometra complex, the most frequent endometrial disorder in the bitch. Toll-like receptors (TLRs) play an essential role in the innate immune system. The aim of this study was to compare transcription of genes encoding TLR2, TLR4 and LPS ligands (CD14, MD-2, LBP), prostaglandin synthesis enzymes (COX1, COX2, PGES1 and PGFS), and to compare COX1 and COX2 protein expression and PGE(2) and PGF(2alpha) endometrial content in the endometrium of canine diestrous uteri with (n=7) or without (n=7) pyometra. All cases of pyometra were hyperplastic and E. coli was the only isolated bacteria, while diestrous normal uteri did not present signs of cystic endometrial hyperplasia and were negative for bacteriology. Except for COX1, transcription of all genes was significantly higher in pyometra than in normal endometria. COX1 protein was observed in both normal and pyometra uteri, but COX2 protein was only present in pyometra cases. Endometrial PGE(2) and PGF(2alpha) content were significantly higher in pyometra than in normal diestrous endometria. In conclusion, data obtained in this study provides evidence that pyometra-isolated E. coli induces the up-regulation of TLR2 and TLR4 genes in the canine diestrous endometrium. This up-regulation, which is probably the result of the stimulation by LPS and lipoprotein E. coli constituents, leads to the endometrial up-regulation of PG synthesis genes. This, in turn, results in a higher endometrial concentration of PGE(2) and PGF(2alpha), which may further regulate the local inflammatory response. PMID:19945173

  14. Factors regulating ovarian function in pigs.

    PubMed

    Madej, A; Lang, A; Brandt, Y; Kindahl, H; Madsen, M T; Einarsson, S

    2005-08-01

    The hormonal interactions of the hypothalamic-pituitary-ovarian-uterine axis are accountable for a normal reproduction in female pigs. It is of importance to have knowledge of estrous symptoms and hormonal profiles around ovulation. The introduction of the transrectal ultrasonography in sows has given us the possibility to study ovarian activity in conscious animals and relate the timing of estrus to ovulation. Combining this technique with measuring of several hormones like luteinizing hormone (LH), follicle-stimulating hormone (FSH), inhibin, estradiol, progesterone, insulin-like growth hormone I (IGF-I), prostaglandin F2alpha (PGF2alpha) metabolite, oxytocin, facilitate our knowledge about the sequence of ovarian events. Evidence suggests that activation of the hypothalamic-pituitary-adrenal axis may hamper the normal gonadotropin secretion and in consequence, the ovarian function. The metabolic status during lactation, weaning of piglets and social stress might affect onset of ovarian activity and the related estrous behavior. The role of seminal plasma, artificial insemination and presence of the boar might also be included as factors regulating the temporal kinetics of ovulation, corpus luteum development, uterine function and steroid production in the ovary. Studies using a simulated stress by means of adrenocorticotrophic hormone (ACTH) administration or food deprivation are tools in understanding how the ovary is susceptible to impairment. The intention of this paper is to review current knowledge concerning the endocrine aspects of normal and stress-influenced ovarian function in pigs.

  15. Regulation of the Na,K-ATPase in MDCK cells by prostaglandin E1: a role for calcium as well as cAMP.

    PubMed

    Taub, Mary; Borsick, Maryanne; Geisel, Janet; Matlhagela, Keikantse; Rajkhowa, Trivikram; Allen, Cheryl

    2004-09-10

    Prostaglandins (PGs) play a significant role in the regulation of sodium reabsorption by the kidney, in addition to accumulating during inflammation as well as in several solid tumors. Previously, we presented evidence indicating that prostaglandin E(1) (PGE(1)), a supplement in the serum-free medium for MDCK cells, increases the activity of the Na,K-ATPase in MDCK cells, in addition to its growth stimulatory effect [J. Cell. Physiol. 151 (1992) 337]. This report defines the molecular mechanisms, and signaling pathways responsible for the increased Na,K-ATPase activity. Our results indicate that the increased activity of the Na,K-ATPase in MDCK monolayers treated with either PGE(1) or 8Bromocyclic AMP (8Br-cAMP) can be attributed to an increase in the rate of biosynthesis of the Na,K-ATPase, and an increase in the levels of Na,K-ATPase alpha and beta subunit mRNAs. As beta subunit mRNA increased to a larger extent than alpha subunit mRNA, transient transfection studies were conducted using a human beta1 promoter/luciferase construct [Nucleic Acids Res. 21 (1993) 2619]. While an 8Br-cAMP stimulation was observed (suggesting the involvement of cAMP), our results also suggest that the observed PGE(1) stimulation could be explained by the involvement of Ca(2+) as well protein kinase C (PKC). Consistent with the involvement of Ca(2+), TMB-8 (which inhibits Ca(2+) efflux from intracellular stores) inhibited the PGE(1) stimulation. Moreover, PGE(1) was observed to stimulate the translocation of PKC beta1 from the soluble to the particulate fraction. The translocation of PKC, the PGE(1) stimulation of transcription, and the PGE(1)-mediated increase in the beta subunit mRNA level were all inhibited by the PKC inhibitor Gö6989. These results can be explained by the involvement of two classes of cell surface receptors in mediating the PGE(1) stimulation, including the EP1subtype (which activates phospholipase C), as well as the EP2 subtype (which activates adenylate cyclase).

  16. Cell cycle arrest by prostaglandin A1 at the G1/S phase interface with up-regulation of oncogenes in S-49 cyc- cells

    NASA Technical Reports Server (NTRS)

    Hughes-Fulford, M.

    1994-01-01

    Our previous studies have implied that prostaglandins inhibit cell growth independent of cAMP. Recent reports, however, have suggested that prostaglandin arrest of the cell cycle may be mediated through protein kinase A. In this report, in order to eliminate the role of c-AMP in prostaglandin mediated cell cycle arrest, we use the -49 lymphoma variant (cyc-) cells that lack adenylate cyclase activity. We demonstrate that dimethyl prostaglandin A1 (dmPGA1) inhibits DNA synthesis and cell growth in cyc- cells. DNA synthesis is inhibited 42% by dmPGA1 (50 microM) despite the fact that this cell line lacks cellular components needed for cAMP generation. The ability to decrease DNA synthesis depends upon the specific prostaglandin structure with the most effective form possessing the alpha, beta unsaturated ketone ring. Dimethyl PGA1 is most effective in inhibiting DNA synthesis in cyc- cells, with prostaglandins PGE1 and PGB1 being less potent inhibitors of DNA synthesis. DmPGE2 caused a significant stimulation of DNA synthesis. S-49 cyc- variant cells exposed to (30-50 microns) dmPGA1, arrested in the G1 phase of the cell cycle within 24 h. This growth arrest was reversed when the prostaglandin was removed from the cultured cells; growth resumed within hours showing that this treatment is not toxic. The S-49 cyc- cells were chosen not only for their lack of adenylate cyclase activity, but also because their cell cycle has been extensively studied and time requirements for G1, S, G2, and M phases are known. Within hours after prostaglandin removal the cells resume active DNA synthesis, and cell number doubles within 15 h suggesting rapid entry into S-phase DNA synthesis from the G1 cell cycle block.(ABSTRACT TRUNCATED AT 250 WORDS).

  17. 15-Deoxy-{delta}{sup 12,14}-prostaglandin J{sub 2}-induced down-regulation of endothelial nitric oxide synthase in association with HSP70 induction

    SciTech Connect

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

    2007-05-25

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

  18. 15-Deoxy-{delta}{sup 12,14}-Prostaglandin J{sub 2} regulates leukemia inhibitory factor signaling through JAK-STAT pathway in mouse embryonic stem cells

    SciTech Connect

    Rajasingh, Johnson; Bright, John J. . E-mail: jbright1@clarian.org

    2006-08-01

    Embryonic stem (ES) cells are genetically normal, pluripotent cells, capable of self-renewal and differentiation into all cell lineages. While leukemia inhibitory factor (LIF) maintains pluripotency in mouse ES cells, retinoic acid and other nuclear hormones induce neuro-glial differentiation in mouse and human ES cells in culture. Peroxisome-proliferator-activated receptors (PPARs) are ligand-dependent nuclear receptor transcription factors that regulate cell growth and differentiation in many cell types. However, the role of PPARs in the regulation of ES cell growth and differentiation is not known. In this study, we show that LIF induces proliferation and self-renewal of mouse D3-ES cells in culture. However, treatment with 15-Deoxy-{delta}{sup 12,14}-Prostaglandin J{sub 2} (15d-PGJ2), a natural ligand for PPAR{gamma}, or all-trans retinoic acid (ATRA) results in a dose-dependent decrease in proliferation and self-renewal in D3-ES cells. Immunoprecipitation and Western blot analyses showed that LIF induces tyrosine phosphorylation of JAK1, TYK2 and STAT3 in 30 min and treatment with 15d-PGJ2 or ATRA results in a dose-dependent decrease in LIF-induced phosphorylation of JAK1 and STAT3 in D3-ES cells. However, treatment of D3-ES cells with Ciglitazone or 15d-PGJ2 for 48 h in culture resulted in a dose-dependent increase in PPAR{gamma} protein expression. These results suggest that PPAR{gamma} agonists regulate LIF signaling through JAK-STAT pathway leading to growth and self-renewal of ES cells.

  19. Role of protein kinase A in collagenase-1 gene regulation by prostaglandin E1: studies in a rabbit synoviocyte cell line, HIG-82.

    PubMed

    Suzuki, K; Rapuano, B E; Bockman, R S

    1997-04-01

    Gene expression of the matrix-degrading enzyme collagenase-1 in rabbit synoviocytes and human fibroblasts is down-regulated by prostaglandin E1 (PGE1) through a cyclic adenosine monophosphate (cAMP)-dependent pathway. In the current study, we examined the role of protein kinase A (PKA) in the PGE1-mediated effect on collagenase-1 gene expression. Collagenase-1 gene expression was rapidly induced several-fold above control both by a phorbol ester, 12-o-tetradecanoyl phorbol 13 acetate, and interleukin-1 beta (IL-1 beta) in HIG-82 synoviocytes. Treatment with PGE1 and forskolin increased PKA activity in the HIG-82 cells within 15 minutes of adding the stimulating agents. Two inhibitors of PKA, the isoquinoline-sulfonamide derivative, H-89 and a cAMP analog, RpcAMP, blocked the ability of PGE1 to down-regulate collagenase-1 gene expression. However, if PGE1 was added from 6 h to 30 minutes before the PKA inhibitor H-89, collagenase-1 gene expression was inhibited. Constitutive PKA activity was increased in HIG-82 synoviocytes stably transfected with an expression vector pCMV.C alpha that caused the HIG-82 cells to overexpress an active catalytic subunit of PKA. Cells stably transfected with an inactive, mutated C-alpha-variant showed no change in PKA activity. Collagenase-1 mRNA levels in TPA-stimulated cells were reduced to baseline levels in the pCMV.C alpha but not in the mutated C-alpha-transfected cells. These data show the importance of PKA in regulating collagenase-1 gene expression in a synoviocyte cell line.

  20. MAP kinase phosphatase-1 expression is regulated by 15-deoxy-Δ12,14-prostaglandin J2 via a HuR-dependent post-transcriptional mechanism.

    PubMed

    Woo, Joo Hong; Lee, Jee Hoon; Kim, Hyunmi; Choi, Yuree; Park, Sang Myun; Joe, Eun-hye; Jou, Ilo

    2015-06-01

    In the present study, we demonstrate a mechanism through which 15-deoxy-Δ(12,14)-prostaglandin J2 (15d-PGJ2) induces MKP-1 expression in rat primary astrocytes, leading to the regulation of inflammatory responses. We show that 15d-PGJ2 enhances the efficiency of MKP-1 pre-mRNA processing (constitutive splicing and 3'-end processing) and increases the stability of the mature mRNA. We further report that this occurs via the RNA-binding protein, Hu antigen R (HuR). Our experiments show that HuR knockdown abrogates the 15d-PGJ2-induced increases in the pre-mRNA processing and mature mRNA stability of MKP-1, whereas HuR overexpression further enhances the 15d-PGJ2-induced increases in these parameters. Using cysteine (Cys)-mutated HuR proteins, we show that the Cys-245 residue of HuR (but not Cys-13 or Cys-284) is critical for the direct binding of HuR with 15d-PGJ2 and the effects downstream of this interaction. Collectively, our data show that HuR is a novel target of 15d-PGJ2 and reveal HuR-mediated pre-mRNA processing and mature mRNA stabilization as important regulatory steps in the 15d-PGJ2-induced expression of MKP-1. The potential to use a small molecule such as 15d-PGJ2 to regulate the induction of MKP-1 at multiple levels of gene expression could be exploited as a novel therapeutic strategy aimed at combating a diverse range of MKP-1-associated pathologies.

  1. Prostamides (prostaglandin-ethanolamides) and their pharmacology.

    PubMed

    Woodward, D F; Liang, Y; Krauss, A H-P

    2008-02-01

    The prostamides are part of a large and continually expanding series of pharmacologically unique neutral lipids. They are COX-2 derived oxidation products of the endocannabinoid/endovanniloid anandamide. Prostamide pharmacology is unique and, as in the case of the endocannabinoids anandamide and 2-arachidonylglycerol, bears little resemblance to that of the corresponding free acids. By virtue of its close relationship to the anti-glaucoma drug bimatoprost, prostamide F(2alpha) has received the greatest research attention. Prostamide F(2alpha) and bimatoprost effects appear independent of prostanoid FP receptor activation, according to a litany of agonist studies. Studies involving freshly isolated and separate feline iridial smooth muscle cells revealed that bimatoprost and FP receptor agonists stimulated different cells, without exception. This suggests the existence of receptors that preferentially recognize prostamide F(2alpha). The recent discovery of prostamide antagonists has provided further support for prostamide receptors as discrete entities. The prototypical prostamide antagonists, AGN 204396 and 7, blocked the effects of prostamide F(2alpha) and bimatoprost but not those of PGF(2alpha) and FP receptor agonists in the feline iris. Second generation more potent prostamide antagonists, such as AGN 211334, should allow the role of prostamides in health and disease to be elucidated. From the therapeutics standpoint, the prostamide F(2alpha) analogue bimatoprost is the most efficacious ocular hypotensive agent currently available for the treatment of glaucoma. PMID:17721551

  2. Cannabinoid Receptor-2 Regulates Embryonic Hematopoietic Stem Cell Development via Prostaglandin E2 and P-Selectin Activity.

    PubMed

    Esain, Virginie; Kwan, Wanda; Carroll, Kelli J; Cortes, Mauricio; Liu, Sarah Y; Frechette, Gregory M; Sheward, Lea M V; Nissim, Sahar; Goessling, Wolfram; North, Trista E

    2015-08-01

    Cannabinoids (CB) modulate adult hematopoietic stem and progenitor cell (HSPCs) function, however, impact on the production, expansion, or migration of embryonic HSCs is currently uncharacterized. Here, using chemical and genetic approaches targeting CB-signaling in zebrafish, we show that CB receptor (CNR) 2, but not CNR1, regulates embryonic HSC development. During HSC specification in the aorta-gonad-mesonephros (AGM) region, CNR2 stimulation by AM1241 increased runx1;cmyb(+) HSPCs, through heightened proliferation, whereas CNR2 antagonism decreased HSPC number; FACS analysis and absolute HSC counts confirmed and quantified these effects. Epistatic investigations showed AM1241 significantly upregulated PGE2 synthesis in a Ptgs2-dependent manner to increase AGM HSCs. During the phases of HSC production and colonization of secondary niches, AM1241 accelerated migration to the caudal hematopoietic tissue (CHT), the site of embryonic HSC expansion, and the thymus; however these effects occurred independently of PGE2. Using a candidate approach for HSC migration and retention factors, P-selectin was identified as the functional target of CNR2 regulation. Epistatic analyses confirmed migration of HSCs into the CHT and thymus was dependent on CNR2-regulated P-selectin activity. Together, these data suggest CNR2-signaling optimizes the production, expansion, and migration of embryonic HSCs by modulating multiple downstream signaling pathways.

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

    PubMed

    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

  4. Prostaglandins as abortifacients.

    PubMed

    Karim, S M

    1971-12-30

    Clinical trials have demonstrated the use of prostaglandins as effective abortifacients. Continuous intravenous infusion of the drugs however has been associated with certain side effects at therapeutically effective doses, such as nausea, vomiting, diarrhea and a local erythematous reaction at the site of venepuncture. Higher doses result in more serious side effects such as vasovagal symptoms, pyrexia and tachycardia. Direct application of prostaglandins E2 or F2a into the uterine cavity has been shown to minimize the side effects. Appropriate doses of prostaglandins every one or 2 hours administered at the site of action between the fetal membrane and uterine wall (via the cervix) produce the strong and frequent uterine contractions necessary for the expulsion of the products of conception. A drawback of this method is the need for the uterine cavity to be continuously monitored as dosage is determined by the uterine response. Another effective method of terminating 1st and 2nd trimester pregnacy with minimal side effects is vaginal administration (into the posterior fornix) of 50 mg PGF2a or 20 mg PGE2 every 2 or 3 hours. Single injection of prostaglandins into the amniotic sac usually results in complete abortion. The method is simple but should be used only in pregnancies of over 12 weeks' gestation as the amniotic sac is inaccessible in the 1st trimester. The prostaglandin method, compared with other methods of abortion in the 1st trimester of pregnancy (e.g., suction or dilatation and curettage) is inferior in terms of time, expense and convenience. Incomplete abortion is quite common in the 1st trimester when prostaglandins are used. With respect to 2nd trimester methods (hypertonic saline and hysterotomy) however, prostaglandins given by intravaginal, intrauterine, or intraamniotic routes offer clear advantages.

  5. The Enteropathy of Prostaglandin Deficiency

    PubMed Central

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

    2009-01-01

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

  6. Endometrial oxytocin receptor and uterine prostaglandin secretion in mares during the oestrous cycle and early pregnancy.

    PubMed

    Starbuck, G R; Stout, T A; Lamming, G E; Allen, W R; Flint, A P

    1998-07-01

    Circulating concentrations of 13,14-dihydro-15-ketoprostaglandin F2 alpha (PGFM) were measured before and after administration of oxytocin and after endometrial biopsy, with or without uterine flushing performed per vaginam, on days 10, 14 and 18 after ovulation in nine pregnant and nine cyclic mares. Concentrations of oxytocin receptor were measured in endometrial biopsy samples. Neither pregnancy status nor time after ovulation affected basal PGFM concentrations. PGFM concentrations were increased after oxytocin administration on each of the days studied in cyclic mares; on day 14 the mean response was 4.5 times higher than the mean response on days 10 and 18. In contrast, during pregnancy, responses to oxytocin administration occurred only on days 10 and 18. Marked increases in PGFM concentrations in response to endometrial biopsy occurred only on day 14 in cyclic mares and on day 18 in pregnant mares. Mean concentrations of oxytocin receptor were between 200 and 300 fmol mg-1 protein on day 10 in both pregnant and cyclic mares; in cyclic mares oxytocin receptor concentrations were increased approximately threefold on day 14 compared with days 10 and 18, but no such increase was evident during pregnancy. Total amounts of PGFM secreted after oxytocin treatment correlated with endometrial oxytocin receptor concentrations in cyclic (P < 0.001) but not in pregnant (P > 0.5) mares, and the same was true for PGFM release induced by endometrial biopsy (cyclic: P = 0.0025; pregnant: P > 0.5). The data support the hypothesis that endometrial concentrations of oxytocin receptor determine uterine prostaglandin F2 alpha secretion in cyclic mares and that endometrial oxytocin receptor concentrations are reduced in early pregnancy by a product of the conceptus. The increase in response of the pregnant uterus to oxytocin treatment or biopsy-flushing between days 14 and 18 was not due to an increase in the concentration of oxytocin receptors but presumably reflected increased

  7. Pharmacological inhibition of interleukin-1 activity on T cells by hydrocortisone, cyclosporine, prostaglandins, and cyclic nucleotides.

    PubMed

    Tracey, D E; Hardee, M M; Richard, K A; Paslay, J W

    1988-01-01

    The effects of a panel of hormones and pharmacological agents on the activation of T cells by a combination of interleukin-1 and phytohemagglutinin (IL-1/PHA) was studied. Pharmacological effects on various stages of IL-1/PHA-induced interleukin-2 (IL-2) production by the cloned murine thymoma cell line LBRM-33-1A5.7 were dissected using a multi-step assay procedure. A 4-h lag phase in the kinetics of IL-2 production allowed the operational definition of an early, IL-1-dependent programming stage, followed by an IL-2-production stage of the assay. A cell-washing procedure between these stages was introduced in order to distinguish IL-1 receptor antagonists from functional IL-1/PHA antagonists. Hydrocortisone and cyclosporine were potent inhibitors (active in the nM range) of both stages of IL-2 production, suggesting that neither is an IL-1 receptor antagonist. The cyclic adenosine monophosphate (cAMP)-elevating agents prostaglandin E2, dibutyryl cAMP, and theophylline inhibited IL-2 production during the early, IL-1-dependent programming stage. By contrast, prostaglandin F2 alpha and dibutyryl cyclic guanosine monophosphate did not appreciably inhibit IL-1/PHA activity. These results are discussed in relationship to the effects of these test agents in thymocyte IL-1 assays or mitogenesis assays and the implications toward understanding the mechanisms underlying IL-1/PHA activation of T cells.

  8. Oestrus synchronisation and fertility in black Bengal goats following administration of progesterone/prostaglandin and gonadotrophins.

    PubMed

    Ishwar, A K; Pandey, J N

    1992-03-01

    Oestrus synchronisation, fertility and kidding behaviour were studied in 44 Black Bengal goats. They were divided into six experimental groups: group 1, control; group 2, progesterone; group 3, progesterone, pregnant mare serum gonadotrophin (PMSG) and human chorionic gonadotrophin (HCG); group 4, prostaglandin F2 alpha (PGF2 alpha); group 5, PGF2 alpha, PMSG and HCG; group 6, PMSG and HCG. There was 100 per cent synchronisation of oestrus in the groups treated with progesterone, progesterone with PMSG and HCG, and prostaglandin with PMSG and HCG. In the other two treated groups the synchronisation was between 66 and 75 per cent. In the control group only 50 per cent of the animals came into oestrus during the period of observation. The duration of oestrus varied between 19 and 24 hours except in group 5 where it was 40.87 hours. Animals came on heat between 95 and 137 hours after treatment except in group 5 where the interval was only 18.87 hours. A maximum fertility of 75 per cent was observed in group 4 while the kidding percentage was greatest in group 2. There appeared to be no beneficial effect of superovulation on the number of kids produced. Gestation length was similar in all the groups. PMID:1585072

  9. Absorption and elimination of a prostaglandin F analog, fenprostalene, in lactating dairy cows

    SciTech Connect

    Tomlinson, R.V.; Spires, H.R.; Bowen, J.L.

    1985-08-01

    Pharmacokinetic characteristics of the prostaglandin F2 alpha analog, fenprostalene, were studied in five lactating Holstein cows. Blood samples, milk, urine, and feces were collected for up to 7 d following a single subcutaneous injection of 1 mg of 13,14-hydrogen-3-fenprostalene in polyethylene glycol-400. The maximum concentration of tritium in plasma was observed 4 h after injection and declined by 48 h. Likewise, milk contained .53 ngeq/ml fenprostalene at 4 h and the concentration declined with a fractional disappearance rate of .069 X h to less than .03 ngeq/ml by 48 h. Milk was a very minor route of elimination of fenprostalene. Recovery of tritium in urine accounted for 55% of the total dose and recovery in feces accounted for an additional 43%. Residues from fenprostalene at 7 d after injection were less than .1 ppb in all edible tissues. Differences in the molecular structure, formulation, and route of injection of fenprostalene resulted in a slower rate of absorption and elimination of this analog than previously reported for other prostaglandin products. Nonetheless, the percentage of the injected dose of fenprostalene secreted in milk was not increased appreciably, and no persistent tissue residues of fenprostalene were observed.

  10. ERG oncogene modulates prostaglandin signaling in prostate cancer cells.

    PubMed

    Mohamed, Ahmed A; Tan, Shyh-Han; Sun, Chen; Shaheduzzaman, Syed; Hu, Ying; Petrovics, Gyorgy; Chen, Yongmei; Sesterhenn, Isabell A; Li, Hua; Sreenath, Taduru; McLeod, David G; Dobi, Albert; Srivastava, Shiv

    2011-02-15

    Androgen dependent induction of the ETS related gene (ERG) expression in more than half of all prostate cancers results from gene fusions involving regulatory sequence of androgen regulated genes (i.e. TMPRSS2, SLC45A3 and NDRG1) and protein coding sequence of the ERG. Emerging studies in experimental models underscore the functions of ERG in prostate tumorigenesis. However, biological and biochemical functions of ERG in prostate cancer (CaP) remain to be elucidated. This study suggests that ERG activation plays a role in prostaglandin signaling because knockdown of ERG expression in TMPRSS2-ERG fusion containing CaP cells leads to altered levels of the 15-hydroxy-prostaglandin dehydrogenase (HPGD), a tumor suppressor and prostaglandin catabolizing enzyme, and prostaglandin E2 (PGE2) . We demonstrate that HPGD expression is regulated by the binding of the ERG protein to the core promoter of this gene. Moreover, prostaglandin E2 dependent cell growth and urokinase-type plasminogen activator (uPA) expression are also affected by ERG knockdown. Together, these data imply that the ERG oncoprotein in CaP cells positively influence prostaglandin mediated signaling, which may contribute to tumor progression. PMID:21178489

  11. Histamine and prostaglandin E2 up-regulate the production of Th2-attracting chemokines (CCL17 and CCL22) and down-regulate IFN-γ-induced CXCL10 production by immature human dendritic cells

    PubMed Central

    McIlroy, Anne; Caron, Gersende; Blanchard, Simon; Frémaux, Isabelle; Duluc, Dorothée; Delneste, Yves; Chevailler, Alain; Jeannin, Pascale

    2006-01-01

    Effector memory T helper 2 (Th2) cells that accumulate in target organs (i.e. skin or bronchial mucosa) have a central role in the pathogenesis of allergic disorders. To date, the factors that selectively trigger local production of Th2-attracting chemokines remain poorly understood. In mucosa, at the sites of allergen entry, immature dendritic cells (DC) are in close contact with mast cells. Histamine and prostaglandin E2 (PGE2) are two mediators released by allergen-activated mast cells that favour the polarization of maturing DC into Th2-polarizing cells. We analysed here the effects of histamine and PGE2 on the prototypic, Th2-(CCL17, CCL22) versus Th1-(CXCL10) chemokine production by human DC. We report that histamine and PGE2 dose-dependently up-regulate CCL17 and CCL22 by monocyte-derived immature DC. These effects were potentiated by tumour necrosis factor-α, still observed in the presence of the Th1-cytokine interferon-γ (IFN-γ) and abolished by the immunomodulatory cytokine interleukin-10. In addition, histamine and PGE2 down-regulated IFN-γ-induced CXCL10 production by monocyte-derived DC. These properties of histamine and PGE2 were observed at the transcriptional level and were mediated mainly through H2 receptors for histamine and through EP2 and EP4 receptors for PGE2. Finally, histamine and PGE2 also up-regulated CCL17 and CCL22 and decreased IFN-γ-induced CXCL10 production by purified human myeloid DC. In conclusion, these data show that, in addition to polarizing DC into mature cells that promote naïve T-cell differentiation into Th2 cells, histamine and PGE2 may act on immature DC to trigger local Th2 cell recruitment through a selective control of Th1/Th2-attracting chemokine production, thereby contributing to maintain a microenvironment favourable to persistent immunoglobulin E synthesis. PMID:16556265

  12. Misidentification of prostamides as prostaglandins.

    PubMed

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

    2005-07-01

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

  13. Plasmodium falciparum produces prostaglandins that are pyrogenic, somnogenic, and immunosuppressive substances in humans.

    PubMed

    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. PMID:9743538

  14. Peripartal changes of estrone, progesterone and prostaglandin in the water buffalo.

    PubMed

    Perera, B M; Abeygunawardena, H; Thamotharam, A; Kindahl, H; Edqvist, L E

    1981-05-01

    The peripheral blood plasma concentration of estrone, progesterone and 15-keto-13, 14-dihydroprostaglandin F2alpha (PGF2alpha metabolite) were determined by radioimmunoassay techniques during the peripartal period in 5 buffalo cows belonging to a river type breed. Estrone levels started to increase from below 200 pg/ml about 15 days prior to parturition, and reached high concentrations (400-750 pg/ml) during the last 5 days of pregnancy. The estrone concentration decreased to baseline levels after delivery. The concentration of progesterone fluctuated between 800 and 2000 pg/ml until 15 days before calving and showed a gradual increase during the last 15 days of pregnancy. The progesterone levels declined abruptly on the day of calving and remained below 100 pg/ml for up to 60 days post-partum. Increased levels of the prostaglandin metabolite were recorded from 15 days prior to parturition with further increases occurring during the last 3 days of pregnancy. PGF2alpha metabolite levels declined gradually after parturition, reaching base line levels 15-20 days after calving.

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

    SciTech Connect

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

    2008-10-01

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

  16. Prostaglandins and corticosterone in the oviparous female lizard, Podarcis sicula sicula, during reproduction.

    PubMed

    Gobbetti, A; Zerani, M; Bellini-Cardellini, L; Bolelli, G F

    1995-03-01

    The in vitro effects of prostaglandin F2 alpha (PGF2 alpha) and prostaglandin E2 (PGE2) on corticosterone release by ovarian follicles, corpora lutea (CL), and interrenals were studied in the female lizard, Podarcis sicula sicula, during reproduction. Follicles and CL studied in the female lizard, Podarcis sicula sicula, during reproduction. Follicles and CL were divided according to their different developmental stages; follicles: previtellogenic, early-vitellogenic, mid-vitellogenic and fully-grown; CL: CL1 (unshelled eggs in the oviducts), CL2 (shelled eggs in the oviducts), CL3 (eggs laid 6 h previously) and CL4 (eggs laid 48 h previously). Interrenals were divided according to the reproductive stages: pre-vitellogenesis, vitellogenesis, ovulation, post-ovulation, and post-deposition. PGF2 alpha release was highest in fully-grown follicles and PGE2 in early-vitellogenic follicles, corticosterone was highest in pre-vitellogenic and lowest in early-vitellogenic follicles. PGE2 decreased corticosterone in pre-vitellogenic, mid-vitellogenic and fully-grown follicles. PGF2 alpha release was highest in CL4, and PGE2 in CL1 and CL2, corticosterone was highest in CL4. PGF2 alpha increased corticosterone in CL1, CL2 and CL3. In interrenals, PGF2 alpha release was highest and PGE2 lowest during ovulation, corticosterone was highest during ovulation. PGF2 alpha increased and PGE2 decreased interrenal corticosterone during vitellogenesis, ovulation, and post-ovulation. In the plasma, PGF2 alpha levels were highest and PGE2 lowest during ovulation, corticosterone was highest during ovulation. These results suggest that corticosterone, modulated by PGF2 alpha and PGE2, is implied in the reproductive processes with different roles. In fact this steroid could favour ovulatory and luteolytic processes. In addition the hypothesis of an anti-vitellogenic role of corticosterone is discussed. PMID:7625183

  17. Formation of the early canine CL and the role of prostaglandin E2 (PGE2) in regulation of its function: an in vivo approach.

    PubMed

    Kowalewski, M P; Ihle, S; Siemieniuch, M J; Gram, A; Boos, A; Zduńczyk, S; Fingerhut, J; Hoffmann, B; Schuler, G; Jurczak, A; Domosławska, A; Janowski, T

    2015-04-01

    The mechanisms governing corpus luteum (CL) function in domestic dogs remain not fully elucidated. The upregulated expression of cyclooxygenase 2 and prostaglandin (PG) E2 synthase (PGES) at the beginning of the canine luteal phase indicated their luteotrophic roles, and the steroidogenic activity of PGE2 in the early canine CL has been confirmed in vitro. Recently, by applying a cyclooxygenase 2 (COX2)-specific inhibitor (firocoxib [Previcox]; Merial) from the day of ovulation until the midluteal phase, the luteotrophic effects of PGs have been shown in vivo. This is a follow-up study investigating the underlying endocrine mechanisms associated with the firocoxib-mediated effects on the canine CL. Experimental groups were formed with ovariohysterectomies performed on Days 5, 10, 20, or 30 of firocoxib treatments (10 mg/kg bw/24h; TGs = treated groups). Untreated dogs served as controls. A decrease of steroidogenic acute regulatory (STAR) protein expression was observed in TGs. The expression of PGE2 synthase was significantly suppressed in TGs 5 and 10, and both PGE2 and PGF2α levels were decreased in luteal homogenates, particularly from CL in TG 5. Similarly, expression of the prolactin receptor (PRLR) was diminished in TGs 5 and 20. The expression of PGE2 receptors PTGER2 (EP2) and PTGER4 (EP4), the PG- transporter (PGT), and 15-hydroxy PG dehydrogenase (HPGD) was not affected in TGs. Our results substantiate a direct luteotrophic role of PGs in the early canine CL, i.e., by upregulating the steroidogenic machinery. Additionally, the possibility of an indirect effect on PRL function arises from the increased prolactin receptor expression in response to PGE2 treatment in canine lutein cells observed in vitro.

  18. Formation of the early canine CL and the role of prostaglandin E2 (PGE2) in regulation of its function: an in vivo approach.

    PubMed

    Kowalewski, M P; Ihle, S; Siemieniuch, M J; Gram, A; Boos, A; Zduńczyk, S; Fingerhut, J; Hoffmann, B; Schuler, G; Jurczak, A; Domosławska, A; Janowski, T

    2015-04-01

    The mechanisms governing corpus luteum (CL) function in domestic dogs remain not fully elucidated. The upregulated expression of cyclooxygenase 2 and prostaglandin (PG) E2 synthase (PGES) at the beginning of the canine luteal phase indicated their luteotrophic roles, and the steroidogenic activity of PGE2 in the early canine CL has been confirmed in vitro. Recently, by applying a cyclooxygenase 2 (COX2)-specific inhibitor (firocoxib [Previcox]; Merial) from the day of ovulation until the midluteal phase, the luteotrophic effects of PGs have been shown in vivo. This is a follow-up study investigating the underlying endocrine mechanisms associated with the firocoxib-mediated effects on the canine CL. Experimental groups were formed with ovariohysterectomies performed on Days 5, 10, 20, or 30 of firocoxib treatments (10 mg/kg bw/24h; TGs = treated groups). Untreated dogs served as controls. A decrease of steroidogenic acute regulatory (STAR) protein expression was observed in TGs. The expression of PGE2 synthase was significantly suppressed in TGs 5 and 10, and both PGE2 and PGF2α levels were decreased in luteal homogenates, particularly from CL in TG 5. Similarly, expression of the prolactin receptor (PRLR) was diminished in TGs 5 and 20. The expression of PGE2 receptors PTGER2 (EP2) and PTGER4 (EP4), the PG- transporter (PGT), and 15-hydroxy PG dehydrogenase (HPGD) was not affected in TGs. Our results substantiate a direct luteotrophic role of PGs in the early canine CL, i.e., by upregulating the steroidogenic machinery. Additionally, the possibility of an indirect effect on PRL function arises from the increased prolactin receptor expression in response to PGE2 treatment in canine lutein cells observed in vitro. PMID:25595355

  19. Prostaglandins, bioassay and inflammation

    PubMed Central

    Flower, R J

    2006-01-01

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

  20. Coordinate Functional Regulation between Microsomal Prostaglandin E Synthase-1 (mPGES-1) and Peroxisome Proliferator-activated Receptor γ (PPARγ) in the Conversion of White-to-brown Adipocytes*

    PubMed Central

    García-Alonso, Verónica; López-Vicario, Cristina; Titos, Esther; Morán-Salvador, Eva; González-Périz, Ana; Rius, Bibiana; Párrizas, Marcelina; Werz, Oliver; Arroyo, Vicente; Clària, Joan

    2013-01-01

    Peroxisome proliferator-activated receptor γ (PPARγ) is a ligand-activated nuclear receptor and a master regulator of adipogenesis. Microsomal prostaglandin E (PGE) synthase-1 (mPGES-1) is an inducible enzyme that couples with cyclooxygenase-2 for the biosynthesis of PGE2. In this study we demonstrate the existence of a coordinate functional interaction between PPARγ and mPGES-1 in controlling the process of pre-adipocyte differentiation in white adipose tissue (WAT). Adipocyte-specific PPARγ knock-out mice carrying an aP2 promoter-driven Cre recombinase transgene showed a blunted response to the adipogenic effects of a high fat diet. Pre-adipocytes from these knock-out mice showed loss of PPARγ and were resistant to rosiglitazone-induced WAT differentiation. In parallel, WAT from these mice showed increased expression of uncoupling protein 1, a mitochondrial enzyme that dissipates chemical energy as heat. Adipose tissue from mice lacking PPARγ also showed mPGES-1 up-regulation and increased PGE2 levels. In turn, PGE2 suppressed PPARγ expression and blocked rosiglitazone-induced pre-adipocyte differentiation toward white adipocytes while directly elevating uncoupling protein 1 expression and pre-adipocyte differentiation into mature beige/brite adipocytes. Consistently, pharmacological mPGES-1 inhibition directed pre-adipocyte differentiation toward white adipocytes while suppressing differentiation into beige/brite adipocytes. This browning effect was reproduced in knockdown experiments using a siRNA directed against mPGES-1. The effects of PGE2 on pre-adipocyte differentiation were not seen in mice lacking PPARγ in adipose tissue and were not mirrored by other eicosanoids (i.e. leukotriene B4). Taken together, these findings identify PGE2 as a key regulator of white-to-brown adipogenesis and suggest the existence of a coordinate regulation of adipogenesis between PPARγ and mPGES-1. PMID:23943621

  1. Loading-related regulation of transcription factor EGR2/Krox-20 in bone cells is ERK1/2 protein-mediated and prostaglandin, Wnt signaling pathway-, and insulin-like growth factor-I axis-dependent.

    PubMed

    Zaman, Gul; Sunters, Andrew; Galea, Gabriel L; Javaheri, Behzad; Saxon, Leanne K; Moustafa, Alaa; Armstrong, Victoria J; Price, Joanna S; Lanyon, Lance E

    2012-02-01

    Of the 1,328 genes revealed by microarray to be differentially regulated by disuse, or at 8 h following a single short period of osteogenic loading of the mouse tibia, analysis by predicting associated transcription factors from annotated affinities revealed the transcription factor EGR2/Krox-20 as being more closely associated with more pathways and functions than any other. Real time quantitative PCR confirmed up-regulation of Egr2 mRNA expression by loading of the tibia in vivo. In vitro studies where strain was applied to primary cultures of mouse tibia-derived osteoblastic cells and the osteoblast UMR106 cell line also showed up-regulation of Egr2 mRNA expression. In UMR106 cells, inhibition of β1/β3 integrin function had no effect on strain-related Egr2 expression, but it was inhibited by a COX2-selective antagonist and imitated by exogenous prostaglandin E2 (PGE2). This response to PGE(2) was mediated chiefly through the EP1 receptor and involved stimulation of PKC and attenuation by cAMP/PKA. Neither activators nor inhibitors of nitric oxide, estrogen signaling, or LiCl had any effect on Egr2 mRNA expression, but it was increased by both insulin-like growth factor-1 and high, but not low, dose parathyroid hormone and exogenous Wnt-3a. The increases by strain, PGE2, Wnt-3a, and phorbol 12-myristate 13-acetate were attenuated by inhibition of MEK-1. EGR2 appears to be involved in many of the signaling pathways that constitute early responses of bone cells to strain. These pathways all have multiple functions. Converting their strain-related responses into coherent "instructions" for adaptive (re)modeling is likely to depend upon their contextual activation, suppression, and interaction probably on more than one occasion. PMID:22049075

  2. Prostaglandin (PG)D2 and 15-deoxy-Δ12,14-PGJ2, but not PGE2, Mediate Shear-Induced Chondrocyte Apoptosis via Protein Kinase A-dependent Regulation of Polo-like Kinases

    PubMed Central

    Zhu, Fei; Wang, Pu; Kontrogianni-Konstantopoulos, Aikaterini; Konstantopoulos, Konstantinos

    2010-01-01

    Excessive mechanical loading of cartilage producing hydrostatic stress, tensile strain and fluid flow leads to chondrocyte apoptosis and osteoarthritis. High fluid flow induces cyclooxygenase-2 (COX-2) expression in sheared chondrocytes, which suppresses their antioxidant capacity and contributes to apoptosis. The pivotal role of COX-2 in shear-induced chondrocyte apoptosis and the conflicting literature data on the roles of prostaglandin (PG)E2, PGD2 and its metabolite 15-deoxy-Δ12,14-PGJ2 (15d-PGJ2) in chondrocyte apoptosis prompted us to investigate which COX-2-derived PG is involved in this process. We show that exogenously added PGD2 and 15d-PGJ2, but not PGE2, diminish the viability of human T/C-28a2 chondrocytes under static conditions. In agreement with these observations, knockdown of L-PGD synthase (L-PGDS) abolishes shear-induced chondrocyte apoptosis. Using cDNA microarrays in conjunction with clustering algorithms, we propose a novel signaling pathway by which high fluid shear mediates COX-2/L-PGDS-dependent chondrocyte apoptosis, which is validated by molecular interventions. We demonstrate that L-PGDS controls the downregulation of Protein Kinase A (PKA), which in turn regulates Polo-like kinase1 (Plk1) and Plk3. Plks target p53, which controls the transcription of p53 effectors (TP53INPs, FAS and Bax) involved in chondrocyte apoptosis. Reconstructing the signaling network regulating chondrocyte apoptosis may provide insights to optimize conditions for culturing artificial cartilage in bioreactors and for developing therapeutic strategies for arthritic disorders. PMID:20150912

  3. Suppression of fibroblast proliferation by activated macrophages: involvement of H2O2 and a non-prostaglandin E product of the cyclooxygenase pathway.

    PubMed

    Metzger, Z; Hoffeld, J T; Oppenheim, J J

    1986-07-01

    Macrophages are considered promoters of fibroblast proliferation; however, suppression by activated macrophages may outweigh this effect. Activated murine peritoneal macrophages obtained by in vivo exposure to C. parvum or by in vitro LPS-activation of thioglycollate-induced macrophages, were tested for their effect on normal syngeneic dermal fibroblasts. C. parvum-activated macrophages, but not resident peritoneal macrophages suppressed fibroblast proliferation. Similarly, macrophages activated in vitro by LPS, but not those unexposed to LPS, suppressed fibroblast proliferation. Catalase partially protected fibroblasts from suppression by either activated macrophage population, suggesting involvement of H2O2 in the suppression. The effect of cyclooxygenase inhibitors on the suppression was also tested. Indomethacin, acetylsalicyclic acid, or eicosatetraynoic acid, all partially protected the fibroblasts from macrophage-mediated suppression. Prostaglandins E2, E1, and F2 alpha, added exogenously at concentrations as high as 10(-6) M, failed to suppress the proliferation of the fibroblasts. These findings suggest that a non-prostaglandin product of the cyclooxygenase pathway is involved in macrophage-mediated suppression of fibroblast proliferation.

  4. Femtomole analysis of prostaglandin pharmaceuticals.

    PubMed

    McGuffin, V L; Zare, R N

    1985-12-01

    An analytical method is described whereby the major classes of prostaglandins are fully resolved by microcolumn liquid chromatography and detected at the subfemtomole level by laser-induced fluorescence. The prostaglandins are labeled with the fluorescent reagent 4-bromo-methyl-7-methoxycoumarin and are subsequently separated on a high-efficiency fused-silica microcolumn (0.2 mm i.d., 1.06 m length, 150,000 theoretical plates). The optimal chromatographic conditions consist of a 3-micron octadecylsilica packing material and an isocratic mobile phase of 47.6% methanol, 23.8% acetonitrile, and 28.6% water. The prostaglandin derivatives are detected directly on the microcolumn by laser fluorimetry, using a helium/cadmium laser (325 nm, 15 mW) as the excitation source together with a simple filter/photo-multiplier optical detection system. In real sample matrices, the prostaglandin PGF2 alpha is readily quantifiable from the detection limit (0.3 fmol) to the formulation strength of the therapeutic agent Lutalyse (Upjohn), spanning more than six orders of magnitude in concentration. The simplicity and general applicability of the present analytical methodology and instrumentation suggest that this technique can be used to attack a wide variety of biomedically important problems with exceptional sensitivity and selectivity.

  5. Prostaglandin E3 metabolism and cancer

    PubMed Central

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

    2015-01-01

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

  6. Oxidized low-density lipoprotein-induced periodontal inflammation is associated with the up-regulation of cyclooxygenase-2 and microsomal prostaglandin synthase 1 in human gingival epithelial cells

    SciTech Connect

    Nagahama, Yu; Obama, Takashi; Usui, Michihiko; Kanazawa, Yukari; Iwamoto, Sanju; Suzuki, Kazushige; Miyazaki, Akira; Yamaguchi, Tomohiro; Yamamoto, Matsuo; Itabe, Hiroyuki

    2011-10-07

    Highlights: {yields} OxLDL-induced responses in human gingival epithelial cells were studied. {yields} OxLDL enhanced the production of IL-8, IL-1{beta} and PGE{sub 2} in Ca9-22 cells. {yields} An NF-{kappa}B inhibitor suppressed the expression of COX-2 and mPGES1 induced by oxLDL. {yields} Unlike the case in macrophages, oxLDL did not increase the CD36 level. -- Abstract: Periodontitis is characterized by chronic gingival tissue inflammation, and inflammatory mediators such as IL-8 and prostaglandin E{sub 2} (PGE{sub 2}) are associated with disease progression. Previously we showed that oxidatively modified low-density lipoprotein (oxLDL) was present in gingival crevicular fluid. In this study, the role of oxLDL in the gingival epithelial cell inflammatory response was further investigated using Ca9-22 cells and primary human oral keratinocytes (HOK). Treatment of Ca9-22 cells and HOK with oxLDL induced an up-regulation of IL-8 and the PGE{sub 2}-producing enzymes, cyclooxygenase-2 and microsomal PGE{sub 2} synthase-1. These responses induced by oxLDL were significantly suppressed by a nuclear factor-kappa B (NF-{kappa}B) inhibitor. However, unlike the result in macrophages, oxLDL did not lead to an increase in CD36 expression in these two cells. These results suggest that oxLDL elicits gingival epithelial cell inflammatory responses through an activation of the NF-{kappa}B pathway. These data suggest a mechanistic link between periodontal disease and lipid metabolism-related disorders, including atherosclerosis.

  7. Prostaglandin EP2 receptor signaling protects human trabecular meshwork cells from apoptosis induced by ER stress through down-regulation of p53.

    PubMed

    Kalouche, Georges; Boucher, Céline; Coste, Annick; Debussche, Laurent; Orsini, Cécile; Baudouin, Christophe; Debeir, Thomas; Vigé, Xavier; Rostène, William

    2016-09-01

    E-prostanoid receptor subtype 2 (EP2) agonists are currently under clinical development as hypotensive agents for the treatment of ocular hypertension. However, the effects of EP2 receptor agonists on trabecular meshwork (TM) alterations leading to primary open-angle glaucoma (POAG) are still unknown. Here, we evaluated whether EP2 receptor activation exhibits protective functions on TM cell death induced by endoplasmic reticulum (ER) stress. We show that the EP2 receptor agonist butaprost protects TM cell death mediated by the ER stress inducer tunicamycin through a cyclic AMP (cAMP)-dependent mechanism, but independent of the classical cAMP sensors, protein kinase A and exchange proteins activated by cAMP. The ER stress-induced intrinsic apoptosis inhibited by the EP2 receptor agonist was correlated with a decreased accumulation of the cellular stress sensor p53. In addition, p53 down-regulation was associated with inhibition of its transcriptional activity, which led to decreased expression of the pro-apoptotic p53-upregulated modulator of apoptosis (PUMA). The stabilization of p53 by nutlin-3a abolished butaprost-mediated cell death protection. In conclusion, we showed that EP2 receptor activation protects against ER stress-dependent mitochondrial apoptosis through down-regulation of p53. The specific inhibition of this pathway could reduce TM alterations observed in POAG patients. PMID:27321910

  8. Relationship between endotoxin and prostaglandin (PGE2 and PGFM) concentrations and ovarian function in dairy cows with puerperal endometritis.

    PubMed

    Mateus, L; Lopes da Costa, L; Diniz, P; Ziecik, A J

    2003-04-15

    Blood concentrations of progesterone, 13,14-dihydro-15-keto-prostaglandin F2alpha (PGFM) and endotoxin, and uterine fluid concentrations of prostaglandin E(2) (PGE(2)), PGFM and endotoxin were evaluated in 14 dairy cows with puerperal endometritis (mild (n=6) and heavy (n=8)). Endotoxin was measured using a quantitative kinetic assay. Cows with heavy endometritis had significantly higher concentrations of plasma PGFM (P<0.01) and uterine fluid PGE(2) and endotoxin (P<0.05) than cows with mild endometritis. Concentrations of PGFM in plasma and uterine fluid, of PGFM and PGE(2), and PGE(2) and endotoxin in uterine fluid were positively and significantly (P<0.05) correlated. The presence of endotoxin in plasma was detected in one out of six mild and in eight out of eight heavy endometritis cows. Peak plasma endotoxin concentrations (0.08-9.14 endotoxin units/ml (EU/ml) were observed between 1 and 12 days postpartum (pp) and thereafter amounts generally remained below 0.1 EU/ml (last day of detection: Day 27 pp). Abnormal ovarian function was observed in six cows (four with prolonged anoestrus and two with long luteal phase after the first postpartum ovulation). Plasma endotoxin concentrations were detected in the anoestric cows. The results suggest that: (i) concentrations of uterine fluid endotoxin and PGE(2) and of plasma PGFM are related to the degree of endometritis; (ii) absorption of endotoxin from the uterus to the bloodstream occurs, mainly in heavy endometritis cows; and (iii) there is a relationship between uterine infection, endotoxin production and resumption of pp ovarian activity. PMID:12586488

  9. [Treatment of postpartal atony with prostaglandins].

    PubMed

    Heinzl, S; Hendry, M

    1986-01-01

    Uterine contraction can be brought about at any time with prostaglandins. This effect is exploited in the treatment of postpartal atonia. Prostaglandin was administered intravenously to 21 women for postpartal atonia. In 19 women the bleeding subsequently stopped. There were no side effects of the treatment. These results are presented and discussed with reference to other data in the literature.

  10. Prostaglandins, Thromboxanes and Leukotrienes in Clinical Medicine

    PubMed Central

    Zipser, Robert D.; Laffi, Giacomo

    1985-01-01

    Although prostaglandin research began about 50 years ago, many of the most important advances in understanding the biochemistry, physiology and pharmacology have taken place within the past five to ten years. There is great potential for the extension of this research to the clinical practice of medicine. At this time, the most common interaction that clinicians have with the prostaglandin field is in administering nonsteroidal anti-inflammatory drugs, which function by inhibiting prostaglandins. The uses of these drugs include treating not only inflammation, but also dysmenorrhea, some renal disease, thrombotic diseases and some metabolic disorders. Prostaglandin analogs, with their potent effects on uterine contraction, are in common use in obstetrics. Other analogs, with gastric and duodenal cytoprotective effects are useful in treating peptic ulcer disease. Future benefits from prostaglandin and leukotriene research may include new therapy for inflammatory and hypersensitivity diseases such as asthma, inflammatory bowel diseases and dermatitis. PMID:3004043

  11. Prostaglandins in human seminal plasma. Prostaglandins and related factors 46.

    PubMed

    Hamberg, M; Samuelsson, B

    1966-01-25

    This study on human seminal plasma sought after the compounds which either possess the dienone chromophore or can be converted into it by treatment with sodium hydroxide. In addition, this investigation led to the isolation of 8 more (PGs) prostaglandins which were present in higher concentrations than the previously recognized PGs. Samples of human seminal plasma were subjected to silicic acid chromatography, reversed phase partition chromatography, thin layer chromatography, and gas liquid chromatography which isolated those 8 PGs not previously recognized. 4 of these compounds, PGE1-217, PGE2-217, PGE1-278, and PGE2-278 were known from earlier studies but had not been isolated from natural sources. The other 4 were 19 hydroxy derivatives of the 4 abovementioned compounds. The concentrations of the previously recognized PGs were recently determined and it was found that the 19 hydroxy derivatives were present in concentrations 4 times higher than the PGE compounds.

  12. Acute prostaglandin reduction with indomethacin and chronic prostaglandin reduction with an essential fatty acid deficient diet both decrease plasma flow to the renal papilla in the rat.

    PubMed

    Ganguli, M; Tobian, L; Ferris, T; Johnson, M A

    1989-07-01

    Renal distribution of prostaglandin synthetase is mainly medullary, whereas the major degrading enzyme, prostaglandin dehydrogenase is primarily cortical. This suggests that prostaglandins (PG) released from the renal medulla could affect the medullary blood vessels. In two different experiments we studied the role of PG in the regulation of renal papillary plasma flow in the rat. First study: PG synthesis were stimulated in 34 adult Sprague-Dawley rats by bleeding from the femoral artery 1% of the body weight over a period of 10 minutes. Following this, indomethacin (a PG inhibitor, 10 mg/kg i.v.) was given slowly and then renal papillary plasma flow was measured 25 minutes after the end of infusion. In 17 indomethacin rats the renal papillary plasma flow averaged 18.8 ml/100 g/minute, whereas it averaged 23.0 in 17 non-indomethacin rats given diluent, an 18% reduction (p less than .025). Second study: Male Sprague-Dawley rats were made prostaglandin deficient by fasting rats for one week, followed by 10% dextrose fluid for one week and subsequent institution of an essential fatty acid (EFA) deficient diet for two weeks. With urinary PG excretion in prostaglandin deficient rats 28 ng/24 hours compared to 149 ng in control rats, they could be considered as prostaglandin deficient. When renal papillary plasma flow was measured, the 16 prostaglandin deficient rats had a 16% lower papillary plasma flow than 16 control rats, 21.6 vs 25.6 (p less than .005). These results clearly demonstrate that PG inhibition in rats decreases plasma flow to the papilla, strongly suggesting that PG are vasodilators for the vessels supplying the renal papilla.

  13. In vitro assessment of progesterone and prostaglandin e(2) production by the corpus luteum in cattle following pharmacological synchronization of estrus.

    PubMed

    Skarzynski, Dariusz Jan; Siemieniuch, Marta Jolanta; Pilawski, Wojciech; Woclawek Potocka, Izabela; Bah, Mamadou Moussa; Majewska, Magdalena; Jaroszewski, Jerzy Jan

    2009-04-01

    We studied the secretory function of the corpus luteum (CL) in cows following different estrus synchronization protocols. Estrus was synchronized using one (n=4) or two injections (n=5) of prostaglandin F(2alpha) (PGF(2alpha); dinoprost), two injections of different analogues of PGF(2alpha) (aPGF(2alpha)), luprostiol (n=5) and cloprostenol (n=5), at eleven-day intervals, a gestagen implant (norgestomet, n=5, for 10 days) or norgestomet together with a subsequent dinoprost injection on the day of implant removal (n=5). CL samples were collected by ovariectomy on Day 7-8 of the estrous cycle. Luteal strips were stimulated with LH (100 ng/ml) or prostaglandin E(2) (PGE(2), 10(-6)M) for 24 h in culture media. The progesterone (P(4)) and PGE(2) concentrations in the media were measured by enzyme immunoassay. In the control CL (spontaneous estrus; n=5), LH and PGE(2) stimulated P(4) and PGE(2) (P<0.001). The effects of both factors on P(4) were reduced in the CL following dinoprost- and cloprostenol-synchronized estrus (P<0.05) and were absent in the luprostiol-synchronized CL (P>0.05). In the norgestomet-synchronized CL, the stimulatory effects of LH and PGE(2) were higher compared with the CL synchronized by aPGF(2alpha) (P<0.05). Pharmacological manipulation of the estrous cycle using aPGF(2alpha) may cause lower P(4) secretion. Estrus synchronization inhibited CL sensitivity to luteotropic factors. Therefore, attention should be focused on the estrous synchronization method in both in vivo and in vitro studies of CL functions in cattle.

  14. Effect of folic acid plus glycine supplement on uterine prostaglandin and endometrial granulocyte-macrophage colony-stimulating factor expression during early pregnancy in pigs.

    PubMed

    Guay, Frédéric; Matte, J Jacques; Girard, Christiane L; Palin, Marie-France; Giguère, Alain; Laforest, Jean-Paul

    2004-01-15

    The objective was to determine the effects of folic acid+glycine supplement on uterine metabolism of prostaglandin and mRNA expression of endometrial granulocyte-macrophage colony-stimulating factor (GM-CSF) in nulliparous (NYL) and multiparous Yorkshire-Landrace (YL) sows, and in multiparous Meishan-Landrace sows (ML). In each of these three groups, sows were randomly assigned to two treatments: 15 ppm folic acid+0.6% glycine or no supplement. The dietary supplement was given from the estrus before mating to slaughter on Day 25 of pregnancy. At slaughter, endometrial tissue was collected to determine endometrial expression levels of GM-CSF mRNA, cyclooxygenase-1 (COX1) and -2 (COX2) and to evaluate in vitro endometrial secretion of prostaglandin E2 (PGE2) secretion. Allantoic fluid samples were also collected to determine the concentration of PGE2, prostaglandin F2alpha (PGF2alpha), estradiol-17beta (E2), progesterone (P4), and transforming-growth factor-beta2 (TGF-beta2). The allantoic contents of PGF2alpha, E2 and P4, and endometrial in vitro secretion of PGE2 were not significantly influenced by the folic acid+glycine supplement. The folic acid+glycine supplement tended (P<0.07) to increase allantoic content of PGE2 and TGF-beta2 in all sows and increased (P<0.05) endometrial expression of COX2, especially in NYL sows. The endometrial expression of COX1 was decreased (P<0.05) by folic acid+glycine supplement, especially in multiparous YL sows. The allantoic contents of PGE2 and PGF2alpha were not significantly affected by sow type. However, NYL sows had higher (P<0.05) endometrial in vitro secretion of PGE2 and allantoic content of P4 than multiparous YL and ML sows. The allantoic content of E2 was also higher (P<0.05) in NYL sows than in multiparous ML sows only. The allantoic content of TGF-beta2 was lower (P<0.05) in multiparous ML than in multiparous YL only sows. Finally, in YL and NYL sows, folic acid+glycine supplement decreased (P<0.05) the endometrial

  15. Prostaglandin synthetase and prostacyclin synthetase in mature rat skeletal muscles: immunohistochemical localisation to arterioles, tendons and connective tissues.

    PubMed Central

    McLennan, I S; Macdonald, R E

    1991-01-01

    Mature skeletal muscles produce appreciable quantities of prostacyclin (PGI2) and smaller amounts of PGF2 alpha and PGE2, but the sources of these prostaglandins within skeletal muscle are unknown. Monoclonal antibodies to prostaglandin synthetase and prostacyclin synthetase were used to determine which muscle cells produce prostaglandins. The antibody to prostacyclin synthetase stained the tendon, fascia, epimysium and the arteries leading to the muscles. The endothelia of arterioles were also stained in the tibialis anterior and cremaster but not in the soleus muscles. Only trace levels of immunoreactivity were observed with the antibody to prostaglandin synthetase in normal muscles. However, immunoreactivity was observed in the muscles of rats that had been pretreated with aspirin, a drug that inhibits and stabilises prostaglandin synthetase. In muscles of the aspirin-treated rats, all cell types that were stained by the antiprostacyclin synthetase also reacted weakly with the antibody to prostaglandin synthetase. In addition, some cells in the endomysium were strongly stained with the antiprostaglandin synthetase but not with the antiprostacyclin synthetase. We conclude that (1) at least one aspect of the regulation of blood flow in the microcirculation of slow muscles is different from that of fast muscles, (2) that the tendon and connective tissue is the major source of PGI2 in mature skeletal muscles, and (3) that the prostaglandin-dependent effects of insulin and some other stimuli on skeletal muscle may be mediated by the muscle's arterioles or connective tissue. Images Fig. 1 Fig. 2 Fig. 3 PMID:1810931

  16. Prostaglandins as mediators of acidification in the urinary bladder of Bufo marinus

    SciTech Connect

    Frazier, L.W.; Yorio, T. )

    1990-05-01

    Experiments were performed to determine whether prostaglandins (PG) play a role in H+ and NH4+ excretion in the urinary bladder of Bufo marinus. Ten paired hemibladders from normal toads were mounted in chambers. One was control and the other hemibladder received PGE2 in the serosal medium (10(-5) M). H+ excretion was measured by change in pH in the mucosal fluid and reported in units of nmol (100 mg tissue)-1 (min)-1. NH4+ excretion was measured colorimetrically and reported in the same units. The control group H+ excretion was 8.4 +/- 1.67, while the experimental group was 16.3 +/- 2.64 (P less than 0.01). The NH4+ excretion in the experimental and control group was not significantly different. Bladders from toads in a 48-hr NH4+Cl acidosis (metabolic) did not demonstrate this response to PGE2 (P greater than 0.30). Toads were put in metabolic acidosis by gavaging with 10 ml of 120 mM NH4+Cl 3 x day for 2 days. In another experiment, we measured levels of PG in bladders from control (N) and animals placed in metabolic acidosis (MA). Bladders were removed from the respective toad, homogenized, extracted, and PG separated using high-pressure liquid chromatography and quantified against PG standards. The results are reported in ng (mg tissue)-1. PGE2 fraction in N was 1.09 +/- 0.14 and in MA was 3.21 +/- 0.63 (P less than 0.01). PGF1 alpha, F2 alpha and I2 were not significantly different in N and MA toads. Bladders were also removed from N and MA toads, and incubated in Ringer's solution containing (3H)arachidonic acid (0.2 microCi/ml) at 25 degrees C for 2 hr. Bladders were then extracted for PG and the extracts separated by thin layer chromatography. PG were identified using standards and autoradiography, scraped from plates, and counted in a scintillation detector. The results are reported in cpm/mg tissue x hr +/- SEM.

  17. Prostaglandin transporter mutations cause pachydermoperiostosis with myelofibrosis.

    PubMed

    Diggle, Christine P; Parry, David A; Logan, Clare V; Laissue, Paul; Rivera, Carolina; Restrepo, Carlos Martín; Fonseca, Dora J; Morgan, Joanne E; Allanore, Yannick; Fontenay, Michaela; Wipff, Julien; Varret, Mathilde; Gibault, Laure; Dalantaeva, Nadezhda; Korbonits, Márta; Zhou, Bowen; Yuan, Gang; Harifi, Ghita; Cefle, Kivanc; Palanduz, Sukru; Akoglu, Hadim; Zwijnenburg, Petra J; Lichtenbelt, Klaske D; Aubry-Rozier, Bérengère; Superti-Furga, Andrea; Dallapiccola, Bruno; Accadia, Maria; Brancati, Francesco; Sheridan, Eamonn G; Taylor, Graham R; Carr, Ian M; Johnson, Colin A; Markham, Alexander F; Bonthron, David T

    2012-08-01

    Pachydermoperiostosis, or primary hypertrophic osteoarthropathy (PHO), is an inherited multisystem disorder, whose features closely mimic the reactive osteoarthropathy that commonly accompanies neoplastic and inflammatory pathologies. We previously described deficiency of the prostaglandin-degrading enzyme 15-hydroxyprostaglandin dehydrogenase (HPGD) as a cause of this condition, implicating elevated circulating prostaglandin E(2) (PGE(2)) as causative of PHO, and perhaps also as the principal mediator of secondary HO. However, PHO is genetically heterogeneous. Here, we use whole-exome sequencing to identify recessive mutations of the prostaglandin transporter SLCO2A1, in individuals lacking HPGD mutations. We performed exome sequencing of four probands with severe PHO, followed by conventional mutation analysis of SLCO2A1 in nine others. Biallelic SLCO2A1 mutations were identified in 12 of the 13 families. Affected individuals had elevated urinary PGE(2), but unlike HPGD-deficient patients, also excreted considerable quantities of the PGE(2) metabolite, PGE-M. Clinical differences between the two groups were also identified, notably that SLCO2A1-deficient individuals have a high frequency of severe anemia due to myelofibrosis. These findings reinforce the key role of systemic or local prostaglandin excess as the stimulus to HO. They also suggest that the induction or maintenance of hematopoietic stem cells by prostaglandin may depend upon transporter activity. PMID:22553128

  18. Prostaglandins inhibit lipoprotein lipase gene expression in macrophages.

    PubMed Central

    Desanctis, J B; Varesio, L; Radzioch, D

    1994-01-01

    In the present investigation of the effects of prostaglandin E2 (PGE2) on lipoprotein lipase (LPL) gene expression in macrophages, we observed that treatment of macrophages with PGE2 increased the levels of adenosine 3',5'-cyclic monophosphate (cAMP), while the addition of exogenous 5-bromo-cAMP to macrophage cultures resulted in down-regulation of LPL expression. Using indomethacin (INDO), an inhibitor of cyclo-oxygenase and prostaglandins production, we determined that PGE2 acts as a feedback inhibitor of LPL expression. We found that inhibited secretion of LPL protein in lipopolysaccharide (LPS)-treated macrophages could be restored to control levels by the addition of INDO to the medium. In contrast, INDO did not reverse the inhibition of LPL mRNA induced by LPS. Overall, our results have demonstrated that PGE2 is a potent inhibitor of LPL gene expression and indicated that its action may play an important physiological role in the regulation of LPL gene expression during bacterial infections. Images Figure 1 Figure 4 Figure 7 PMID:8039811

  19. Prostaglandin E2-prostaglandin E receptor subtype 4 (EP4) signaling mediates UV irradiation-induced systemic immunosuppression.

    PubMed

    Soontrapa, Kitipong; Honda, Tetsuya; Sakata, Daiji; Yao, Chengcan; Hirata, Takako; Hori, Shohei; Matsuoka, Toshiyuki; Kita, Yoshihiro; Shimizu, Takao; Kabashima, Kenji; Narumiya, Shuh

    2011-04-19

    UV radiation induces systemic immunosuppression. Because nonsteroidal anti-inflammatory drugs suppress UV-induced immunosuppression, prostanoids have been suspected as a crucial mediator of this UV effect. However, the identity of the prostanoid involved and its mechanism of action remain unclear. Here, we addressed this issue by subjecting mice deficient in each prostanoid receptor individually or mice treated with a subtype-specific antagonist to UV irradiation. Mice treated with an antagonist for prostaglandin E receptor subtype 4 (EP4), but not those deficient in other prostanoid receptors, show impaired UV-induced immunosuppression, whereas administration of an EP4 agonist rescues the impairment of the UV-induced immunosuppression in indomethacin-treated mice. The EP4 antagonist treatment suppresses an increase in the number of CD4(+)/forkhead box P3-positive (Foxp3(+)) regulatory T cells (Treg cells) in the peripheral lymph nodes (LNs) and dendritic cells expressing DEC205 in the LNs and the skin after UV irradiation. Furthermore, the EP4 antagonist treatment down-regulates UV-induced expression of receptor activator of NF-κB ligand (RANKL) in skin keratinocytes. Finally, administration of anti-RANKL antibody abolishes the restoration of UV-induced immunosuppression by EP4 agonism in indomethacin-treated mice. Thus, prostaglandin E(2) (PGE(2))-EP4 signaling mediates UV-induced immunosuppression by elevating the number of Treg cells through regulation of RANKL expression in the epidermis.

  20. Prostaglandins and their receptors in insect biology

    Technology Transfer Automated Retrieval System (TEKTRAN)

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

  1. Canine gastric mucosal vasodilation with prostaglandins and histamine analogs

    SciTech Connect

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

    1982-10-01

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

  2. Effects of Camphorquinone on Cytotoxicity, Cell Cycle Regulation and Prostaglandin E2 Production of Dental Pulp Cells: Role of ROS, ATM/Chk2, MEK/ERK and Hemeoxygenase-1.

    PubMed

    Chang, Mei-Chi; Lin, Li-Deh; Wu, Min-Tsz; Chan, Chiu-Po; Chang, Hsiao-Hua; Lee, Ming-Shu; Sun, Tzu-Ying; Jeng, Po-Yuan; Yeung, Sin-Yuet; Lin, Hsueh-Jen; Jeng, Jiiang-Huei

    2015-01-01

    Camphorquinone (CQ) is a popularly-used photosensitizer in composite resin restoration. In this study, the effects of CQ on cytotoxicity and inflammation-related genes and proteins expression of pulp cells were investigated. The role of reactive oxygen species (ROS), ATM/Chk2/p53 and hemeoxygenase-1 (HO-1) and MEK/ERK signaling was also evaluated. We found that ROS and free radicals may play important role in CQ toxicity. CQ (1 and 2 mM) decreased the viability of pulp cells to about 70% and 50% of control, respectively. CQ also induced G2/M cell cycle arrest and apoptosis of pulp cells. The expression of type I collagen, cdc2, cyclin B, and cdc25C was inhibited, while p21, HO-1 and cyclooxygenase-2 (COX-2) were stimulated by CQ. CQ also activated ATM, Chk2, and p53 phosphorylation and GADD45α expression. Besides, exposure to CQ increased cellular ROS level and 8-isoprostane production. CQ also stimulated COX-2 expression and PGE2 production of pulp cells. The reduction of cell viability caused by CQ can be attenuated by N-acetyl-L-cysteine (NAC), catalase and superoxide dismutase (SOD), but can be promoted by Zinc protoporphyin (ZnPP). CQ stimulated ERK1/2 phosphorylation, and U0126 prevented the CQ-induced COX-2 expression and prostaglandin E2 (PGE2) production. These results indicate that CQ may cause cytotoxicity, cell cycle arrest, apoptosis, and PGE2 production of pulp cells. These events could be due to stimulation of ROS and 8-isoprostane production, ATM/Chk2/p53 signaling, HO-1, COX-2 and p21 expression, as well as the inhibition of cdc2, cdc25C and cyclin B1. These results are important for understanding the role of ROS in pathogenesis of pulp necrosis and pulpal inflammation after clinical composite resin filling. PMID:26658076

  3. Sperm Binding to Oviduct Epithelial Cells Enhances TGFB1 and IL10 Expressions in Epithelial Cells as Well as Neutrophils In Vitro: Prostaglandin E2 As a Main Regulator of Anti-Inflammatory Response in the Bovine Oviduct

    PubMed Central

    Yousef, Mohamed Samy; Marey, Mohamed Ali; Hambruch, Nina; Hayakawa, Hiroyuki; Shimizu, Takashi; Hussien, Hassan Ali; Abdel-Razek, Abdel-Razek Khalifa; Pfarrer, Christiane; Miyamoto, Akio

    2016-01-01

    Sperm are allogenic to the female genital tract; however, oviducts provide optimal conditions for survival and capacitation of these non-self cells until fertilization. Recently, we showed that oviduct-conditioned media and prostaglandin E2 (PGE2) suppress sperm phagocytosis by polymorphonuclear neutrophils (PMNs) under physiological conditions. We hypothesized that sperm binding to bovine oviduct epithelial cells (BOECs) could change the local innate immunity via PGE2. As the first step to obtain basic information, sub-confluent BOEC monolayers were co-cultured with swim-up sperm for 2 h. BOECs with viable bound sperm were cultured for an additional 3, 6, 12, or 24 h. Then, we confirmed the impact of the sperm-BOEC binding on both BOECs and PMN gene expression. Immunohistochemistry revealed that BOECs strongly express TGFB1 and IL10 in the oviduct. Sperm binding to BOECs in culture induced the anti-inflammatory cytokines (TGFB1 and IL10) and PGE2 production by BOECs. Exogenous PGE2 in vitro suppressed pro-inflammatory cytokine expression (TNF and IL1B) in BOECs. Moreover, pre-exposure of PMNs to BOEC-conditioned media suppressed the TNF expression, but the BOEC media co-cultured with sperm stimulated PMNs to express TGFB1 and IL10, with increasing PGE2 secretion. Of note, exogenous PGE2 led PMNs in vitro to decrease their TNF expression and increase anti-inflammatory cytokines expression. Our findings strongly suggest that BOECs provide an anti-inflammatory environment under physiological conditions and the sperm-BOEC binding further strengthens this milieu thus suppresses PMNs in the bovine oviduct. PGE2 is likely to drive this stable anti-inflammatory environment in the oviduct. PMID:27662642

  4. Prostaglandin F2α Induces the Normoxic Activation of the Hypoxia-Inducible Factor-1 Transcription Factor in Differentiating 3T3-L1 Preadipocytes: Potential Role in the Regulation of Adipogenesis

    PubMed Central

    Liu, Li; Clipstone, Neil A.

    2008-01-01

    Prostaglandin F2α (PGF2α) is a potent paracrine inhibitor of adipocyte differentiation. Here we show that treatment of differentiating 3T3-L1 preadipocytes with PGF2α induces the expression of DEC1, a transcriptional repressor that has previously been implicated in the inhibition of adipogenesis in response to hypoxia as a downstream effector of the hypoxia-inducible factor-1 (HIF-1) transcription factor. Surprisingly, despite performing our experiments under normal ambient oxygen conditions, we find that treatment of differentiating 3T3-L1 preadipocytes with PGF2α also results in the marked activation of HIF-1, as measured by an increase in the accumulation of the HIF-1α regulatory subunit. However, unlike the effects of hypoxia, this PGF2α-induced normoxic increase in HIF-1α is not mediated by an increase in the stability of the HIF-1α polypeptide, rather we find that PGF2α selectively increases the expression of the alternatively spliced HIF-1α I.1 mRNA isoform. Significantly, we demonstrate that the shRNA-mediated knockdown of endogenous HIF-1α expression attenuates the PGF2α-induced expression of DEC1, overcomes the inhibitory effects of PGF2α on the expression of proadipogenic transcription factors C/EBPα and PPARγ and partially rescues the PGF2α-induced inhibition of adipogenesis. Taken together, these results indicate that PGF2α promotes the activation of the HIF-1 transcription factor pathway under normal oxygen conditions, and highlight a potential role for the normoxic activation of the HIF-1/DEC1-pathway in mediating the inhibitory effects of PGF2α on adipocyte differentiation. PMID:18461556

  5. Effects of Camphorquinone on Cytotoxicity, Cell Cycle Regulation and Prostaglandin E2 Production of Dental Pulp Cells: Role of ROS, ATM/Chk2, MEK/ERK and Hemeoxygenase-1

    PubMed Central

    Chang, Mei-Chi; Lin, Li-Deh; Wu, Min-Tsz; Chan, Chiu-Po; Chang, Hsiao-Hua; Lee, Ming-Shu; Sun, Tzu-Ying; Jeng, Po-Yuan; Yeung, Sin-Yuet; Lin, Hsueh-Jen; Jeng, Jiiang-Huei

    2015-01-01

    Camphorquinone (CQ) is a popularly-used photosensitizer in composite resin restoration. In this study, the effects of CQ on cytotoxicity and inflammation-related genes and proteins expression of pulp cells were investigated. The role of reactive oxygen species (ROS), ATM/Chk2/p53 and hemeoxygenase-1 (HO-1) and MEK/ERK signaling was also evaluated. We found that ROS and free radicals may play important role in CQ toxicity. CQ (1 and 2 mM) decreased the viability of pulp cells to about 70% and 50% of control, respectively. CQ also induced G2/M cell cycle arrest and apoptosis of pulp cells. The expression of type I collagen, cdc2, cyclin B, and cdc25C was inhibited, while p21, HO-1 and cyclooxygenase-2 (COX-2) were stimulated by CQ. CQ also activated ATM, Chk2, and p53 phosphorylation and GADD45α expression. Besides, exposure to CQ increased cellular ROS level and 8-isoprostane production. CQ also stimulated COX-2 expression and PGE2 production of pulp cells. The reduction of cell viability caused by CQ can be attenuated by N-acetyl-L-cysteine (NAC), catalase and superoxide dismutase (SOD), but can be promoted by Zinc protoporphyin (ZnPP). CQ stimulated ERK1/2 phosphorylation, and U0126 prevented the CQ-induced COX-2 expression and prostaglandin E2 (PGE2) production. These results indicate that CQ may cause cytotoxicity, cell cycle arrest, apoptosis, and PGE2 production of pulp cells. These events could be due to stimulation of ROS and 8-isoprostane production, ATM/Chk2/p53 signaling, HO-1, COX-2 and p21 expression, as well as the inhibition of cdc2, cdc25C and cyclin B1. These results are important for understanding the role of ROS in pathogenesis of pulp necrosis and pulpal inflammation after clinical composite resin filling. PMID:26658076

  6. Prostaglandin Endoperoxides. A New Concept Concerning the Mode of Action and Release of Prostaglandins*

    PubMed Central

    Hamberg, Mats; Svensson, Jan; Samuelsson, Bengt

    1974-01-01

    Methods were developed for quantitative determination of the three major metabolites of arachidonic acid in human platelets, i.e., 12L-hydroxy-5,8,10,14-eicosatetraenoic acid (HETE), 12L-hydroxy-5,8,10-heptadecatrienoic acid (HHT) and 8-(1-hydroxy-3-oxopropyl)-9,12L-dihydroxy-5,10-heptadecadienoic acid (PHD). Aggregation of washed platelets by thrombin was accompanied by release of 1163-2175 ng/ml of HETE, 1129-2430 ng/ml of HHT, and 998-2299 ng/ml of PHD. The amount of PGG2 (prostaglandin G2) produced as calculated from the sum of the amounts of its metabolites (HHT and PHD) was 2477-5480 ng/ml. In contrast, the amounts of PGE2 (prostaglandin E2) and PGF2α (prostaglandin F2α) released were approximately two orders of magnitude lower. In this system, the prostaglandins thus exert their biological action through the endoperoxides, which are almost exclusively metabolized to nonprostanoate structures and only to a small extent to the classical prostaglandins. Platelets from subjects given aspirin produced less than 5% of the above mentioned amounts of HHT and PHD, whereas the production of HETE was stimulated about 3-fold. This provides additional evidence for our earlier proposal [Hamberg, M., Svensson, J., Wakabayashi, T. & Samuelsson, B. (1974) Proc. Nat. Acad. Sci. USA 71, 345-349] that the anti-aggregating effect of aspirin is through inhibition of PGG2 formation. PMID:4530264

  7. Postpartum levels of 8-iso-prostaglandin F2α in plasma and milk phospholipid fractions as biomarker of oxidative stress in first-lactating dairy cows.

    PubMed

    Vernunft, A; Viergutz, T; Plinski, C; Weitzel, J M

    2014-08-01

    F2-isoprostanes such as 8-iso-prostaglandin F2<alpha> (8-iso-PGF2α) are formed by free radical-catalyzed mechanisms from membrane phospholipids and from low density lipoproteins through peroxidation of arachidonic acid. Esterified 8-iso-PGF2α is cleaved by phospholipases, circulates in blood and is excreted as putatively harmful oxidatively modified lipid via the kidney into urine. In this study we demonstrate that 8-iso-PGF2α concentrations in plasma samples from heifers are higher (p<0.005) compared to those from first-lactating dairy cows at 71 days postpartum. Furthermore, plasma 8-iso-PGF2α concentrations vary with ovarian activity and differ in response to luteolytic initiation as well as activation of the hypothalamic-pituitary-gonadal axis between heifers and first-lactating cows. Sustainable concentrations of 8-iso-PGF2α (50-150 pg/ml) are detectable in the phospholipid fraction of milk, suggesting milk as an additional excretion route for 8-isoprostanes. Plasma levels largely paralleled levels in milk (p<0.001). Plasma phospholipid 8-iso-PGF2α concentrations in cyclic cows decreased (p<0.05) from day 38 to day 71 postpartum, whereas milk phospholipid 8-iso-PGF2α rather increased (p<0.05). Cyclic cows tend to have higher 8-isoprostane levels compared to acyclic animals. In contrast to lipohydroperoxides, concentration of 8-iso-PGF2α were not correlated with milk yield (p>0.05). Our data indicate 8-iso-PGF2α may be a novel biomarker of oxidative stress in dairy cow, which is detectable in blood as well as in milk.

  8. Captopril-induced Changes in Prostaglandin Production

    PubMed Central

    Swartz, Stephen L.; Williams, Gordon H.; Hollenberg, Norman K.; Levine, Lawrence; Dluhy, Robert G.; Moore, Thomas J.

    1980-01-01

    Captopril is a potent hypotensive agent whose efficacy has hitherto been attributed to its ability to alter either angiotensin II formation or kinin degradation. Our purpose was to examine captopril's acute effect on prostaglandin production, because changes in neither the renin-angiotensin nor the kallikrein-kinin systems appear adequate to account for the fall in arterial pressure. The plasma levels of angiotensin II, kinins, and prostaglandins were determined in response to increasing doses (5, 12.5, and 25 mg) of captopril and these responses were compared with the change in arterial pressure observed in nine supine normal male subjects studied on both a high (200 meq) and low (10 meq) sodium intake. Captopril significantly (P < 0.01) increased the levels of the 13,14-dihydro-15-keto metabolite of prostaglandin E2 (PGE2-M), a potent vasodilator, with similar responses being observed on both a high and a low sodium intake. No significant changes in the plasma levels of 6-keto-prostaglandin F 1α, or thromboxane B2, the stable products of prostacyclin and thromboxane A2, respectively, occurred. The depressor response to captopril correlated with the change in PGE2-M (r = 0.52, t = 5.44, P < 0.0001). On the other hand, although significant (P < 0.02) decrements in angiotensin II and increments in plasma kinins accompanied the hypotensive response in sodium-restricted subjects, in sodium-loaded subjects where the renin-angiotensin system was suppressed, no change in angiotensin II, and only a modest change in kinins was noted, even though significant (P < 0.01) decrements in diastolic blood pressure occurred (−10±2 mm Hg). Thus, changes in depressor prostaglandin production can better account for the hypotensive response to captopril, thereby extending to yet another vasoactive system an influence by this class of drugs and providing a new approach to dissecting the abnormality in the control of vascular tone in patients with hypertension. PMID:6997332

  9. Accumulation of ascorbate by endocrine-regulated and glucose-sensitive transport of dehydroascorbic acid in luteinized rat ovarian cells.

    PubMed

    Kodaman, P H; Aten, R F; Behrman, H R

    1998-02-01

    The corpus luteum is notable for very high levels of ascorbic acid. In luteal cells, ascorbic acid depletion occurs as a result of consumption during radical scavenging, inhibition of ascorbic acid uptake, and stimulation of its secretion. Oxidation of ascorbic acid generates dehydroascorbic acid (DHAA). Although levels of DHAA in blood are much lower than those of ascorbic acid, DHAA serves as the major transportable form of ascorbate for certain cell types. The aim of the present studies was to investigate whether DHAA transport is a potential mechanism for conserving ascorbic acid in the corpus luteum. DHAA uptake by rat luteal cells precultured for 24 h was linear for up to 30 min. Kinetics studies showed that uptake of DHAA was a concentration-dependent and saturable process with an estimated Michaelis constant (Km) of 830 microM and a maximum velocity (Vmax) of 700 pmol/min per 10(6) cells, a rate 50 times that of ascorbate transport. More than 90% of DHAA was reduced to ascorbic acid within 2 h of cellular uptake. DHAA uptake was energy- and microfilament-dependent, as transport was inhibited by 2,4-dinitrophenol (1 mM) and cytochalasin B (10 microM). Menadione (50 microM), an intracellular generator of reactive oxygen species, also markedly reduced DHAA uptake. In contrast to ascorbic acid transport, DHAA uptake was potently inhibited by glucose and phloretin, an inhibitor of glucose transporters, with IC50s of approximately 5 mM and 10 microM, respectively. DHAA uptake appears to occur via an insulin-insensitive transporter, as insulin (10 nM) had no effect on uptake. However, 24-h preincubation with insulin-like growth factor (IGF)-I dose-dependently (10-100 ng/ml) stimulated DHAA uptake; similar concentrations of IGF-II had no effect. The secretion of radioactivity by cells preloaded with radiolabeled DHAA was significantly increased by prostaglandin F2alpha (1 microM). The ability of luteal cells to transport DHAA in a regulated manner may serve to

  10. Protective effect of (±)α-tocopherol on brominated diphenyl ether-47-stimulated prostaglandin pathways in human extravillous trophoblasts in vitro.

    PubMed

    Park, Hae-Ryung; Loch-Caruso, Rita

    2015-10-01

    Brominated diphenyl ether (BDE)-47 is a prevalent flame retardant chemical found in human tissues and is linked to adverse pregnancy outcomes in humans. Because dysregulation of the prostaglandin pathway is implicated in adverse pregnancy outcomes, the present study investigates BDE-47 induction of prostaglandin synthesis in a human extravillous trophoblast cell line, HTR-8/SVneo, examining the hypothesis that BDE-47 increases generation of reactive oxygen species (ROS) to stimulate the prostaglandin response. Treatment with 20 μM BDE-47 significantly increased mRNA expression of prostaglandin-endoperoxide synthase 2 (PTGS2) at 4, 12 and 24 h, and 24-h treatment significantly increased cyclooxygenase (COX)-2 cellular protein expression and prostaglandin E2 (PGE2) concentration in culture medium. The BDE-47-stimulated PGE2 release was inhibited by the COX inhibitors indomethacin and NS398, implicating COX activity. Exposure to 20 μM BDE-47 significantly increased ROS generation as measured by carboxydichlorofluorescein fluorescence, and this response was blocked by cotreatment with the peroxyl radical scavenger (±)-α-tocopherol. (±)-α-Tocopherol cotreatment suppressed BDE-47-stimulated increases of PGE2 release without significant effects on COX-2 mRNA and protein expression, implicating a role for ROS in post-translational regulation of COX activity. Because prostaglandins regulate trophoblast functions necessary for placentation and pregnancy, further investigation is warranted of BDE-47 impacts on trophoblast responses. PMID:26026498

  11. Protective Effect of (±)α-Tocopherol on Brominated Diphenyl Ether-47-Stimulated Prostaglandin Pathways in Human Extravillous Trophoblasts In Vitro

    PubMed Central

    Park, Hae-Ryung; Loch-Caruso, Rita

    2015-01-01

    Brominated diphenyl ether (BDE)-47 is a prevalent flame retardant chemical found in human tissues and is linked to adverse pregnancy outcomes in humans. Because dysregulation of the prostaglandin pathway is implicated in adverse pregnancy outcomes, the present study investigates BDE-47 induction of prostaglandin synthesis in a human extravillous trophoblast cell line, HTR-8/SVneo, examining the hypothesis that BDE-47 increases generation of reactive oxygen species (ROS) to stimulate the prostaglandin response. Treatment with 20 μM BDE-47 significantly increased mRNA expression of prostaglandin-endoperoxide synthase 2 (PTGS2) at 4, 12 and 24 h, and 24-h treatment significantly increased cyclooxygenase (COX)-2 cellular protein expression and prostaglandin E2 (PGE2) concentration in culture medium. The BDE-47-stimulated PGE2 release was inhibited by the COX inhibitors indomethacin and NS398, implicating COX activity. Exposure to 20 μM BDE-47 significantly increased ROS generation as measured by carboxydichlorofluorescein fluorescence, and this response was blocked by cotreatment with the peroxyl radical scavenger (±)-α-tocopherol. (±)-α-Tocopherol cotreatment suppressed BDE-47-stimulated increases of PGE2 release without significant effects on COX-2 mRNA and protein expression, implicating a role for ROS in post-translational regulation of COX activity. Because prostaglandins regulate trophoblast functions necessary for placentation and pregnancy, further investigation is warranted of BDE-47 impacts on trophoblast responses. PMID:26026498

  12. Prostaglandin E2-induced up-regulation of c-fos messenger ribonucleic acid is primarily mediated by 3',5'-cyclic adenosine monophosphate in MC3T3-E1 osteoblasts

    NASA Technical Reports Server (NTRS)

    Fitzgerald, J.; Dietz, T. J.; Hughes-Fulford, M.

    2000-01-01

    The mechanism by which the proto-oncogene, c-fos, is up-regulated in response to PGE2 in the mouse osteoblastic (MC3T3-E1) cell line was investigated using RT-PCR. c-fos messenger RNA up-regulation by dmPGE2 is rapid, starting 10 min post stimulation, and transient. The specific protein kinase A (PKA) inhibitor, H89, inhibited c-fos induction. Moreover, down-regulation of protein kinase C (PKC) activity by chronic TPA treatment had no effect on the induction of c-fos by dmPGE2. We conclude that up-regulation of c-fos by dmPGE2 is primarily dependent on PKA in MC3T3-E1 osteoblasts. In S49 lymphoma wild-type but not S49 cyc- cells, which are deficient in cAMP signaling, dmPGE2 up-regulates c-fos and increases cell growth compared with unstimulated cells. Thus in S49 lymphoma cells, c-fos induction by PGE2 is also dependent on cAMP signaling. The minimal c-fos promoter region required for dmPGE2-induced expression was identified by transfecting c-fos promoter deletion constructs coupled to the chloramphenicol acetyltransferase (CAT) reporter gene into Vero cells. Transfection of a plasmid containing 99 bp c-fos proximal promoter was sufficient to direct c-fos/CAT expression following stimulation with dmPGE2. Because induction of c-fos is mediated by cAMP, these data are consistent with activation of c-fos via the CRE/ATF cis element.

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

    PubMed

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

    2016-05-11

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

  14. Prostaglandin E2 signals white-to-brown adipogenic differentiation.

    PubMed

    García-Alonso, Verónica; Clària, Joan

    2014-01-01

    The formation of new adipocytes from precursor cells is a crucial aspect of normal adipose tissue function. During the adipogenic process, adipocytes differentiated from mesenchymal stem cells give rise to two main types of fat: white adipose tissue (WAT) characterized by the presence of adipocytes containing large unilocular lipid droplets, and brown adipose tissue (BAT) composed by multilocular brown adipocytes packed with mitochondria. WAT is not only important for energy storage but also as an endocrine organ regulating whole body homeostasis by secreting adipokines and other mediators, which directly impact metabolic functions in obesity. By contrast, BAT is specialized in dissipating energy in form of heat and has salutary effects in combating obesity and associated disorders. Unfortunately, WAT is the predominant fat type, whereas BAT is scarce and located in discrete pockets in adult humans. Luckily, another type of brown adipocytes, called beige or brite (brown-in-white) adipocytes, with similar functions to those of "classical" brown adipocytes has recently been identified in WAT. In this review, a close look is given into the role of bioactive lipid mediators in the regulation of adipogenesis, with a special emphasis on the role of the microsomal prostaglandin E (PGE) synthase-1, a terminal enzyme in PGE2 biosynthesis, as a key regulator of white-to-brown adipogenesis in WAT. PMID:26317053

  15. Pulmonary biosynthesis and metabolism of prostaglandins and related substances.

    PubMed Central

    Eling, T E; Ally, A I

    1984-01-01

    On passage through the lung vascular bed, prostaglandins are removed from the circulation by a transport carrier and subsequently inactivated by intracellular enzymes. However, PGI2 is not inactivated by the lung in vivo. Although PGI2 is an excellent substrate for the intracellular enzymes in vitro, PGI2 is not a substrate for the carrier system. Thus, the transport carrier determines which circulating prostaglandin is inactivated by the pulmonary vascular bed. Also, the lung has a high capacity for forming prostaglandins from arachidonic acid. Considerable differences exist between species in relation to amount and specific prostaglandin formed as determined by incubation of 11C-PGH2 with pulmonary microsomes. The pulmonary biosynthesis and metabolism of these prostaglandins and related substances are discussed. PMID:6428876

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

    PubMed Central

    Flitney, F W; Singh, J

    1980-01-01

    reached: thus, 8-bromo-3'5'-cyclic GMP accelerates the decline in contractility and depresses the steady-state level, whereas dibutyryl 3'5'-cyclic AMP delays the development of hypodynamic depression, and elevates the final twitch tension. The effects of both 3'5' cyclic nucleotide derivatives are dose-dependent. 7. The possible involvement of prostaglandins and 3'5'-cyclic nucleotides as causal agents in the mechanism of hypodynamic depression is discussed. The biochemical basis for the implied antangonistic effects of 3'5'-cyclic AMP and 3'5'-cyclic GMP in regulating ventricular contractility is considered in the following paper (Flitney & Singh, 1980). PMID:6255139

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

    SciTech Connect

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

    1988-10-01

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

  18. Involvement of prostaglandins F/sub 2. cap alpha. / and E/sub 1/ with rabbit endometrium

    SciTech Connect

    Orlicky, D.J.

    1985-01-01

    Several growth factors and hormones are thought to play a role in the growth control of endometrial cells. The authors have shown that prostaglandin F/sub 2..-->../ (PGF/sub 2..cap alpha../) is a growth factor for primary cultures of rabbit endometrium cultured in chemically-defined serum-free medium and that prostaglandin E/sub 1/ (PGE/sub 1/) antagonizes the PGF/sub 2..-->../ induction of growth. Both (/sup 3/H)PGF/sub 2..cap alpha../ and (/sup 3/H)PGE/sub 1/ bind in a time and temperature dependent, dissociable, saturable and specific manner. The binding of (/sup 3/H)PGF/sub 2..cap alpha../ and (/sup 3/H)PGE/sub 1/ can be both down and up regulated and is enzyme sensitive. PGE /sub 1/ stimulates intracellular cAMP synthesis and accumulation in a time and concentration dependent manner. PGF/sub 2..cap alpha../ probably exerts its effects through an amiloride-sensitive intermediate. Both PGF/sub 2..cap alpha../ and PGE/sub 1/ are constitutively synthesized by these primary cultures, and they have shown this synthesis to be both drug and hormone sensitive. They hypothesize that it is the ratio, rather than the absolute quantities, of PGF/sub 2..cap alpha../ and PGE/sub 1/ which is of more importance in the regulation of endometrial cell growth. Furthermore, they believe this regulation of endometrial growth plays a role in control of proliferation during the decidual response and that a derangement in the ratio of these prostaglandins may lead to either infertility or hyperplasia. The ability of these cultures to synthesize prostaglandins in a hormonally regulatable manner may be of importance in the study of dysmenorrhea and uterine cramping as caused by the myometrial contracting prostaglandin, PGF/sub 2..cap alpha../.

  19. Prostaglandins and estradiol-induced attenuation of hypoxic pulmonary vasoconstriction.

    PubMed

    Sylvester, J T; Gordon, J B; Malamet, R L; Wetzel, R C

    1985-10-01

    Pretreatment with estradiol (20 mg IM) attenuated vasoreactivity to decreases in inspired PIO2, lowered baseline resistance measured under conditions of maximal vasodilation (PIO2 = 0 mm Hg), and appeared to increase prostaglandin release in isolated, blood-perfused lungs of juvenile female sheep. Indomethacin (40 micrograms/ml) inhibited prostaglandin release and restored hypoxic vasoreactivity in estrogen-treated lungs, but did not alter the estrogen-induced decrease in baseline resistance. These results suggest that estradiol enhanced the production of prostaglandins which secondarily attenuated hypoxic vasoreactivity. The estradiol-induced decrease in baseline resistance, however, must have been mediated by some other mechanism.

  20. Neural Circuitry Engaged by Prostaglandins during the Sickness Syndrome

    PubMed Central

    Saper, Clifford B.; Romanovsky, Andrej A.; Scammell, Thomas E.

    2013-01-01

    During illnesses caused by infectious disease or other sources of inflammation, a suite of brain-mediated responses called the “sickness syndrome” occurs, including fever, anorexia, sleepiness, hyperalgesia, and elevated corticosteroid secretion. Much of the sickness syndrome is mediated by prostaglandins acting on the brain, and can be prevented by non-steroidal anti-inflammatory drugs, such as aspirin or ibuprofen, that block prostaglandin synthesis. By examining which prostaglandins are produced at which sites and how they interact with the nervous system, researchers have identified specific neural circuits that underlie the sickness syndrome. PMID:22837039

  1. Antihypertensive effects of selective prostaglandin E2 receptor subtype 1 targeting

    PubMed Central

    Guan, Youfei; Zhang, Yahua; Wu, Jing; Qi, Zhonghua; Yang, Guangrui; Dou, Dou; Gao, Yuansheng; Chen, Lihong; Zhang, Xiaoyan; Davis, Linda S.; Wei, Mingfeng; Fan, Xuefeng; Carmosino, Monica; Hao, Chuanming; Imig, John D.; Breyer, Richard M.; Breyer, Matthew D.

    2007-01-01

    Clinical use of prostaglandin synthase–inhibiting NSAIDs is associated with the development of hypertension; however, the cardiovascular effects of antagonists for individual prostaglandin receptors remain uncharacterized. The present studies were aimed at elucidating the role of prostaglandin E2 (PGE2) E-prostanoid receptor subtype 1 (EP1) in regulating blood pressure. Oral administration of the EP1 receptor antagonist SC51322 reduced blood pressure in spontaneously hypertensive rats. To define whether this antihypertensive effect was caused by EP1 receptor inhibition, an EP1-null mouse was generated using a “hit-and-run” strategy that disrupted the gene encoding EP1 but spared expression of protein kinase N (PKN) encoded at the EP1 locus on the antiparallel DNA strand. Selective genetic disruption of the EP1 receptor blunted the acute pressor response to Ang II and reduced chronic Ang II–driven hypertension. SC51322 blunted the constricting effect of Ang II on in vitro–perfused preglomerular renal arterioles and mesenteric arteriolar rings. Similarly, the pressor response to EP1-selective agonists sulprostone and 17-phenyltrinor PGE2 were blunted by SC51322 and in EP1-null mice. These data support the possibility of targeting the EP1 receptor for antihypertensive therapy. PMID:17710229

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

    SciTech Connect

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

    1987-02-01

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

  3. Novel contraceptive targets to inhibit ovulation: the prostaglandin E2 pathway

    PubMed Central

    Duffy, Diane M.

    2015-01-01

    BACKGROUND Prostaglandin E2 (PGE2) is an essential intrafollicular regulator of ovulation. In contrast with the one-gene, one-protein concept for synthesis of peptide signaling molecules, production and metabolism of bioactive PGE2 requires controlled expression of many proteins, correct subcellular localization of enzymes, coordinated PGE2 synthesis and metabolism, and prostaglandin transport in and out of cells to facilitate PGE2 action and degradation. Elevated intrafollicular PGE2 is required for successful ovulation, so disruption of PGE2 synthesis, metabolism or transport may yield effective contraceptive strategies. METHODS This review summarizes case reports and studies on ovulation inhibition in women and macaques treated with cyclooxygenase inhibitors published from 1987 to 2014. These findings are discussed in the context of studies describing levels of mRNA, protein, and activity of prostaglandin synthesis and metabolic enzymes as well as prostaglandin transporters in ovarian cells. RESULTS The ovulatory surge of LH regulates the expression of each component of the PGE2 synthesis-metabolism-transport pathway within the ovulatory follicle. Data from primary ovarian cells and cancer cell lines suggest that enzymes and transporters can cooperate to optimize bioactive PGE2 levels. Elevated intrafollicular PGE2 mediates key ovulatory events including cumulus expansion, follicle rupture and oocyte release. Inhibitors of the prostaglandin-endoperoxide synthase 2 (PTGS2) enzyme (also known as cyclooxygenase-2 or COX2) reduce ovulation rates in women. Studies in macaques show that PTGS2 inhibitors can reduce the rates of cumulus expansion, oocyte release, follicle rupture, oocyte nuclear maturation and fertilization. A PTGS2 inhibitor reduced pregnancy rates in breeding macaques when administered to simulate emergency contraception. However, PTGS2 inhibition did not prevent pregnancy in monkeys when administered to simulate monthly contraceptive use. CONCLUSION

  4. The role of prostaglandines in peristalsis of the human colon.

    PubMed

    Bruch, H P; Schmidt, E; Laven, R; Kehrer, G; Wasner, K H

    1978-08-01

    Prostaglandines (PG) of the E and F series cause peristaltic activity in isolated longitudinal muscle strips of the human colon. As this phasic motor reaction can be varied by acetyl choline and adrenaline it was supposed, that prostaglandines contribute to peristalsis. The role of PG E and F in the human colon was studied by inhibiting the prostaglandine synthesis and by antagonizing the prostaglandine-effects. Indomethacin proved to be a suitable inhibitor. HR 546 was found a powerful antagonist. The effect of Pentagastrin and Cholecystokinin (CCK) on peristaltic activity were suppressed by Indomethacin and HR 546. The inhibition of peristalsis by Indomethacin and HR 546 was removed by high doses of PG E and F. On the basis of these results the role of PG for the motility of the gut is discussed.

  5. Effects of Prostaglandin Analogues on Aqueous Humor Outflow Pathways

    PubMed Central

    Winkler, Nelson S.

    2014-01-01

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

  6. Prostaglandin-modulated umbilical cord blood hematopoietic stem cell transplantation.

    PubMed

    Cutler, Corey; Multani, Pratik; Robbins, David; Kim, Haesook T; Le, Thuy; Hoggatt, Jonathan; Pelus, Louis M; Desponts, Caroline; Chen, Yi-Bin; Rezner, Betsy; Armand, Philippe; Koreth, John; Glotzbecker, Brett; Ho, Vincent T; Alyea, Edwin; Isom, Marlisa; Kao, Grace; Armant, Myriam; Silberstein, Leslie; Hu, Peirong; Soiffer, Robert J; Scadden, David T; Ritz, Jerome; Goessling, Wolfram; North, Trista E; Mendlein, John; Ballen, Karen; Zon, Leonard I; Antin, Joseph H; Shoemaker, Daniel D

    2013-10-24

    Umbilical cord blood (UCB) is a valuable source of hematopoietic stem cells (HSCs) for use in allogeneic transplantation. Key advantages of UCB are rapid availability and less stringent requirements for HLA matching. However, UCB contains an inherently limited HSC count, which is associated with delayed time to engraftment, high graft failure rates, and early mortality. 16,16-Dimethyl prostaglandin E2 (dmPGE2) was previously identified to be a critical regulator of HSC homeostasis, and we hypothesized that brief ex vivo modulation with dmPGE2 could improve patient outcomes by increasing the "effective dose" of HSCs. Molecular profiling approaches were used to determine the optimal ex vivo modulation conditions (temperature, time, concentration, and media) for use in the clinical setting. A phase 1 trial was performed to evaluate the safety and therapeutic potential of ex vivo modulation of a single UCB unit using dmPGE2 before reduced-intensity, double UCB transplantation. Results from this study demonstrated clear safety with durable, multilineage engraftment of dmPGE2-treated UCB units. We observed encouraging trends in efficacy, with accelerated neutrophil recovery (17.5 vs 21 days, P = .045), coupled with preferential, long-term engraftment of the dmPGE2-treated UCB unit in 10 of 12 treated participants.

  7. Differential Stem and Progenitor Cell Trafficking by Prostaglandin E2

    PubMed Central

    Hoggatt, Jonathan; Mohammad, Khalid S.; Singh, Pratibha; Hoggatt, Amber F.; Chitteti, Brahmananda Reddy; Speth, Jennifer M.; Hu, Peirong; Poteat, Bradley A.; Stilger, Kayla N.; Ferraro, Francesca; Silberstein, Lev; Wong, Frankie K.; Farag, Sherif S.; Czader, Magdalena; Milne, Ginger L.; Breyer, Richard M.; Serezani, Carlos H.; Scadden, David T.; Guise, Theresa; Srour, Edward F.; Pelus, Louis M.

    2013-01-01

    SUMMARY To maintain lifelong production of blood cells, hematopoietic stem cells (HSC) are tightly regulated by inherent programs and extrinsic regulatory signals received from their microenvironmental niche. Long-term repopulating HSC (LT-HSC) reside in several, perhaps overlapping, niches that produce regulatory molecules/signals necessary for homeostasis and increased output following stress/injury 1–5. Despite significant advances in specific cellular or molecular mechanisms governing HSC/niche interactions, little is understood about regulatory function within the intact mammalian hematopoietic niche. Recently, we and others described a positive regulatory role for Prostaglandin E2 (PGE2) on HSC function ex vivo 6,7. While exploring the role of endogenous PGE2 we unexpectedly observed hematopoietic egress after nonsteroidal anti-inflammatory drug (NSAID) treatment. Surprisingly, this was independent of the SDF-1/CXCR4 axis. Stem and progenitor cells were found to have differing mechanisms of egress, with HSC transit to the periphery dependent on niche attenuation and reduction in the retentive molecule osteopontin (OPN). Hematopoietic grafts mobilized with NSAIDs had superior repopulating ability and long-term engraftment. Treatment of non-human primates and healthy human volunteers confirmed NSAID-mediated egress in higher species. PGE2 receptor knockout mice demonstrated that progenitor expansion and stem/progenitor egress resulted from reduced EP4 receptor signaling. These results not only uncover unique regulatory roles for EP4 signaling in HSC retention in the niche but also define a rapidly translatable strategy to therapeutically enhance transplantation. PMID:23485965

  8. Prostaglandin E2 Regulation of Macrophage Innate Immunity.

    PubMed

    Kimmel, Danielle W; Rogers, Lisa M; Aronoff, David M; Cliffel, David E

    2016-01-19

    Globally, maternal and fetal health is greatly impacted by extraplacental inflammation. Group B Streptococcus (GBS), a leading cause of chorioamnionitis, is thought to take advantage of the uterine environment during pregnancy in order to cause inflammation and infection. In this study, we demonstrate the metabolic changes of murine macrophages caused by GBS exposure. GBS alone prompted a delayed increase in lactate production, highlighting its ability to redirect macrophage metabolism from aerobic to anaerobic respiration. This production of lactate is thought to aid in the development and propagation of GBS throughout the surrounding tissue. Additionally, this study shows that PGE2 priming was able to exacerbate lactate production, shown by the rapid and substantial lactate increases seen upon GBS exposure. These data provide a novel model to study the role of GBS exposure to macrophages with and without PGE2 priming. PMID:26656203

  9. Transforming growth factor beta 1 augments mitogen-induced prostaglandin synthesis and expression of the TIS10/prostaglandin synthase 2 gene both in Swiss 3T3 cells and in murine embryo fibroblasts.

    PubMed

    Gilbert, R S; Reddy, S T; Kujubu, D A; Xie, W; Luner, S; Herschman, H R

    1994-04-01

    Transforming growth factor-beta (TGF-beta), a potent cytokine, modulates a wide variety of biological responses. Among its actions, TGF-beta can augment prostaglandin synthesis in several cell types. Although TGF-beta alone has no effect on prostaglandin production in Swiss 3T3 cells, we find that TGF-beta augments the ability of tetradecanoyl phorbol acetate (TPA) or serum to stimulate PGE2 production. The TIS10 gene is a primary response gene encoding a second form of prostaglandin synthase (PGS), the rate-limiting enzyme in the biosynthesis of prostaglandins, thromboxanes, and prostacyclins from arachidonic acid. TIS10/PGS-2 expression is induced by mitogens in Swiss 3T3 cells. TGF-beta also augments mitogen-induced synthesis and accumulation of TIS10/PGS-2 protein and induction of TIS10/PGS-2 message in Swiss 3T3 cells. In contrast, TGF-beta has little or no effect on the level of PGS-1 (EC1.14.99.1) message, either alone or in concert with TPA or serum. TGF-beta concentrations in the range of 0.01-0.10 ng/ml (0.4-4.0 pM) maximally enhance mitogen induction of TIS10/PGS-2 message. TPA-induced accumulation of unspliced TIS10/PGS-2 transcript is augmented by TGF-beta, suggesting that this cytokine exerts its effect on expression of the TIS10/PGS-2 gene by transcriptional regulation. TGF-beta also augments TPA-induced prostaglandin production, TIS10/PGS-2 antigen accumulation, and TIS10/PGS-2 message induction in primary cultures of mouse embryo fibroblasts. Dexamethasone attenuates TGF-beta enhancement of all these mitogen-induced responses: PGE2 accumulation, appearance of TIS10/PGS-2 protein and message, and accumulation of TIS10/PGS-2 unprocessed transcript.

  10. Pharmacogenomics of Prostaglandin and Leukotriene Receptors

    PubMed Central

    Cornejo-García, José A.; Perkins, James R.; Jurado-Escobar, Raquel; García-Martín, Elena; Agúndez, José A.; Viguera, Enrique; Pérez-Sánchez, Natalia; Blanca-López, Natalia

    2016-01-01

    Individual genetic background together with environmental effects are thought to be behind many human complex diseases. A number of genetic variants, mainly single nucleotide polymorphisms (SNPs), have been shown to be associated with various pathological and inflammatory conditions, representing potential therapeutic targets. Prostaglandins (PTGs) and leukotrienes (LTs) are eicosanoids derived from arachidonic acid and related polyunsaturated fatty acids that participate in both normal homeostasis and inflammatory conditions. These bioactive lipid mediators are synthesized through two major multistep enzymatic pathways: PTGs by cyclooxygenase and LTs by 5-lipoxygenase. The main physiological effects of PTGs include vasodilation and vascular leakage (PTGE2); mast cell maturation, eosinophil recruitment, and allergic responses (PTGD2); vascular and respiratory smooth muscle contraction (PTGF2), and inhibition of platelet aggregation (PTGI2). LTB4 is mainly involved in neutrophil recruitment, vascular leakage, and epithelial barrier function, whereas cysteinyl LTs (CysLTs) (LTC4, LTD4, and LTE4) induce bronchoconstriction and neutrophil extravasation, and also participate in vascular leakage. PTGs and LTs exert their biological functions by binding to cognate receptors, which belong to the seven transmembrane, G protein-coupled receptor superfamily. SNPs in genes encoding these receptors may influence their functionality and have a role in disease susceptibility and drug treatment response. In this review we summarize SNPs in PTGs and LTs receptors and their relevance in human diseases. We also provide information on gene expression. Finally, we speculate on future directions for this topic. PMID:27708579

  11. Simulated microgravity upregulates an endothelial vasoconstrictor prostaglandin

    NASA Technical Reports Server (NTRS)

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

    2001-01-01

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

  12. Cyclooxygenase and prostaglandins in somatic cell populations of the testis.

    PubMed

    Frungieri, Mónica B; Calandra, Ricardo S; Mayerhofer, Artur; Matzkin, María E

    2015-04-01

    Prostaglandins (PGs) are synthesized through the action of the rate-limiting enzyme cyclooxygenase (COX) and further specific enzymes. The development of Cox-deficient mice in the 1990s gave insights into the reproductive roles of PGs. Female Cox-knockout mice were subfertile or infertile. Interestingly, fertility was not affected in male mice deficient in Cox, suggesting that PGs may not be critical for the functioning of the testis. However, this conclusion has recently been challenged by observations of important roles for PGs in both physiological and pathological processes in the testis. The two key somatic cell types in the testis, Leydig and Sertoli cells, express the inducible isoenzyme COX2 and produce PGs. Testicular COX2 expression in these somatic cells is regulated by hormonal input (FSH, prolactin (PRL), and testosterone) as well as by IL1β. PGs modulate steroidogenesis in Leydig cells and glucose uptake in Sertoli cells. Hence, the COX2/PG system in Leydig and Sertoli cells acts as a local modulator of testicular activity, and consequently may regulate spermatogenic efficiency. In addition to its expression in Leydig and Sertoli cells, COX2 has been detected in the seminiferous tubule wall, and in testicular macrophages and mast cells of infertile patients. These observations highlight the possible relevance of PGs in testicular inflammation associated with idiopathic infertility. Collectively, these data indicate that the COX2/PG system plays crucial roles not only in testicular physiology (i.e., development, steroidogenesis, and spermatogenesis), but more importantly in the pathogenesis or maintenance of infertility status in the male gonad. Further studies of these actions could lead to new therapeutic approaches to idiopathic male infertility.

  13. Effect of resveratrol and beta-sitosterol in combination on reactive oxygen species and prostaglandin release by PC-3 cells.

    PubMed

    Awad, Atif B; Burr, Andrew T; Fink, Carol S

    2005-03-01

    The objective of this project was to identify some possible mechanisms by which two common phytochemicals, resveratrol and beta-sitosterol, inhibit the growth of human prostate cancer PC-3 cells. These mechanisms include the effect of the phytochemicals on apoptosis, cell cycle progression, prostaglandin synthesis and the production of reactive oxygen species (ROS). Prostaglandins have been known to play a role in regulating cell growth and apoptosis. PC-3 cells were supplemented with 50 microM resveratrol or 16 microM beta-sitosterol alone or in combination for up to 5 days. Phytochemical supplementation resulted in inhibition in cell growth. beta-Sitosterol was more potent than resveratrol and the combination of the two resulted in greater inhibition than supplementation with either alone. Long-term supplementation with resveratrol or beta-sitosterol elevated basal prostaglandin release but beta-sitosterol was much more potent than resveratrol in this regard. beta-Sitosterol was more effective than resveratrol in inducing apoptosis and the combination had an intermediate effect after 1 day of supplementation. Cells supplemented with resveratrol were arrested at the G1 phase and at the G2/M phase in the case of beta-sitosterol while the combination resulted in cell arrest at the two phases of the cell cycle. beta-Sitosterol increased ROS production while resveratrol decreased ROS production. The combination of the two phytochemicals resulted in an intermediate level of ROS. The observed changes in prostaglandin levels and ROS production by these two phytochemicals may suggest their mediation in the growth inhibition. The reduction in ROS level and increase by resveratrol supplementation in PC-3 cells reflects the antioxidant properties of resveratrol. It was concluded that these phytochemicals may induce the inhibition of tumor growth by stimulating apoptosis and arresting cells at different locations in the cell cycle and the mechanism may involve alterations in

  14. Prostaglandin E synthase is upregulated by Gas6 during cancer-induced venous thrombosis.

    PubMed

    Aghourian, Meghedi N; Lemarié, Catherine A; Bertin, Francois-René; Blostein, Mark D

    2016-02-11

    Venous thromboembolism is a common complication of cancer. Based on recent evidence that (1) growth arrest-specific 6 (Gas6) regulates the expression of tissue factor during venous thrombosis, and (2) cancer promotes a procoagulant milieu, we hypothesize that Gas6 may be involved in cancer-induced coagulopathy. Venous thrombi were induced in both wild-type (WT) and Gas6-deficient ((-/-)) mice with cancer. WT mice with cancer developed larger thrombi than their healthy counterparts; these larger thrombi induced by cancer were not seen in Gas6(-/-) mice. Whole genome microarray analysis of differential gene expression in WT and Gas6(-/-) endothelial cells exposed to M27 murine lung carcinoma cells reveal that Gas6 increases prostaglandin E synthase (Ptges) expression in endothelial cells. This was confirmed using real-time polymerase chain reaction and immunofluorescence staining. Culture of WT endothelial cells with M27 increases the secretion of prostaglandin E2 (PGE2), the enzymatic product of Ptges, in WT but not in Gas6(-/-) endothelial cells. In WT endothelial cells, Ptges expression was regulated through extracellular signal-regulated kinase 1/2 phosphorylation (ERK1/2). In vitro, PGE2 activates platelets after binding to its receptor, EP3. In vivo, EP3 receptor antagonism reversed the effect of cancer-induced thrombosis in WT mice. These results show that Gas6, through upregulation of PGE2, contributes to cancer-induced venous thrombosis. PMID:26585956

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

    PubMed Central

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

    2012-01-01

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

  16. Suppression of Alzheimer-associated inflammation by microglial prostaglandin-E2 EP4 receptor signaling.

    PubMed

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

    2014-04-23

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

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

    PubMed

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

    2013-09-01

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

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

    PubMed Central

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

    2016-01-01

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

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

    PubMed

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

    2015-01-01

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

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

    PubMed

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

    2016-03-01

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

  1. Prostaglandin receptor EP4 in abdominal aortic aneurysms.

    PubMed

    Cao, Richard Y; St Amand, Tim; Li, XinZhi; Yoon, Sung-Hee; Wang, Carol P; Song, Hui; Maruyama, Takayuki; Brown, Peter M; Zelt, David T; Funk, Colin D

    2012-07-01

    Abdominal aortic aneurysm (AAA) pathogenesis is distinguished by vessel wall inflammation. Cyclooxygenase (COX)-2 and microsomal prostaglandin E synthase-1, key components of the most well-characterized inflammatory prostaglandin pathway, contribute to AAA development in the 28-day angiotensin II infusion model in mice. In this study, we used this model to examine the role of the prostaglandin E receptor subtype 4 (EP4) and genetic knockdown of COX-2 expression (70% to 90%) in AAA pathogenesis. The administration of the prostaglandin receptor EP4 antagonist AE3-208 (10 mg/kg per day) to apolipoprotein E (apoE)-deficient mice led to active drug plasma concentrations and reduced AAA incidence and severity compared with control apoE-deficient mice (P < 0.01), whereas COX-2 genetic knockdown/apoE-deficient mice displayed only a minor, nonsignificant decrease in incidence of AAA. EP4 receptor protein was present in human and mouse AAA, as observed by using Western blot analysis. Aortas from AE3-208-treated mice displayed evidence of a reduced inflammatory phenotype compared with controls. Atherosclerotic lesion size at the aortic root was similar between all groups. In conclusion, the prostaglandin E(2)-EP4 signaling pathway plays a role in the AAA inflammatory process. Blocking the EP4 receptor pharmacologically reduces both the incidence and severity of AAA in the angiotensin II mouse model, potentially via attenuation of cytokine/chemokine synthesis and the reduction of matrix metalloproteinase activities.

  2. Control of parturition in the sow using progesterone and prostaglandin.

    PubMed

    Gooneratne, A; Hartmann, P E; McCauley, I; Martin, C E

    1979-12-01

    The effect of progesterone and prostaglandin administration on the timing of farrowing was studied in three groups of 25 sows each. Progesterone treatment (100 mg/day) on days 112, 113 and 114 of gestation (group I) significantly prolonged the gestation length to 116.4 +/- 0.4 (mean +/- s.e.) days compared to the control sows (group III; 115.5 +/- 0.2; P less than 0.05). Administration of prostaglandin (200 micrograms Cloprostanol intramuscularly) on day 115 of gestation following progesterone treatment (group II) resulted in a gestation length of 116.0 +/- 0.1 days, with the sows farrowing 25.4 +/- 1.0 h after the prostaglandin injection. 80% of the sows farrowed between 0800 and 1700 h of day 116 of gestation. Plasma progesterone levels were maintained by the exogenous progesterone during treatment. At farrowing, higher levels of progesterone were observed in groups I and II compared to controls. Prostaglandin treatment did not significantly alter withdrawal of progesterone in progesterone treated sows, suggesting that the actions of exogenous prostaglandin is primarily on the myometrium and the cervix. Hormonal treatment in late pregnancy did not have any adverse effects on piglet viability and growth rate, or subsequent reproductive performances of sows. Lactation was initiated normally, and the concentrations of lactose, protein, fat, IgG, Na+, Ca2+ and K+ in colostrum and milk were similar in all groups during the first 5 days of lactation.

  3. Impotence evaluated by the use of prostaglandin E1

    SciTech Connect

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

    1989-06-01

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

  4. Homologous desensitization to prostaglandins in rabbit ileum

    SciTech Connect

    Musch, M.W.; Field, M.; Miller, R.J.; Stoff, J.S.

    1987-01-01

    Prostaglandins (PG's) increase short-circuit current (I/sub sc/), inhibit NaCl absorption, and stimulate Cl secretion in rabbit ileum. These changes occur with the following PGs; E/sub 3/, E/sub 1/, nitrilo-I/sub 2/ and, to a lesser extent, with A/sub 2/, D/sub 2/, and F/sub 2..cap alpha../. Arachidonic acid (AA) also stimulates secretion. The PG- or AA-stimulated I/sub sc/ does not persist, however, and on prolonged exposure tachyphylaxis develops. Resensitization of the I/sub sc/ response to PGE/sub 2/ is rapid, being essentially complete in 15 min after the PG is removed. Desensitization to AA is not reflected by diminished PG generation. PGE/sub 2/ release from the mucosa after AA addition is constant, although the AA-stimulated I/sub sc/ decreases. I/sub sc/ measurements indicate that PGE/sub 2/ at slightly below its EC/sub 50/ partially desensitizes and a near-maximal concentration completely desensitizes to PGE/sub 2/ but does not, however, inhibit the subsequent change in I/sub sc/ caused by theophylline or vasoactive intestinal peptide (VIP). Adenosine 3',5'-cyclic monophosphate (cAMP) measurements suggest that desensitization applies to cAMP production. PGE/sub 2/ (10/sup -5/ M) increases mucosal cAMP three- to sevenfold, but this elevation is transient; a second challenge dose, which fails to elicit a I/sub sc/ change, also fails to increase mucosal cAMP. Adenylate cyclase measurements from untreated and PGE/sub 2/-treated enterocytes demonstrate a decrease in stimulation by PGE/sub 2/ but not in stimulation by VIP, fluoride, or 5-guanylylimidodiphosphate.

  5. Prostaglandins, H2-receptor antagonists and peptic ulcer disease.

    PubMed

    Bright-Asare, P; Habte, T; Yirgou, B; Benjamin, J

    1988-01-01

    Peptic ulcer develops when offensive factors overwhelm defensive processes in the gastroduodenal mucosa. Offensive factors include NSAIDs, hydrochloric acid-peptic activity, bile reflux, and some products of the lipoxygenase pathway such as leukotriene B4; whereas defensive processes are largely mediated by prostaglandins through poorly understood mechanisms uniformly termed cytoprotection. Cytoprotection, a physiological process working through the products of arachidonic acid metabolism, may result from the net effect of the protective actions of prostaglandins versus the damaging actions of leukotrienes. Some prostaglandins also have antisecretory effects. Therefore the peptic ulcer healing effects of prostaglandin analogues, all of which have significant antisecretory activity, may be more due to their antisecretory effects than primarily to their effects on mucosal defences. Certain drug-induced gastroduodenal lesions, e.g. NSAID-induced ulcers, which are often unresponsive to H2-receptor antagonists, have been healed and their recurrence prevented by the use of PGE1 and PGE2 analogues. All the prostaglandin analogues investigated to date in humans have the potential for inducing abortion, an important side effect which may limit their worldwide use. The optimal prostaglandin analogue for ulcer healing should not induce abortion and should be potently cytoprotective. The predominant damaging agent in the development of peptic ulcer disease is gastric hydrochloric acid. Thus, the worldwide established efficacy and safety of H2-receptor antagonists such as cimetidine, ranitidine, famotidine and most recently of roxatidine acetate suggest that these agents have become the standard by which other forms of anti-ulcer therapy should be judged. PMID:2905237

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

    PubMed Central

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

    2014-01-01

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

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

    PubMed

    Neacsu, Alina Mihaela

    2009-01-01

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

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

    PubMed

    Neacsu, Alina Mihaela

    2009-01-01

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

  9. Biochemistry of prostaglandin endoperoxide H synthase-1 and synthase-2 and their differential susceptibility to nonsteroidal anti-inflammatory drugs.

    PubMed

    Smith, W L; DeWitt, D L

    1995-05-01

    The principal pharmacological effects of nonsteroidal anti-inflammatory drugs (NSAIDs) are due to their ability to inhibit prostaglandin synthesis. NSAIDs block the cyclooxygenase activities of the closely related PGH synthase-1 and PGH synthase-2 (PGHS-1 and PGHS-2) isozymes. NSAIDs are therapeutically useful due to their analgesic, anti-pyretic, anti-inflammatory, and anti-thrombogenic properties. Major side-effects of NSAIDs include their ulcerogenic and nephrotoxic activities. All clinically approved NSAIDs in general use today inhibit both PGHS-1 and PGHS-2. Recently, inhibitors have been identified that are selective toward PGHS-2 and that have potent analgesic and anti-inflammatory activities with minimal ulcerogenic activity. If the new PGHS-2 selective NSAIDs can effectively inhibit inflammatory prostaglandin synthesis by PGHS-2, without inhibiting PGHS-1 prostaglandin synthesis required to regulate sodium and water resorption, and renal blood flow, it is likely that these new drugs will also have significantly less renal toxicity than present-day NSAIDs. In this article, the mechanisms of actions of NSAIDs primarily at the biochemical level, including the reactions catalyzed by PGHSs, will be discussed. In addition, the biochemical properties of these isozymes, and the differential regulation of the PGHS-1 and PGHS-2 genes, will be examined. PMID:7631045

  10. Role of intracellular prostaglandin E₂ in cancer-related phenotypes in PC3 cells.

    PubMed

    Madrigal-Martínez, Antonio; Cazaña, Francisco J Lucio; Fernández-Martínez, y Ana B

    2015-02-01

    Prostaglandin E2 (PGE2) and hypoxia-inducible factor-1α (HIF-1α) affect many mechanisms that have been shown to play a role in prostate cancer. In PGE2-treated LNCaP cells, up-regulation of HIF-1α requires the internalization of PGE2, which is in sharp contrast with the generally accepted view that PGE2 acts through EP receptors located at the cell membrane. Here we aimed to study in androgen-independent PC3 cells the role of intracellular PGE2 in several events linked to prostate cancer progression. To this end, we used bromocresol green, an inhibitor of prostaglandin uptake that blocked the immediate rise in intracellular immunoreactive PGE2 following treatment with 16,16-dimethyl-PGE2. Bromocresol green prevented the stimulatory effect of 16,16-dimethyl-PGE on cell proliferation, adhesion, migration and invasion and on HIF-1α expression and activity, the latter assessed as the HIF-dependent activation of (i) a hypoxia response element-luciferase plasmid construct, (ii) production of angiogenic factor vascular endothelial growth factor-A and (iii) in vitro angiogenesis. The basal phenotype of PC3 cells was also affected by bromocresol green, that substantially lowered expression of HIF-1α, production of vascular endothelial growth factor-A and cell proliferation. These results, and the fact that we found functional intracellular EP receptors in PC3 cells, suggest that PGE2-dependent intracrine mechanisms play a role in prostate cancer Therefore, inhibition of the prostaglandin uptake transporter might be a novel therapeutic approach for the treatment of prostate cancer.

  11. Hypoxia activates the cyclooxygenase-2–prostaglandin E synthase axis

    PubMed Central

    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

  12. Dendritic cells express hematopoietic prostaglandin D synthase and function as a source of prostaglandin D2 in the skin.

    PubMed

    Shimura, Chieko; Satoh, Takahiro; Igawa, Ken; Aritake, Kosuke; Urade, Yoshihiro; Nakamura, Masataka; Yokozeki, Hiroo

    2010-01-01

    Prostaglandin D2 (PGD2), an arachidonic acid metabolite, has been implicated in allergic responses. A major source of PGD2 in the skin is mast cells that express hematopoietic PGD synthase (H-PGDS). In this study, we show the expression of H-PGDS in human dendritic cells (DCs) and the regulatory mechanisms by which DCs produce PGD2. We detected H-PGDS in epidermal Langerhans cells, dermal DCs, plasmacytoid DCs, and myeloid DCs. Monocyte-derived DCs rapidly secreted PGD2 when stimulated with the calcium ionophore A23187. More importantly, pretreatment of monocyte-derived DCs with PMA (phorbol 12-myrisate 13-acetate) synergistically enhanced the rapid PGD2 secretion induced by A23187, whereas PMA alone did not induce PGD2 secretion. Lipopolysaccharide (LPS) reduced H-PGDS expression, but interferon-gamma followed by LPS induced significant PGD2 production in a delayed time course at 6 hours. This effect was associated with inhibition of LPS-induced H-PGDS reduction. Interestingly, an irritant compound, SDS, also induced a rapid PGD2 release. PGD2 synergistically enhanced CCL22/macrophage-derived chemokine synthesis in interferon-gamma-treated human keratinocytes. In addition, bone marrow-derived DCs from wild-type mice stimulated lymph node cells to produce higher amounts of interleukin-17 than did DCs from mice lacking the H-PGDS gene. Thus, DCs could be an important source of skin PGD2 and may mediate or regulate skin inflammation by releasing PGD2 in response to various stimuli, contributing to the innate and/or acquired immune responses.

  13. Compartmentalization of prostaglandins in the canine kidney

    SciTech Connect

    Morgan-Boyd, R.L.

    1986-01-01

    The kidney has been shown to synthesize all of the naturally occurring major prostaglandins which may be restricted to a discrete part of the kidney where their actions are physiologically important, such as the vascular compartment and the tubular compartment. In order to examine this concept of compartmentalization, the authors conducted a series of experiments to determine whether PGl/sub 2/, measured as 6-keto-pGF/sub 1..cap alpha../, produced in the kidney is restricted to the renal vascular compartment or whether it also has access to the tubular compartment. Experiments were performed in the pentobarbital-anesthetized dog. Increasing pre-glomerular levels of 6-keto-PFG/sub 1..cap alpha../ caused marked increases in both the urinary excretion and the renal venous outflow to 6-keto-PGF/sub 1..cap alpha../. When /sup 3/H-6-keto-PGF/sub 1..cap alpha../ was co-infused with inulin into the renal artery, 33% of the radioactivity and 23% of the inulin was recovered on first pass. With infusion of /sup 3/H-PGl/sub 2/ and inulin, 20% of the radioactivity and 28% of the inulin reached the urine on first pass. Radioactive PGl/sub 2/ appeared to be less filterable at the glomeruli than either /sup 3/H-6-keto-PGF/sub 1..cap alpha../ or inulin. In the final set of experiments, in which dogs were prepared for a ureteral stopped-flow study, the PGE/sub 2//U/P/sub In/ ratio a peak was observed proximal to the Na/sup +/ plateau but distal to the Na+ nadir. In light of the results from the stopped-flow study and the intrarenal infusion studies, they conclude that PGE/sub 2/ synthesized in the kidney enters both the renal and tubular compartments. In contrast, they find that 6-keto-PGF/sub 1..cap alpha../ of renal origin enters only the renal origin enters only the renal vascular compartment and not the tubular compartment.

  14. Characterization of Prostaglandin E2 Production by Candida albicans▿

    PubMed Central

    Erb-Downward, John R.; Noverr, Mairi C.

    2007-01-01

    Candida albicans produces lipid metabolites that are functionally similar to host prostaglandins. These studies, using mass spectrometry, demonstrate that C. albicans produces authentic prostaglandin E2 (PGE2) from arachidonic acid. Maximal PGE2 production was achieved at 37°C in stationary-phase culture supernatants and in cell-free lysates generated from stationary-phase cells. Interestingly, PGE2 production is inhibited by both nonspecific cyclooxygenase and lipoxygenase inhibitors but not by inhibitors specific for the cyclooxygenase 2 isoenzyme. The C. albicans genome does not possess a cyclooxygenase homolog; however, several genes that may play a role in prostaglandin production from C. albicans were investigated. It was found that a C. albicans fatty acid desaturase homolog (Ole2) and a multicopper oxidase homolog (Fet3) play roles in prostaglandin production, with ole2/ole2 and fet3/fet3 mutant strains exhibiting reduced PGE2 levels compared with parent strains. This work demonstrates that the synthesis of PGE2 in C. albicans proceeds via novel pathways. PMID:17470538

  15. Influence of endogenous prostaglandins on mTAL injury.

    PubMed

    Silva, P; Rosen, S; Spokes, K; Taylor, M; Epstein, F H

    1990-11-01

    We altered renal prostaglandin production by isolated rat kidneys in several ways to see if this would influence the susceptibility of cells lining the medullary thick ascending limb to injury. Rats were fed a diet containing either safflower oil (high in linoleic acid) or fish oil (low in arachidonate precursors) as a source of fat. After 90 min of perfusion, the kidneys of rats fed safflower oil showed only 32.7 +/- 6.7% of medullary thick ascending limb cells near the inner medulla with severe damage, whereas the same zone in perfused kidneys of rats fed fish oil showed 96.6 +/- 1.3% severely damaged cells (P less than 0.01). The protection afforded by safflower oil was accompanied by a doubling of urinary excretion of PGE2 and 6-keto-PGF1 alpha, and was eliminated by indomethacin, which suppressed prostaglandin synthesis. Perfusion with bradykinin also greatly increased prostaglandin excretion and reduced severe medullary thick ascending limb damage in the deepest zone of the outer medulla from 51.3 +/- 6.6% in controls to 28.5 +/- 5.9% (P less than 0.02). The protection provided by bradykinin was also completely reversed by indomethacin. The results suggest that endogenous prostaglandins serve a protective function against hypoxic injury for cells of the medullary thick ascending limb.

  16. Reducing prostaglandin E2 production to raise cancer immunogenicity.

    PubMed

    Zelenay, Santiago; Reis E Sousa, Caetano

    2016-05-01

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

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

    PubMed

    Nordmann, J-P

    2005-06-01

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

  18. Effects of blood-dialyser interaction on prostaglandins in uraemic patients and in healthy man.

    PubMed

    Mahiout, A; Jörres, A; Hiss, R; Meinhold, H; Kessel, M

    1987-01-01

    The present study examines extracorporeal prostaglandin production during routine and simulated haemodialysis in healthy volunteers. The roles of dialyser membranes and alcohol washing procedures were investigated. The source of extracorporeal prostaglandin E2 was estimated by a specific platelet cyclo-oxygenase antagonist. Extracorporeal thromboxane production, with and without antagonist, was compared in an attempt to substantiate the role of the cyclo-oxygenase pathway by sources other than platelets. Clinical investigations show that prostaglandin liberation in the extracorporeal bloodstream is detectable. Additionally, laboratory results suggest an association between the type of dialyser membrane and extracorporeal prostaglandin release. The amount of prostaglandin E2 was reduced when dialysers were pre-washed with alcohol. Furthermore, it was experimentally possible to determine that a large part of extracorporeal prostaglandin E2 is released by sources other than platelets, suggesting a possible role of monocytes in extracorporeal prostaglandin production.

  19. Prostaglandin control of renal circulation in the unanesthetized dog and baboon

    NASA Technical Reports Server (NTRS)

    Swain, J. A.; Vatner, S. F.; Heyndrickx, G. R.; Boettcher, D. H.

    1975-01-01

    Effects of indomethacin and meclofenamate, inhibitors of prostaglandin synthesis, were evaluated in the regulation of renal blood flow in conscious and anesthetized dogs and in tranquilized baboons, instrumented with arterial pressure catheters and renal blood flow probes. Indomethacin, 10 mg/kg, did not alter renal blood flow or resistance significantly in the conscious dog. In the anesthetized dog, however, indomethacin caused a reduction in renal blood flow and an elevation of renal vascular resistance. Meclofenamate, 4 mg/kg, reduced renal flow and increased renal vascular resistance in conscious dogs. In conscious dogs and tranquilized primates, indomethacin and meclofenamate reduced the reactive hyperemia in the renal bed. Methoxamine and angiotensin II infused in graded doses induced significantly greater renal vasoconstriction in conscious dogs in the presence of indomethacin. Thus, in the conscious animal, prostaglandins appear to play only a minor part in the control of renal circulation at rest, but they are of greater importance in mediating the renal responses to reactive hyperemia and to vasoconstriction.

  20. Conceptus elongation in ruminants: roles of progesterone, prostaglandin, interferon tau and cortisol.

    PubMed

    Brooks, Kelsey; Burns, Greg; Spencer, Thomas E

    2014-01-01

    The majority of pregnancy loss in ruminants occurs during the first three weeks after conception, particularly during the period of conceptus elongation that occurs prior to pregnancy recognition and implantation. This review integrates established and new information on the biological role of ovarian progesterone (P4), prostaglandins (PGs), interferon tau (IFNT) and cortisol in endometrial function and conceptus elongation. Progesterone is secreted by the ovarian corpus luteum (CL) and is the unequivocal hormone of pregnancy. Prostaglandins (PGs) and cortisol are produced by both the epithelial cells of the endometrium and the trophectoderm of the elongating conceptus. In contrast, IFNT is produced solely by the conceptus trophectoderm and is the maternal recognition of pregnancy signal that inhibits production of luteolytic pulses of PGF2α by the endometrium to maintain the CL and thus production of P4. Available results in sheep support the idea that the individual, interactive, and coordinated actions of P4, PGs, IFNT and cortisol regulate conceptus elongation and implantation by controlling expression of genes in the endometrium and/or trophectoderm. An increased knowledge of conceptus-endometrial interactions during early pregnancy in ruminants is necessary to understand and elucidate the causes of infertility and recurrent early pregnancy loss and provide new strategies to improve fertility and thus reproductive efficiency.

  1. A theoretical model of biochemical control engineering based on the relation between oestrogens/progestagens and prostaglandins.

    PubMed

    van der Veen, P H E

    2015-06-01

    A biological complex organism is involuntarily guided from all sides by measure and regulation systems. The human being is such a complex organism. Many cyclical processes are simultaneously at work, making it unclear how and why which process takes place at which moment. Noticeable examples are the 28-day menstrual cycle and the 40-week pregnancy. The time of activation in the middle of the menstrual is fairly clear. Hormonal changes also occur in this period. Why the hormonal changes occur, and what their relationship is with the activation of the processes is unclear. That is also the case during pregnancies. What is it that determines that a pregnancy should last an average of 40 weeks? What causes the changes in a complicated pregnancy? What are those changes? Prostaglandin concentrations have been found to have some relationship with these changes, but the activation of these changes and how to examine them is unknown. Using an example from practical experience, this article illustrates what Horrobin and Manku already reported in 1977, namely, the properties of prostaglandin E1 and 6-keto pgF1α: reversal effect with elevated concentration. The properties described is exceptionally suitable for the time of activation in a biochemically regulated measure and regulation system. These properties can help explain the occurrence of physiological cycles. The known electronic saw-tooth wave has a biochemical analogue with this. This paper describes the presumed relationship between hormones and the accompanying prostaglandins with the hormone effects based on what is known regarding their concentrations progress. This relationship reveals the practical consequences of the experimentally found sensitivity of biochemical effects with regard to the accompanying prostaglandins. This paper shows how the theoretical relationship between effects of oestrogens and progestagens result in a curve that comprise observable aspects of the Basal Body Temperature Curve. The

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

    PubMed Central

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

    2016-01-01

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

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

    PubMed

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

    2016-07-01

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

  4. cAMP-synthesis in a medullary thyroid carcinoma cell line: response to adrenergic agents and prostaglandines.

    PubMed

    Mertens, P R; Goretzki, P E; Keck, E

    1999-01-01

    Calcitonin secretion by C-cells is mediated through intracellular 3'5'-cyclic adenosine monophosphate (cAMP) and calcium signaling. Calcitonin release stimulation tests may take advantage of both signaling cascades in screening for medullary thyroid carcinomas (MTC). To elucidate the regulation of the adenylyl cyclase system we have determined cAMP levels of a calcitonin-expressing MTC cell line (RG) after exposure to adrenergic agents and prostaglandines. In early passages (20-30) cAMP concentrations were significantly elevated in RG cells after exposure to beta-adrenergic agents and prostaglandines E1 and E2. In advanced passages (60-80) the beta-adrenergic response was no longer detectable and adrenergic receptors were uncoupled from the adenylyl cyclase complex; while the effect of prostaglandines E1 and E2 remained unaffected. Preincubation with dexamethasone, in a process requiring protein new synthesis, re-established the adrenergic response in later passages, indicating that RG cells dedifferentiated in culture over time. Our in vitro findings suggest that MTC cell dedifferentiation may be accompanied by adrenergic receptor-uncoupling from the adenylate cyclase system and that this process may be reversed by dexamethasone incubation.

  5. Prostaglandin-E2 is a potent inhibitor of human interleukin 12 production

    PubMed Central

    1995-01-01

    During human immunodeficiency virus infection and allergic diseases, characterized by a dominant T helper (Th) 2 response, overproduction of prostaglandin E2 (PGE2) is observed. In this paper we studied the effect of PGE2 on interleukin (IL)-12 synthesis, because this cytokine has been described to be essential in induction of Th1 responses. IL-12 synthesis was induced in monocytes that were stimulated with Neisseria meningitidis-derived lipopolysaccharide in whole blood cultures. PGE2 almost completely inhibited lipopolysaccharide induced IL-12 production, whereas IL-6 production was only partially inhibited by PGE2. In contrast, the production of IL-10 was approximately twofold enhanced at these conditions. The effects of PGE2 were due to its cAMP- inducing capacity, since they could be mimicked by other cAMP inducers. Recombinant human IL-10 also inhibited IL-12 and IL-6 production. However, the inhibitory effect of PGE2 on IL-12 production was independent of IL-10 since neutralizing anti-IL-10 antibodies were unable to reverse this inhibition. These results suggest that the capacity of an antigen to induce PGE2 synthesis may play a crucial role in the development of either a Th1 or Th2 response. PMID:7836930

  6. Cloning and expression of the rabbit prostaglandin EP2 receptor

    PubMed Central

    Guan, Youfei; Stillman, Brett A; Zhang, Yahua; Schneider, André; Saito, Osamu; Davis, Linda S; Redha, Reyadh; Breyer, Richard M; Breyer, Matthew D

    2002-01-01

    Background Prostaglandin E2 (PGE2) has multiple physiologic roles mediated by G protein coupled receptors designated E-prostanoid, or "EP" receptors. Evidence supports an important role for the EP2 receptor in regulating fertility, vascular tone and renal function. Results The full-length rabbit EP2 receptor cDNA was cloned. The encoded polypeptide contains 361 amino acid residues with seven hydrophobic domains. COS-1 cells expressing the cloned rabbit EP2 exhibited specific [3H]PGE2 binding with a Kd of 19.1± 1.7 nM. [3H]PGE2 was displaced by unlabeled ligands in the following order: PGE2>>PGD2=PGF2α=iloprost. Binding of [3H]PGE2 was also displaced by EP receptor subtype selective agonists with a rank order of affinity consistent with the EP2 receptor (butaprost>AH13205>misoprostol>sulprostone). Butaprost free acid produced a concentration-dependent increase in cAMP accumulation in rabbit EP2 transfected COS-1 cells with a half-maximal effective concentration of 480 nM. RNase protection assay revealed high expression in the ileum, spleen, and liver with lower expression in the kidney, lung, heart, uterus, adrenal gland and skeletal muscle. In situ hybridization localized EP2 mRNA to the uterine endometrium, but showed no distinct localization in the kidney. EP2 mRNA expression along the nephron was determined by RT-PCR and its expression was present in glomeruli, MCD, tDL and CCD. In cultured cells EP2 receptor was not detected in collecting ducts but was detected in renal interstitial cells and vascular smooth muscle cells. EP2 mRNA was also detected in arteries, veins, and preglomerular vessels of the kidney. Conclusion EP2 expression pattern is consistent with the known functional roles for cAMP coupled PGE2 effects in reproductive and vascular tissues and renal interstitial cells. It remains uncertain whether it is also expressed in renal tubules. PMID:12097143

  7. [Effect of prostaglandin synthesis inhibitors of diabetic cystoid macular edema].

    PubMed

    Kieselbach, G; Juen, S

    1990-01-01

    In most cases, diabetic macular edema is treated successfully with central laser photocoagulation. However, only few studies report such favorable results in cystoid macular edema, which has a poor visual prognosis. In the present prospective study on diabetics with cystoid macular edema, aged less than 40 years, a better visual outcome was obtained in patients treated with prostaglandin synthesis inhibitors than in an untreated group. PMID:2345629

  8. Prostaglandin E2 constrains systemic inflammation through an innate lymphoid cell–IL-22 axis**

    PubMed Central

    Duffin, Rodger; O’Connor, Richard A.; Crittenden, Siobhan; Forster, Thorsten; Yu, Cunjing; Zheng, Xiaozhong; Smyth, Danielle; Robb, Calum T.; Rossi, Fiona; Skouras, Christos; Tang, Shaohui; Richards, James; Pellicoro, Antonella; Weller, Richard B.; Breyer, Richard M.; Mole, Damian J.; Iredale, John P.; Anderton, Stephen M.; Narumiya, Shuh; Maizels, Rick M.; Ghazal, Peter; Howie, Sarah E.; Rossi, Adriano G.

    2016-01-01

    Systemic inflammation, resulting from massive release of pro-inflammatory molecules into the circulatory system, is a major risk factor for severe illness, but the precise mechanisms underlying its control are incompletely understood. We observed that prostaglandin E2 (PGE2) through its receptor EP4 is down-regulated in human systemic inflammatory disease. Mice with reduced PGE2 synthesis develop systemic inflammation, associated with translocation of gut bacteria, which can be prevented by treating with EP4 agonists. Mechanistically, we demonstrate that PGE2–EP4 signaling directly acts on type 3 innate lymphoid cells (ILCs), promoting their homeostasis and driving them to produce interleukin-22 (IL-22). Disruption of the ILC/IL-22 axis impairs PGE2–mediated inhibition of systemic inflammation. Hence, PGE2–EP4 signaling inhibits systemic inflammation through ILC/IL-22 axis–dependent protection of gut barrier dysfunction. PMID:26989254

  9. Eicosanoids Derived From Arachidonic Acid and Their Family Prostaglandins and Cyclooxygenase in Psychiatric Disorders

    PubMed Central

    Yui, Kunio; Imataka, George; Nakamura, Hiroyuki; Ohara, Naoki; Naito, Yukiko

    2015-01-01

    Arachidonic acid (AA)-derived lipid mediators are called eicosanoids. Eicosanoids have emerged as key regulators of a wide variety of physiological responses and pathological processes, and control important cellular processes. AA can be converted into biologically active compounds by metabolism by cyclooxygenases (COX). Beneficial effect of COX-2 inhibitor celecoxib add-on therapy has been reported in early stage of schizophrenia. Moreover, add-on treatment of celecoxib attenuated refractory depression and bipolar depression. Further, the COX/prostaglandin E pathway play an important role in synaptic plasticity and may be included in pathophysiology in autism spectrum disorders (ASD). In this regard, plasma transferrin, which is an iron mediator related to eicosanoid signaling, may be related to social impairment of ASD. COX-2 is typically induced by inflammatory stimuli in the majority of tissues, and the only isoform responsible for propagating the inflammatory response. Thus, COX-2 inhibitors considered as the best target for Alzheimer’s disease. PMID:26521945

  10. Prostaglandin E₂ constrains systemic inflammation through an innate lymphoid cell-IL-22 axis.

    PubMed

    Duffin, Rodger; O'Connor, Richard A; Crittenden, Siobhan; Forster, Thorsten; Yu, Cunjing; Zheng, Xiaozhong; Smyth, Danielle; Robb, Calum T; Rossi, Fiona; Skouras, Christos; Tang, Shaohui; Richards, James; Pellicoro, Antonella; Weller, Richard B; Breyer, Richard M; Mole, Damian J; Iredale, John P; Anderton, Stephen M; Narumiya, Shuh; Maizels, Rick M; Ghazal, Peter; Howie, Sarah E; Rossi, Adriano G; Yao, Chengcan

    2016-03-18

    Systemic inflammation, which results from the massive release of proinflammatory molecules into the circulatory system, is a major risk factor for severe illness, but the precise mechanisms underlying its control are not fully understood. We observed that prostaglandin E2 (PGE2), through its receptor EP4, is down-regulated in human systemic inflammatory disease. Mice with reduced PGE2 synthesis develop systemic inflammation, associated with translocation of gut bacteria, which can be prevented by treatment with EP4 agonists. Mechanistically, we demonstrate that PGE2-EP4 signaling acts directly on type 3 innate lymphoid cells (ILCs), promoting their homeostasis and driving them to produce interleukin-22 (IL-22). Disruption of the ILC-IL-22 axis impairs PGE2-mediated inhibition of systemic inflammation. Hence, the ILC-IL-22 axis is essential in protecting against gut barrier dysfunction, enabling PGE2-EP4 signaling to impede systemic inflammation. PMID:26989254

  11. Prostaglandin E₂ constrains systemic inflammation through an innate lymphoid cell-IL-22 axis.

    PubMed

    Duffin, Rodger; O'Connor, Richard A; Crittenden, Siobhan; Forster, Thorsten; Yu, Cunjing; Zheng, Xiaozhong; Smyth, Danielle; Robb, Calum T; Rossi, Fiona; Skouras, Christos; Tang, Shaohui; Richards, James; Pellicoro, Antonella; Weller, Richard B; Breyer, Richard M; Mole, Damian J; Iredale, John P; Anderton, Stephen M; Narumiya, Shuh; Maizels, Rick M; Ghazal, Peter; Howie, Sarah E; Rossi, Adriano G; Yao, Chengcan

    2016-03-18

    Systemic inflammation, which results from the massive release of proinflammatory molecules into the circulatory system, is a major risk factor for severe illness, but the precise mechanisms underlying its control are not fully understood. We observed that prostaglandin E2 (PGE2), through its receptor EP4, is down-regulated in human systemic inflammatory disease. Mice with reduced PGE2 synthesis develop systemic inflammation, associated with translocation of gut bacteria, which can be prevented by treatment with EP4 agonists. Mechanistically, we demonstrate that PGE2-EP4 signaling acts directly on type 3 innate lymphoid cells (ILCs), promoting their homeostasis and driving them to produce interleukin-22 (IL-22). Disruption of the ILC-IL-22 axis impairs PGE2-mediated inhibition of systemic inflammation. Hence, the ILC-IL-22 axis is essential in protecting against gut barrier dysfunction, enabling PGE2-EP4 signaling to impede systemic inflammation.

  12. Prostaglandin-secreting cells: a portable first aid kit for tissue repair

    PubMed Central

    Rakoff-Nahoum, Seth; Medzhitov, Ruslan

    2007-01-01

    After intestinal injury, both the number and type of intestinal epithelial cells must be restored. Intestinal stem cells, located at the base of the intestinal crypt, repopulate the depleted crypt in a process known as compensatory proliferation. In this issue of the JCI, Brown et al. describe a new mechanism by which this process is regulated (see the related article beginning on page 258). Surprisingly, they find that a subset of stromal cells present within the intestinal tissue and expressing the proliferative factor prostaglandin-endoperoxidase synthase 2 (Ptgs2) is repositioned next to the intestinal stem cell compartment where local production of PGE2 controls injury-induced epithelial cell proliferation. PMID:17200710

  13. Intraluteal prostaglandin biosynthesis and signaling are selectively directed towards PGF2alpha during luteolysis but towards PGE2 during the establishment of pregnancy in sheep.

    PubMed

    Lee, JeHoon; McCracken, John A; Stanley, Jone A; Nithy, Thamizh K; Banu, Sakhila K; Arosh, Joe A

    2012-10-01

    In ruminants, endometrial prostalgandin (PG) F(2alpha) causes functional luteolysis, whereas luteal synthesis of PGF(2alpha) is required for structural luteolysis. PGE(2) is considered to be a luteoprotective mediator. Molecular aspects of luteal PGF(2alpha) and PGE(2) biosynthesis and signaling during the estrous cycle and establishment of pregnancy are largely unknown. The objectives of the present study were 1) to determine the regulation of proteins involved in PGF(2alpha) and PGE(2) biosynthesis, catabolism, transport and signaling in the corpus luteum (CL); 2) to investigate the transport of interferon tau (IFNT), PGF(2alpha), and PGE(2) from the uterus to the ovary through the vascular utero-ovarian plexus (UOP); and 3) to compare the intraluteal production of PGF(2alpha) and PGE(2) on Days 12, 14, and 16 of the estrous cycle and pregnancy in sheep. Our results indicate that luteal PG biosynthesis is selectively directed towards PGF(2alpha) at the time of luteolysis and towards PGE(2) during the establishment of pregnancy. Moreover, the ability of the CL of early pregnancy to resist luteolysis is due to increased intraluteal biosynthesis of PGE(2) and PGE(2) receptor (PTGER) 2 (also known as EP2)- and PTGER4 (also known as EP4)-mediated signaling. We also found that IFNT protein is not transported through the UOP from the uterus to the ovary; in contrast, a large proportion of endometrial PGE(2) is transported from the uterus to the ovary through the UOP. These results indicate that endometrial PGE(2) stimulated by pregnancy is transported locally to the ovary, which increases luteal PGE(2) biosynthesis and hence activates luteal PTGER2 and PTGER4 signaling, thus protecting the CL during the establishment of pregnancy in sheep.

  14. Effects of nonhypotensive endotoxemia in conscious rats: Role of prostaglandins

    SciTech Connect

    Burnier, M.; Waeber, B.; Aubert, J.F.; Nussberger, J.; Brunner, H.R. )

    1988-03-01

    A nonhypotensive dose of endotoxin was administered to normal conscious rats to evaluate the vascular and humoral effects of endotoxemia per se. Mean blood pressure and heart rate remained stable during the 45 min infusion of Escherichia coli endotoxin. However, a marked increase in plasma renin activity plasma epinephrine and plasma norepinephrine was observed during infusion in endotoxin-treated rats when compared with the vehicle-treated animals. In addition, the blood pressure response to exogenous norepinephrine was significantly reduced during nonhypotensive endotoxemia. Significant changes in regional blood flow distribution, as assessed by radiolabeled microspheres, were observed in endotoxemic rats; in particular a decrease in renal blood flow, and an increase in coronary blood flow were found. The role of prostaglandins in the vascular and humoral alterations induced by nonhypotensive endotoxemia was also examined. Pretreatment with indomethacin (5 mg) prevent the increase in plasma renin activity as well as plasma catecholamine levels. On the contrary, the decreased vascular reactivity and the reduction in renal blood flow observed during endotoxemia were not affected by prostaglandin synthesis inhibition. Thus significant vascular and humoral changes have been found during endotoxemia even in absence of hypotension. The humoral but not the vascular effects of endotoxemia were abolished when prostaglandin synthesis was inhibited.

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

    SciTech Connect

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

    1986-03-01

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

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

    PubMed Central

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

    2010-01-01

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

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

    NASA Technical Reports Server (NTRS)

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

    1994-01-01

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

  18. A bilateral antidiuresis to renal artery infusion of prostaglandin E1 in dogs treated with phenylbutazone

    PubMed Central

    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 < 0·001) and the response to a high dose (0·5 μg/min) from 1·82 ± 0·19 to 0·99 ± 0·31 ml./min (P < 0·002). 4. A significantly less dilute urine was excreted during prostaglandin infusion in the dog after 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

  19. Evaluation of genes involved in prostaglandin action in equine endometrium during estrous cycle and early pregnancy.

    PubMed

    Atli, Mehmet O; Kurar, Ercan; Kayis, Seyit A; Aslan, Selim; Semacan, Ahmet; Celik, Sefa; Guzeloglu, Aydin

    2010-10-01

    The aim was to evaluate expression of genes involved in the biosynthesis of prostaglandins (PTG), Prostaglandin H Synthase-1 (PTGS1) and PTGS2, PGF synthase (PTGFS), and PGE synthase (PTGES), PGF receptor (PTGFR), PGE receptors (PTGER2 and PTGER4), prostaglandin transporter (SLCO2A1) and hydroxyprostaglandin dehydrogenase-15 (HPGD). Endometrial biopsies were obtained from mares on day of ovulation (d0, n=4), late diestrus (LD, n=4), early luteolysis (EL, n=4) and after luteolysis (AL, n=4) during the cycle. Stages of the cycle were confirmed by plasma progesterone concentrations measured daily and ultrasound examinations. Biopsies were also taken on days 14 (P14; n=4), 15 (P15, n=4), 18 (P18, n=4) and 22 (P22; n=4) of pregnancy. Relative mRNA expressions were quantified using real-time RT-PCR. A mixed model was fitted on the normalized data and least significant difference test (α=0.05) was employed. Expression of PTGS1 mRNA was low throughout the estrous cycle and early days of pregnancy, but upregulated on P18 and P22. PTGS2 expression was increased on EL, but it was suppressed by pregnancy on P15, P18, and P22. PTGFS expression was upregulated in both cyclic and pregnant mares compared to d0 and its level was the highest on LD. PTGFR expression was transiently increased on LD and EL and was suppressed during early pregnancy. Both PTGES and PTGER2 expressions were increased on LD, EL, and early pregnancy, but were decreased after the luteolysis in cyclic mares as they remained high on P18 and P22. PTGER4 expression did not change throughout the cycle and early pregnancy. Levels of HPGD and SLCO2A1 were significantly increased only on P22. In conclusion, PTGS2 expression increases around the time of luteolysis and concurrent upregulation of PTGFS and PTGES indicates that equine endometrium has increased capability of PTG production around the time of luteolysis. However, pregnancy reduces PTGS2 expression, but maintains the high levels of PTGES during early

  20. Ureaplasma diversum infection in vitro alters prostaglandin E2 and prostaglandin F2a production by bovine endometrial cells without affecting cell viability.

    PubMed Central

    Kim, J J; Quinn, P A; Fortier, M A

    1994-01-01

    Bovine epithelial and stromal cells of the endometrium were inoculated with Ureaplasma diversum, pathogenic strain 2312, at 10(6) or 10(3) color-changing units (ccu)/ml in the presence of 1% fetal bovine serum (depleted of steroids by dextran-charcoal treatment) to assess the effect of infection on prostaglandin biosynthesis. When the inoculum of U. diversum was 10(6) ccu/ml, the concentration of U. diversum in the culture medium decreased with time. U. diversum was found on the epithelial and stromal cell monolayers, increasing in titer 100-fold, indicating that attachment and eventually growth occurred. When the inoculum was 10(3) ccu/ml, the titer of U. diversum remained the same or increased in the supernatant and increased on epithelial and stromal cells. The effect of infection was evaluated by measurement of the primary prostaglandin produced by each cell type, prostaglandin F2a for epithelial cells and prostaglandin E2 for stromal cells. Infection with U. diversum significantly decreased prostaglandin F2a accumulation, by 44.7% +/- 6.0% at 10(6) ccu/ml (P < or = 0.005) and 15.8% +/- 5.3% at 10(3) ccu/ml (P < or = 0.05) in epithelial cells. Prostaglandin E2 accumulation by stromal cells was decreased by 34.0% +/- 4.0% at 10(6) ccu/ml (P < or = 0.001) and by 13.5% +/- 2.7% at 10(3) ccu/ml (P < or = 0.005). Infection with 10(6) ccu/ml did not alter endometrial cell viability, as shown by protein measurement, trypan blue dye exclusion, and cell plating efficiency tests. Thus, alterations in prostaglandin production were not due to cell deterioration. These observations suggest that U. diversum can alter prostaglandin E2 and prostaglandin F2a patterns in primary cultures of bovine endometrial cells without affecting cell viability. PMID:8168914

  1. Prostaglandin E2 levels and platelet function are different in cord blood compared to adults.

    PubMed

    Schlagenhauf, Axel; Haidl, Harald; Leschnik, Bettina; Leis, Hans-Joerg; Heinemann, Akos; Muntean, Wolfgang

    2015-01-01

    Neonatal platelets support primary haemostasis and thrombin generation as well as adult platelets, despite observable hypoaggregability in vitro. High prostaglandin E2 levels at accouchement could account for inhibited platelet function via the EP4 receptor. We set out to determine prostaglandin E2 plasma levels in cord blood of healthy neonates and evaluate the impact of prostaglandin E2 on platelet function in adult and cord blood samples. Prostaglandin E2 plasma levels were measured in cord blood and venous adult blood using GC-MS. Impact of prostaglandin E2 on platelet aggregation was measured by spiking cord blood and adult samples. Contributions of EP3 and EP4 receptors were evaluated using respective antagonists. Intracellular cAMP concentrations were measured using a commercial ELISA-kit. Prostaglandin E2 plasma levels were substantially higher in cord blood than in adult samples. Spiking with prostaglandin E2 resulted in a slight but consistent reduction of platelet aggregation in adult blood, but response to PGE2 was blunted in cord blood samples. Aggregation response of spiked adult samples was still higher than with non-spiked cord blood samples. Blockage of EP4 receptors resulted in improved platelet aggregation in adult platelets upon prostaglandin E2 spiking, while aggregation in cord blood samples remained unaltered. Intracellular cAMP concentrations after preincubation with prostaglandin E2 were only increased in adult samples. In conclusion, very high prostaglandin E2 concentrations in cord blood affect platelet function. This effect may partially explain neonatal platelet hypoaggregability. Peak levels of prostaglandin E2 can potentially protect against birth stress-induced platelet activation.

  2. Activation of prostaglandin E2-EP4 signaling reduces chemokine production in adipose tissue.

    PubMed

    Tang, Eva H C; Cai, Yin; Wong, Chi Kin; Rocha, Viviane Z; Sukhova, Galina K; Shimizu, Koichi; Xuan, Ge; Vanhoutte, Paul M; Libby, Peter; Xu, Aimin

    2015-02-01

    Inflammation of adipose tissue induces metabolic derangements associated with obesity. Thus, determining ways to control or inhibit inflammation in adipose tissue is of clinical interest. The present study tested the hypothesis that in mouse adipose tissue, endogenous prostaglandin E2 (PGE2) negatively regulates inflammation via activation of prostaglandin E receptor 4 (EP4). PGE2 (5-500 nM) attenuated lipopolysaccharide-induced mRNA and protein expression of chemokines, including interferon-γ-inducible protein 10 and macrophage-inflammatory protein-1α in mouse adipose tissue. A selective EP4 antagonist (L161,982) reversed, and two structurally different selective EP4 agonists [CAY10580 and CAY10598] mimicked these actions of PGE2. Adipose tissue derived from EP4-deficient mice did not display this response. These findings establish the involvement of EP4 receptors in this anti-inflammatory response. Experiments performed on adipose tissue from high-fat-fed mice demonstrated EP4-dependent attenuation of chemokine production during diet-induced obesity. The anti-inflammatory actions of EP4 became more important on a high-fat diet, in that EP4 activation suppressed a greater variety of chemokines. Furthermore, adipose tissue and systemic inflammation was enhanced in high-fat-fed EP4-deficient mice compared with wild-type littermates, and in high-fat-fed untreated C57BL/6 mice compared with mice treated with EP4 agonist. These findings provide in vivo evidence that PGE2-EP4 signaling limits inflammation. In conclusion, PGE2, via activation of EP4 receptors, functions as an endogenous anti-inflammatory mediator in mouse adipose tissue, and targeting EP4 may mitigate adipose tissue inflammation.

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

    PubMed Central

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

    2014-01-01

    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). Prostaglandin E2 (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, EP3 or EP4; in mice with total body KO of microsomal PGE synthase-1, or the PGD2 receptor 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. PMID:25532785

  4. Treatment of vasospastic disease with prostaglandin E1.

    PubMed Central

    Clifford, P C; Martin, M F; Sheddon, E J; Kirby, J D; Baird, R N; Dieppe, P A

    1980-01-01

    Prostaglandin E1, a vasodilator and potent inhibitor of platelet aggregation, was administered to 26 patients with severe vasospastic disease of the hands. Patients tolerated infusions well and reported appreciable symptomatic improvement. Five of eight ischaemic ulcers healed in six weeks. Non-invasive studies of blood flow were used to observe haemodynamic changes during and after infusions. The Doppler-derived radial artery pulsatility index fell from 8.8 +/- 0.6 to 4.6 +/0 0.5 (mean +/- SEM), indicating hand vasodilatation. This fall was maintained 24 hours after infusion (5.9 +/- 0.9), but the index had returned to normal values at two weeks. The amplitude of finger pulse volume recordings increased (5.6 +/- 0.7 mm to 23.8 +/- 3.4 mm) and was raised two and six weeks after infusion (13.5 +/- 2.1 mm). Hand temperature measured by infrared radiometry also increased (27.4 +/- 0.7 degrees C to 31.2 +/- 1.2 degrees C). Intensity of digital vasospasm induced by cold water challenge was not objectively affected by prostaglandin E1 despite an increased finger temperature after infusion. Nevertheless, patients reported less frequent and severe attacks. Prostaglandin E1 given by central venous infusion is a safe new vasoactive agent that can produce appreciable symptomatic improvement by increasing digital perfusion, which may last for several weeks after treatment. Further study will define its mode of action and its place in the management of peripheral vascular disease. PMID:7427564

  5. Scalable synthesis of a prostaglandin EP4 receptor antagonist.

    PubMed

    Gauvreau, Danny; Dolman, Sarah J; Hughes, Greg; O'Shea, Paul D; Davies, Ian W

    2010-06-18

    The evolution of scalable, economically viable synthetic approaches to the potent and selective prostaglandin EP4 antagonist 1 is presented. The chromatography-free synthesis of multikilogram quantities of 1 using a seven-step sequence (six in the longest linear sequence) is described. This approach has been further modified in an effort to identify a long-term manufacturing route. Our final synthesis involves no step requiring cryogenic (< -25 degrees C) conditions; comprises a total of four steps, only three of which are in the longest linear synthesis; and features the use of two consecutive iron-catalyzed Friedel-Crafts substitutions.

  6. An Update of Microsomal Prostaglandin E Synthase-1 and PGE2 Receptors in Cardiovascular Health and Diseases

    PubMed Central

    2016-01-01

    Nonsteroidal anti-inflammatory drugs (NSAIDs), especially cyclooxygenase-2 (COX-2) selective inhibitors, are among the most widely used drugs to treat pain and inflammation. However, clinical trials have revealed that these inhibitors predisposed patients to a significantly increased cardiovascular risk, consisting of thrombosis, hypertension, myocardial infarction, heart failure, and sudden cardiac death. Thus, microsomal prostaglandin E (PGE) synthase-1 (mPGES-1), the key terminal enzyme involved in the synthesis of inflammatory prostaglandin E2 (PGE2), and the four PGE2 receptors (EP1–4) have gained much attention as alternative targets for the development of novel analgesics. The cardiovascular consequences of targeting mPGES-1 and the PGE2 receptors are substantially studied. Inhibition of mPGES-1 has displayed a relatively innocuous or preferable cardiovascular profile. The modulation of the four EP receptors in cardiovascular system is diversely reported as well. In this review, we highlight the most recent advances from our and other studies on the regulation of PGE2, particularly mPGES-1 and the four PGE2 receptors, in cardiovascular function, with a particular emphasis on blood pressure regulation, atherosclerosis, thrombosis, and myocardial infarction. This might lead to new avenues to improve cardiovascular disease management strategies and to seek optimized anti-inflammatory therapeutic options.

  7. An Update of Microsomal Prostaglandin E Synthase-1 and PGE2 Receptors in Cardiovascular Health and Diseases

    PubMed Central

    2016-01-01

    Nonsteroidal anti-inflammatory drugs (NSAIDs), especially cyclooxygenase-2 (COX-2) selective inhibitors, are among the most widely used drugs to treat pain and inflammation. However, clinical trials have revealed that these inhibitors predisposed patients to a significantly increased cardiovascular risk, consisting of thrombosis, hypertension, myocardial infarction, heart failure, and sudden cardiac death. Thus, microsomal prostaglandin E (PGE) synthase-1 (mPGES-1), the key terminal enzyme involved in the synthesis of inflammatory prostaglandin E2 (PGE2), and the four PGE2 receptors (EP1–4) have gained much attention as alternative targets for the development of novel analgesics. The cardiovascular consequences of targeting mPGES-1 and the PGE2 receptors are substantially studied. Inhibition of mPGES-1 has displayed a relatively innocuous or preferable cardiovascular profile. The modulation of the four EP receptors in cardiovascular system is diversely reported as well. In this review, we highlight the most recent advances from our and other studies on the regulation of PGE2, particularly mPGES-1 and the four PGE2 receptors, in cardiovascular function, with a particular emphasis on blood pressure regulation, atherosclerosis, thrombosis, and myocardial infarction. This might lead to new avenues to improve cardiovascular disease management strategies and to seek optimized anti-inflammatory therapeutic options. PMID:27594972

  8. Human platelet/erythroleukemia cell prostaglandin G/H synthase: cDNA cloning, expression, and gene chromosomal assignment

    SciTech Connect

    Funk, C.D.; Funk, L.B.; Kennedy, M.E.; Pong, A.S.; Fitzgerald, G.A. )

    1991-06-01

    Platelets metabolize arachidonic acid to thromboxane A{sub 2}, a potent platelet aggregator and vasoconstrictor compound. The first step of this transformation is catalyzed by prostaglandin (PG) G/H synthase, a target site for nonsteroidal antiinflammatory drugs. We have isolated the cDNA for both human platelet and human erythroleukemia cell PGG/H synthase using the polymerase chain reaction and conventional screening procedures. The cDNA encoding the full-length protein was expressed in COS-M6 cells. Microsomal fractions from transfected cells produced prostaglandin endoperoxide derived products which were inhibited by indomethacin and aspirin. Mutagenesis of the serine residue at position 529, the putative aspirin acetylation site, to an asparagine reduced cyclooxygenase activity to barely detectable levels, an effect observed previously with the expressed sheep vesicular gland enzyme. Platelet-derived growth factor and phorbol ester differentially regulated the expression of PGG/H synthase mRNA levels in the megakaryocytic/platelet-like HEL cell line. The PGG/H synthase gene was assigned to chromosome 9 by analysis of a human-hamster somatic hybrid DNA panel. The availability of platelet PGG/H synthase cDNA should enhance our understanding of the important structure/function domains of this protein and it gene regulation.

  9. An Update of Microsomal Prostaglandin E Synthase-1 and PGE2 Receptors in Cardiovascular Health and Diseases.

    PubMed

    Yang, Guangrui; Chen, Lihong

    2016-01-01

    Nonsteroidal anti-inflammatory drugs (NSAIDs), especially cyclooxygenase-2 (COX-2) selective inhibitors, are among the most widely used drugs to treat pain and inflammation. However, clinical trials have revealed that these inhibitors predisposed patients to a significantly increased cardiovascular risk, consisting of thrombosis, hypertension, myocardial infarction, heart failure, and sudden cardiac death. Thus, microsomal prostaglandin E (PGE) synthase-1 (mPGES-1), the key terminal enzyme involved in the synthesis of inflammatory prostaglandin E2 (PGE2), and the four PGE2 receptors (EP1-4) have gained much attention as alternative targets for the development of novel analgesics. The cardiovascular consequences of targeting mPGES-1 and the PGE2 receptors are substantially studied. Inhibition of mPGES-1 has displayed a relatively innocuous or preferable cardiovascular profile. The modulation of the four EP receptors in cardiovascular system is diversely reported as well. In this review, we highlight the most recent advances from our and other studies on the regulation of PGE2, particularly mPGES-1 and the four PGE2 receptors, in cardiovascular function, with a particular emphasis on blood pressure regulation, atherosclerosis, thrombosis, and myocardial infarction. This might lead to new avenues to improve cardiovascular disease management strategies and to seek optimized anti-inflammatory therapeutic options. PMID:27594972

  10. Drosophila Fascin is a novel downstream target of prostaglandin signaling during actin remodeling.

    PubMed

    Groen, Christopher M; Spracklen, Andrew J; Fagan, Tiffany N; Tootle, Tina L

    2012-12-01

    Although prostaglandins (PGs)-lipid signals produced downstream of cyclooxygenase (COX) enzymes-regulate actin cytoskeletal dynamics, their mechanisms of action are unknown. We previously established Drosophila oogenesis, in particular nurse cell dumping, as a new model to determine how PGs regulate actin remodeling. PGs, and thus the Drosophila COX-like enzyme Pxt, are required for both the parallel actin filament bundle formation and the cortical actin strengthening required for dumping. Here we provide the first link between Fascin (Drosophila Singed, Sn), an actin-bundling protein, and PGs. Loss of either pxt or fascin results in similar actin defects. Fascin interacts, both pharmacologically and genetically, with PGs, as reduced Fascin levels enhance the effects of COX inhibition and synergize with reduced Pxt levels to cause both parallel bundle and cortical actin defects. Conversely, overexpression of Fascin in the germline suppresses the effects of COX inhibition and genetic loss of Pxt. These data lead to the conclusion that PGs regulate Fascin to control actin remodeling. This novel interaction has implications beyond Drosophila, as both PGs and Fascin-1, in mammalian systems, contribute to cancer cell migration and invasion.

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

    PubMed

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

    2016-07-01

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

  12. Inhibition of nitric oxide and prostaglandins, but not endothelial-derived hyperpolarizing factors, reduces blood flow and aerobic energy turnover in the exercising human leg.

    PubMed

    Mortensen, Stefan P; González-Alonso, José; Damsgaard, Rasmus; Saltin, Bengt; Hellsten, Ylva

    2007-06-01

    Prostaglandins, nitric oxide (NO) and endothelial-derived hyperpolarizing factors (EDHFs) are substances that have been proposed to be involved in the regulation of skeletal muscle blood flow during physical activity. We measured haemodynamics, plasma ATP at rest and during one-legged knee-extensor exercise (19 +/- 1 W) in nine healthy subjects with and without intra-arterial infusion of indomethacin (Indo; 621 +/- 17 microg min(-1)), Indo + N(G)-monomethyl-L-arginine (L-NMMA; 12.4 +/- 0.3 mg min(-1)) (double blockade) and Indo + L-NMMA + tetraethylammonium chloride (TEA; 12.4 +/- 0.3 mg min(-1)) (triple blockade). Double and triple blockade lowered leg blood flow (LBF) at rest (P<0.05), while it remained unchanged with Indo. During exercise, LBF and vascular conductance were 2.54 +/- 0.10 l min(-1) and 25 +/- 1 mmHg, respectively, in control and they were lower with double (33 +/- 3 and 36 +/- 4%, respectively) and triple (26 +/- 4 and 28 +/- 3%, respectively) blockade (P<0.05), while there was no difference with Indo. The lower LBF and vascular conductance with double and triple blockade occurred in parallel with a lower O(2) delivery, cardiac output, heart rate and plasma [noradrenaline] (P<0.05), while blood pressure remained unchanged and O(2) extraction and femoral venous plasma [ATP] increased. Despite the increased O(2) extraction, leg was 13 and 17% (triple and double blockade, respectively) lower than control in parallel to a lower femoral venous temperature and lactate release (P<0.05). These results suggest that NO and prostaglandins play important roles in skeletal muscle blood flow regulation during moderate intensity exercise and that EDHFs do not compensate for the impaired formation of NO and prostaglandins. Moreover, inhibition of NO and prostaglandin formation is associated with a lower aerobic energy turnover and increased concentration of vasoactive ATP in plasma. PMID:17347273

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

    PubMed

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

    2014-09-01

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

  14. Induction of prostaglandin E(2) and interleukin-6 in gingival fibroblasts by oral biofilms.

    PubMed

    Belibasakis, Georgios N; Guggenheim, Bernhard

    2011-12-01

    Polymicrobial oral biofilms attaching on tooth surfaces can trigger inflammatory responses by the neighbouring tooth-supporting periodontal tissues. An excessive inflammatory response can cause destruction of the periodontal tissues, including the alveolar bone, thus resulting in periodontitis. Mediators of inflammation, such as prostaglandin E(2) (PGE(2) ) and interleukin-6, are primary regulators of alveolar bone destruction in periodontitis. The present study aimed to comparatively investigate the effects of in vitro supragingival and subgingival biofilms, on the regulation of PGE(2) and interleukin-6 in human gingival fibroblasts. The cells were challenged with culture supernatants of the two biofilms for 6 h. Cyclo-oxygenase (COX)-2, an enzyme responsible for the conversion of PGE(2) , and interleukin-6 gene expression were analysed by quantitative real-time PCR. The production of PGE(2) and interleukin-6 by the cells was analysed by ELISA. While the supragingival biofilm did not induce significant changes, the subgingival biofilm caused an 8.6- and 2.9-fold enhancement of COX-2 and interleukin-6 gene expression, respectively, and a 72.5- and 1.5-fold enhancement of PGE(2) and interleukin-6 production, respectively. In conclusion, subgingival biofilms are potent inducers of PGE(2) in gingival fibroblasts, providing further mechanistic insights into the association of subgingival biofilms with bone resorption periodontitis.

  15. Effects of Prostaglandin F2α on Corpora Lutea Formation and Function in Mated Bitches

    PubMed Central

    Paradis, M.; Post, K.; Mapletoft, R. J.

    1983-01-01

    Fifteen mated bitches were used to study the effects of prostaglandin F2α on ovarian endocrine function during the early and midluteal phase. Five dogs were kept as controls, five were given 250 μg/kg prostaglandin F2α twice daily between the first and fifth day of metestrus, and five were similarly treated with prostaglandin F2α between 31 and 35 days of metestrus. Function of corpora lutea was monitored by measuring serum progesterone concentrations during the first 45 days of gestation. Dogs treated with prostaglandin F2α during the early luteal phase had progesterone concentrations similar to controls and pregnancies were undisturbed in both groups. A dramatic decrease in serum progesterone concentration and abortion resulted after prostaglandin F2α administration at midpregnancy. These results indicate that prostaglandin F2α was not luteolytic during the early luteal phase and was therefore ineffective for preventing pregnancy at that time. However, at the dosage and frequency used in this study, prostaglandin F2α was luteolytic and abortifacient at midgestation. PMID:17422289

  16. Piglet mortality: the impact of induction of farrowing using prostaglandins and oxytocin.

    PubMed

    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.

  17. Protective Effect of Galectin-1 during Histoplasma capsulatum Infection Is Associated with Prostaglandin E2 and Nitric Oxide Modulation

    PubMed Central

    Secatto, Adriana; Sorgi, Carlos A.; Prado, Morgana Kelly Borges; Ramos, Simone Gusmão; Cummings, Richard D.; Stowell, Sean R.

    2016-01-01

    Histoplasma capsulatum is a dimorphic fungus that develops a yeast-like morphology in host's tissue, responsible for the pulmonary disease histoplasmosis. The recent increase in the incidence of histoplasmosis in immunocompromised patients highlights the need of understanding immunological controls of fungal infections. Here, we describe our discovery of the role of endogenous galectin-1 (Gal-1) in the immune pathophysiology of experimental histoplasmosis. All infected wild-type (WT) mice survived while only 1/3 of Lgals1−/− mice genetically deficient in Gal-1 survived 30 days after infection. Although infected Lgals1−/− mice had increased proinflammatory cytokines, nitric oxide (NO), and elevations in neutrophil pulmonary infiltration, they presented higher fungal load in lungs and spleen. Infected lung and infected macrophages from Lgals1−/− mice exhibited elevated levels of prostaglandin E2 (PGE2, a prostanoid regulator of macrophage activation) and prostaglandin E synthase 2 (Ptgs2) mRNA. Gal-1 did not bind to cell surface of yeast phase of H. capsulatum, in vitro, suggesting that Gal-1 contributed to phagocytes response to infection rather than directly killing the yeast. The data provides the first demonstration of endogenous Gal-1 in the protective immune response against H. capsulatum associated with NO and PGE2 as an important lipid mediator in the pathogenesis of histoplasmosis.

  18. Protective Effect of Galectin-1 during Histoplasma capsulatum Infection Is Associated with Prostaglandin E2 and Nitric Oxide Modulation

    PubMed Central

    Secatto, Adriana; Sorgi, Carlos A.; Prado, Morgana Kelly Borges; Ramos, Simone Gusmão; Cummings, Richard D.; Stowell, Sean R.

    2016-01-01

    Histoplasma capsulatum is a dimorphic fungus that develops a yeast-like morphology in host's tissue, responsible for the pulmonary disease histoplasmosis. The recent increase in the incidence of histoplasmosis in immunocompromised patients highlights the need of understanding immunological controls of fungal infections. Here, we describe our discovery of the role of endogenous galectin-1 (Gal-1) in the immune pathophysiology of experimental histoplasmosis. All infected wild-type (WT) mice survived while only 1/3 of Lgals1−/− mice genetically deficient in Gal-1 survived 30 days after infection. Although infected Lgals1−/− mice had increased proinflammatory cytokines, nitric oxide (NO), and elevations in neutrophil pulmonary infiltration, they presented higher fungal load in lungs and spleen. Infected lung and infected macrophages from Lgals1−/− mice exhibited elevated levels of prostaglandin E2 (PGE2, a prostanoid regulator of macrophage activation) and prostaglandin E synthase 2 (Ptgs2) mRNA. Gal-1 did not bind to cell surface of yeast phase of H. capsulatum, in vitro, suggesting that Gal-1 contributed to phagocytes response to infection rather than directly killing the yeast. The data provides the first demonstration of endogenous Gal-1 in the protective immune response against H. capsulatum associated with NO and PGE2 as an important lipid mediator in the pathogenesis of histoplasmosis. PMID:27698545

  19. The prostaglandin EP1 receptor potentiates kainate receptor activation via a protein kinase C pathway and exacerbates status epilepticus

    PubMed Central

    Rojas, Asheebo; Gueorguieva, Paoula; Lelutiu, Nadia; Quan, Yi; Shaw, Renee; Dingledine, Raymond

    2014-01-01

    Prostaglandin E2 (PGE2) regulates membrane excitability, synaptic transmission, plasticity, and neuronal survival. The consequences of PGE2 release following seizures has been the subject of much study. Here we demonstrate that the prostaglandin E2 receptor 1 (EP1, or Ptger1) modulates native kainate receptors, a family of ionotropic glutamate receptors widely expressed throughout the central nervous system. Global ablation of the EP1 gene in mice (EP1-KO) had no effect on seizure threshold after kainate injection but reduced the likelihood to enter status epilepticus. EP1-KO mice that did experience typical status epilepticus had reduced hippocampal neurodegeneration and a blunted inflammatory response. Further studies with native prostanoid and kainate receptors in cultured cortical neurons, as well as with recombinant prostanoid and kainate receptors expressed in Xenopus oocytes, demonstrated that EP1 receptor activation potentiates heteromeric but not homomeric kainate receptors via a second messenger cascade involving phospholipase C, calcium and protein kinase C. Three critical GluK5 C-terminal serines underlie the potentiation of the GluK2/GluK5 receptor by EP1 activation. Taken together, these results indicate that EP1 receptor activation during seizures, through a protein kinase C pathway, increases the probability of kainic acid induced status epilepticus, and independently promotes hippocampal neurodegeneration and a broad inflammatory response. PMID:24952362

  20. Interactive effect of histamine and prostaglandin D2 on nasal allergic symptoms in rats.

    PubMed

    Rahman, Ashequr; Inoue, Toshio; Ago, Jun; Ishikawa, Takashi; Kamei, Chiaki

    2007-01-12

    This study was undertaken to investigate the interactive effect of histamine and prostaglandin D(2) in nasal allergic symptoms in rats. The intranasal application of histamine at doses lower than 10 mumol/site caused no sneezing or nasal rubbing. In addition, prostaglandin D(2) also showed no significant increase in these responses, even at a dose of 10 nmol/site. On the other hand, the simultaneous instillation of histamine and prostaglandin D(2) resulted in a 1000 times more potent effect in inducing nasal symptoms than the administration of histamine alone. Thus, prostaglandin D(2) enhanced the actions of histamine in inducing sneezing and nasal rubbing in a dose-dependent manner, and significant effects were observed at doses higher than 1 nmol/site. The responses induced by the simultaneous application of histamine and prostaglandin D(2) were inhibited by chlorpheniramine, cyproheptadine, BW A868C and ramatroban. Chlorpheniramine and cyproheptadine showed the dose-related inhibition of nasal symptoms induced by the combined administration of histamine (10 nmol) and prostaglandin D(2) (10 nmol), but the effect of cyproheptadine was relatively weak compared with chlorpheniramine. Moreover, BW A868C and ramatroban also showed the inhibition of nasal symptoms induced by the simultaneous administration of histamine and prostaglandin D(2) in a dose-dependent manner. BW A868C was more potent in inhibiting the nasal symptoms than ramatroban. These results clearly indicate that prostaglandin D(2) showed a synergistic effect on sneezing and nasal rubbing induced by histamine in rats, and its effect occurred through both prostaglandin D(2) and CRTH2 (chemoattractant receptor-homologous molecule expressed on TH2 cells) receptors.

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

    PubMed

    Takeuchi, K; Kogo, H; Aizawa, Y

    1981-04-01

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

  2. Metabolism of prostaglandin E1 in dog kidneys

    PubMed Central

    Nakano, J.

    1970-01-01

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

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

    PubMed

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

    2013-01-01

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

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

    SciTech Connect

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

    1986-05-01

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

  5. Prostaglandin endoperoxide H synthases: peroxidase hydroperoxide specificity and cyclooxygenase activation.

    PubMed

    Liu, Jiayan; Seibold, Steve A; Rieke, Caroline J; Song, Inseok; Cukier, Robert I; Smith, William L

    2007-06-22

    The cyclooxygenase (COX) activity of prostaglandin endoperoxide H synthases (PGHSs) converts arachidonic acid and O2 to prostaglandin G2 (PGG2). PGHS peroxidase (POX) activity reduces PGG2 to PGH2. The first step in POX catalysis is formation of an oxyferryl heme radical cation (Compound I), which undergoes intramolecular electron transfer forming Intermediate II having an oxyferryl heme and a Tyr-385 radical required for COX catalysis. PGHS POX catalyzes heterolytic cleavage of primary and secondary hydroperoxides much more readily than H2O2, but the basis for this specificity has been unresolved. Several large amino acids form a hydrophobic "dome" over part of the heme, but when these residues were mutated to alanines there was little effect on Compound I formation from H2O2 or 15-hydroperoxyeicosatetraenoic acid, a surrogate substrate for PGG2. Ab initio calculations of heterolytic bond dissociation energies of the peroxyl groups of small peroxides indicated that they are almost the same. Molecular Dynamics simulations suggest that PGG2 binds the POX site through a peroxyl-iron bond, a hydrogen bond with His-207 and van der Waals interactions involving methylene groups adjoining the carbon bearing the peroxyl group and the protoporphyrin IX. We speculate that these latter interactions, which are not possible with H2O2, are major contributors to PGHS POX specificity. The distal Gln-203 four residues removed from His-207 have been thought to be essential for Compound I formation. However, Q203V PGHS-1 and PGHS-2 mutants catalyzed heterolytic cleavage of peroxides and exhibited native COX activity. PGHSs are homodimers with each monomer having a POX site and COX site. Cross-talk occurs between the COX sites of adjoining monomers. However, no cross-talk between the POX and COX sites of monomers was detected in a PGHS-2 heterodimer comprised of a Q203R monomer having an inactive POX site and a G533A monomer with an inactive COX site.

  6. The source of thromboxane and prostaglandins in experimental inflammation.

    PubMed Central

    Higgs, G. A.; Moncada, S.; Salmon, J. A.; Seager, K.

    1983-01-01

    Although cyclo-oxygenase products have been detected at inflammatory sites the tissue of origin remains uncertain. Inflammatory exudates were collected from rats 4, 6, 8, 12 or 24 h after subcutaneous implantation of carrageenin-impregnated sponges. Concentrations of the cyclo-oxygenase products prostaglandin E2 (PGE2), 6-oxo-PGF1 alpha and thromboxane B2 (TXB2) in inflammatory exudates and serum (obtained from blood clotted at 37 degrees C) were measured by specific radioimmunoassays. TXB2 concentrations in exudates increased to about 100 ng ml-1 at 8 h but decreased to less than 20 ng ml-1 after 24 h. PGE2 concentrations increased from 4-12 h and remained between 80 and 120 ng ml-1 from 12-24 h. 6-oxo-PGF1 alpha had the same time course as that of PGE2 but concentrations were approximately one third of PGE2 values. TXB2 concentrations in serum from thrombocytopaenic rats were less than 5% of control values. Thrombocytopaenia did not affect TXB2, PGE2 or 6-oxo-PGF1 alpha concentrations or total leukocyte numbers in inflammatory exudates. Methotrexate-induced neutropaenia did not affect serum TXB2 concentrations but cyclo-oxygenase products (including TXB2) in 6 h inflammatory exudates were reduced by 60-95%. Colchicine (1.0 mg kg-1 s.c.) prevented leukocyte accumulation in sponge exudates and this was accompanied by a reduction in TXB2, PGE2 and 6-oxo-PGF1 alpha concentrations at 6 h. These results indicate that platelets are the source of TXB2 in clotting blood but do not contribute to cyclo-oxygenase activity in experimental inflammation. The results also suggest that migrating leukocytes are the major source of thromboxane and to a lesser degree prostaglandins in acute 6 h inflammatory exudates. PMID:6652359

  7. Induction of human microsomal prostaglandin E synthase 1 by activated oncogene RhoA GTPase in A549 human epithelial cancer cells

    SciTech Connect

    Choi, Hye Jin; Lee, Dong-Hyung; Park, Seong-Hwan; Kim, Juil; Do, Kee Hun; An, Tae Jin; Ahn, Young Sup; Park, Chung Berm; Moon, Yuseok

    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.

  8. Inhibition of Prostaglandin Transporter (PGT) Promotes Perfusion and Vascularization and Accelerates Wound Healing in Non-Diabetic and Diabetic Rats.

    PubMed

    Liu, Zhongbo; Benard, Outhiriaradjou; Syeda, Mahrukh M; Schuster, Victor L; Chi, Yuling

    2015-01-01

    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.

  9. Role of EP4 receptor and prostaglandin transporter in prostaglandin E2-induced alteration in colonic epithelial barrier integrity.

    PubMed

    Lejeune, Manigandan; Leung, Pearl; Beck, Paul L; Chadee, Kris

    2010-11-01

    Prostaglandin E(2) (PGE(2)) is a proinflammatory lipid mediator produced in excess in inflammatory bowel disease (IBD). PGE(2) couples to and signals via four different E-prostanoid (EP) receptors, namely EP1, EP2, EP3, and EP4. In this study, we determined a role for PGE(2) and EP4 receptors in altering colonic epithelial barrier integrity. In healthy colonic mucosa, EP4 receptors were localized on apical plasma membrane of epithelial cells at the tip of mucosal folds, whereas, in patients with IBD and in rats with dextran sodium sulfate (DSS)-induced colitis, they were diffusely overexpressed throughout the mucosa. Similarly, expression of EP4 receptor was polarized in T84 colonic epithelial monolayer and mimics the normal epithelium. Apical exposure of T84 monolayer with high levels of PGE(2) decreased barrier integrity, which was abrogated by an EP4 receptor antagonist. To reveal the mechanism of vectorial transport of basally produced PGE(2) toward apical EP4 receptors, we identified prostaglandin transporters (PGT) in human colonic epithelia. PGT were least expressed on epithelial cells at the colonic mucosal folds of control subjects but overexpressed in epithelial cells of patients with IBD or animals with DSS-induced colitis. T84 monolayer also expressed PGT, which increased twofold following stimulation with TNF-α. Importantly, in T84 monolayer stimulated with TNF-α, there was a corresponding increase in the uptake and vectorial transport of (3)H-PGE(2) to the apical surface. Knockdown or pharmacological inhibition of PGT significantly decreased vectorial transport of (3)H-PGE(2). These studies unravel a mechanism whereby EP4 receptor and PGT play a role in PGE(2)-induced alteration of epithelial barrier integrity in colitis.

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

    PubMed Central

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

    1979-01-01

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

  11. Aspirin-like drugs may block pain independently of prostaglandin synthesis inhibition.

    PubMed

    Brune, K; Beck, W S; Geisslinger, G; Menzel-Soglowek, S; Peskar, B M; Peskar, B A

    1991-03-15

    Using flurbiprofen, a chiral anti-inflammatory and analgesic 2-arylpropionic acid derivative, the enantiomers of which are not converted to each other (less than 5%) in rats or man, we obtained evidence that prostaglandin synthesis inhibition is primarily mediating the anti-inflammatory activity but prostaglandin synthesis independent mechanisms contribute to the analgesic effects. Thus, the S-form inhibited prostaglandin synthesis, inflammation and nociception in rats. The R-form had much less effect on prostaglandin synthesis and did not affect inflammation. It did, however, block nociception in rats almost as potently as the S-form. S-flurbiprofen, in contrast to the R-form, was clearly ulcerogenic in the gastrointestinal mucosa. These results indicate additional molecular mechanisms of analgesia and suggest the use of R-arylpropionic acids as analgesics.

  12. Celecoxib Improves Host Defense through Prostaglandin Inhibition during Histoplasma capsulatum Infection

    PubMed Central

    Pereira, Priscilla Aparecida Tartari; Trindade, Bruno Caetano; Secatto, Adriana; Nicolete, Roberto; Peres-Buzalaf, Camila; Ramos, Simone Gusmão; Sadikot, Ruxana; Bitencourt, Claudia da Silva

    2013-01-01

    Prostaglandins act as mediators of inflammation and, similar to cytokines, function as immune modulators during innate and adaptive immune responses. Therefore, using a pharmacological inhibitor, celecoxib, we investigated the role of prostaglandins in host defense against Histoplasma capsulatum infection in C57BL/6 mice. Our results showed that treatment with celecoxib inhibited cyclooxygenase 2, reduced the total fungal burden, and reduced the concentration of PGE2, cytokines, lymphocytes, neutrophils, and mononuclear cells in the bronchoalveolar space and lung parenchyma. In addition, celecoxib treatment increased the synthesis of nitric oxide, IFN-γ, LTB4, and the phagocytic capacity of alveolar macrophages. Moreover, celecoxib treatment increased the survival of mice after infection with a lethal inoculum of H. capsulatum. These results suggest that prostaglandins alter the host immune response and play an important role in the pathogenesis of histoplasmosis. Thus, the inhibition of prostaglandins could be a valuable immunomodulatory strategy and antifungal therapy for histoplasmosis treatment. PMID:23818746

  13. Molecular cloning and spatio-temporal expression of the prostaglandin transporter: a basis for the action of prostaglandins in the bovine reproductive system.

    PubMed

    Banu, Sakhila K; Arosh, Joe A; Chapdelaine, Pierre; Fortier, Michel A

    2003-09-30

    Prostaglandins (PGs) play important roles in mammalian reproductive function through autocrine, paracrine, and endocrine actions. However, they predominate as charged anions and diffuse poorly across the plasma membrane. Recently, a PG transporter (PGT) has been found to mediate PG transport across cell membranes. In ruminants, endometrial PGs are transported by a vascular pathway to the ovary to regress or rescue the corpus luteum. There is no report on the role of PGT in the reproductive functions of any species. We have cloned and characterized the bovine PGT (bPGT) that transports different PGs in the following affinity order: PGE2 = PGF2alpha >/= PGD2 much greater than arachidonate. bPGT mRNA and protein are expressed in endometrium, myometrium, and the utero-ovarian plexus (UOP) during the estrous cycle. The level of bPGT expression is higher in endometrium and UOP on the side of corpus luteum between days 13 and 18 of the estrous cycle. bPGT protein is localized in endometrial stroma, luminal epithelial cells, myometrial smooth muscle cells, and vascular smooth muscle cells of uterine vein and artery. In UOP, bPGT is selectively expressed in vascular smooth muscle cells of uterine vein and ovarian artery. Spatio-temporal expression of bPGT in uterine tissues and UOP supports a significant role of bPGT in cellular and compartmental transport of PGs to mediate the endocrine action at the time of luteolysis or establishment of pregnancy in bovine. This study describes and proposes a role of PGT in the regulation of reproductive processes.

  14. Berberine, an isoquinoline alkaloid, inhibits melanoma cancer cell migration by reducing the expressions of cyclooxygenase-2, prostaglandin E2 and prostaglandin E2 receptors

    PubMed Central

    Singh, Tripti; Vaid, Mudit; Katiyar, Nandan; Sharma, Samriti; Katiyar, Santosh K.

    2011-01-01

    Melanoma is the leading cause of death from skin disease due, in large part, to its propensity to metastasize. We have examined the effect of berberine, an isoquinoline alkaloid, on human melanoma cancer cell migration and the molecular mechanisms underlying these effects using melanoma cell lines, A375 and Hs294. Using an in vitro cell migration assay, we show that over expression of cyclooxygenase (COX)-2, its metabolite prostaglandin E2 (PGE2) and PGE2 receptors promote the migration of cells. We found that treatment of A375 and Hs294 cells with berberine resulted in concentration-dependent inhibition of migration of these cells, which was associated with a reduction in the levels of COX-2, PGE2 and PGE2 receptors (EP2 and EP4). Treatment of cells with celecoxib, a COX-2 inhibitor, or transient transfection of cells with COX-2 small interfering RNA, also inhibited cell migration. Treatment of the cells with 12-O-tetradecanoylphorbol-13-acetate (TPA), an inducer of COX-2 or PGE2, enhanced cell migration, whereas berberine inhibited TPA- or PGE2-promoted cell migration. Berberine reduced the basal levels as well as PGE2-stimulated expression levels of EP2 and EP4. Treatment of the cells with the EP4 agonist stimulated cell migration and berberine blocked EP4 agonist-induced cell migration activity. Moreover, berberine inhibited the activation of nuclear factor-kappa B (NF-κB), an upstream regulator of COX-2, in A375 cells, and treatment of cells with caffeic acid phenethyl ester, an inhibitor of NF-κB, inhibited cell migration. Together, these results indicate for the first time that berberine inhibits melanoma cell migration, an essential step in invasion and metastasis, by inhibition of COX-2, PGE2 and PGE2 receptors. PMID:20974686

  15. Angiotensin II type I and prostaglandin F2α receptors cooperatively modulate signaling in vascular smooth muscle cells.

    PubMed

    Goupil, Eugénie; Fillion, Dany; Clément, Stéphanie; Luo, Xiaoyan; Devost, Dominic; Sleno, Rory; Pétrin, Darlaine; Saragovi, H Uri; Thorin, Éric; Laporte, Stéphane A; Hébert, Terence E

    2015-01-30

    The angiotensin II type I (AT1R) and the prostaglandin F2α (PGF2α) F prostanoid (FP) receptors are both potent regulators of blood pressure. Physiological interplay between AT1R and FP has been described. Abdominal aortic ring contraction experiments revealed that PGF2α-dependent activation of FP potentiated angiotensin II-induced contraction, whereas FP antagonists had the opposite effect. Similarly, PGF2α-mediated vasoconstriction was symmetrically regulated by co-treatment with AT1R agonist and antagonist. The underlying canonical Gαq signaling via production of inositol phosphates mediated by each receptor was also regulated by antagonists for the other receptor. However, binding to their respective agonists, regulation of receptor-mediated MAPK activation and vascular smooth muscle cell growth were differentially or asymmetrically regulated depending on how each of the two receptors were occupied by either agonist or antagonist. Physical interactions between these receptors have never been reported, and here we show that AT1R and FP form heterodimeric complexes in both HEK 293 and vascular smooth muscle cells. These findings imply that formation of the AT1R/FP dimer creates a novel allosteric signaling unit that shows symmetrical and asymmetrical signaling behavior, depending on the outcome measured. AT1R/FP dimers may thus be important in the regulation of blood pressure.

  16. Inhibition of rabbit erythroid 15-lipoxygenase and sheep vesicular gland prostaglandin H synthase by gallic esters.

    PubMed

    Luther, H; Jordanov, D; Ludwig, P; Schewe, T

    1991-02-01

    Gallic acid esters possessing a varying chain length of their alcohol moiety were tested for their inhibitory potencies on 15-lipoxygenase from rabbit reticulocytes and prostaglandin H synthase from sheep vesicular glands. Octyl gallate and decyl gallate proved to be the most powerful inhibitors of both enzymes showing concentrations of half-inhibition of about 0.25 mumol/l for the reticulocyte lipoxygenase and of about 25 mumol/l for the prostaglandin H synthase.

  17. [Do prostaglandins protect other cells besides those of the gastrointestinal epithelium?].

    PubMed

    Müller, P; Dammann, H G; Simon, B

    1982-08-01

    Prostaglandins in very low concentrations, which do not inhibit acid secretion, do protect the mucosa of the gastrointestinal tract against a great number of noxious agents. Similar effects could be shown recently in hepatic, pancreatic, renal, and myocardial tissue. The mechanism of cytoprotective action remains unclear. Since cytoprotection is quite ubiquitous, a common mechanism as for instance stabilisation of membranes seems to be effective. It remains to be seen, if this protective action of prostaglandins can be used in therapy.

  18. Nutritional modulation of mineralocorticoid and prostaglandin production: potential role in prevention and treatment of gastric pathology.

    PubMed

    McCarty, M F

    1983-08-01

    Various lines of evidence indicate that aldosterone and prostaglandins may play physiological roles in protecting the gastric mucosa. This would suggest that low-sodium, high-potassium diets, and supplementation with essential fatty acids that are efficient prostaglandin precursors (as in evening primrose oil), may have value in the prevention and treatment of gastric ulcer and gastritis. A low-sodium, high-potassium diet may also reduce the risk of gastric cancer.

  19. alpha-Lipoic acid inhibits inflammatory bone resorption by suppressing prostaglandin E2 synthesis.

    PubMed

    Ha, Hyunil; Lee, Jong-Ho; Kim, Ha-Neui; Kim, Hyun-Man; Kwak, Han Bok; Lee, Seungbok; Kim, Hong-Hee; Lee, Zang Hee

    2006-01-01

    alpha-Lipoic acid (LA) has been intensely investigated as a therapeutic agent for several pathological conditions, including diabetic polyneuropathy. In the present study, we examined the effects of LA on osteoclastic bone loss associated with inflammation. LA significantly inhibited IL-1-induced osteoclast formation in cocultures of mouse osteoblasts and bone marrow cells, but LA had only a marginal effect on osteoclastogenesis from bone marrow macrophages induced by receptor activator of NF-kappaB ligand (RANKL). LA inhibited both the sustained up-regulation of RANKL expression and the production of PGE2 induced by IL-1 in osteoblasts. In addition, treatment with either prostaglandin E2 (PGE2) or RANKL rescued IL-1-induced osteoclast formation inhibited by LA or NS398, a specific cyclooxygenase-2 (COX-2) inhibitor, in cocultures. LA blocked IL-1-induced PGE2 production even in the presence of arachidonic acid, without affecting the expression of COX-2 and membrane-bound PGE2 synthase. Dihydrolipoic acid (the reduced form of LA), but not LA, attenuated recombinant COX-2 activity in vitro. LA also inhibited osteoclast formation and bone loss induced by IL-1 and LPS in mice. Our results suggest that the reduced form of LA inhibits COX-2 activity, PGE2 production, and sustained RANKL expression, thereby inhibiting osteoclast formation and bone loss in inflammatory conditions.

  20. Gliotransmission by Prostaglandin E2: A Prerequisite for GnRH Neuronal Function?

    PubMed Central

    Clasadonte, Jerome; Sharif, Ariane; Baroncini, Marc; Prevot, Vincent

    2011-01-01

    Over the past four decades it has become clear that prostaglandin E2 (PGE2), a phospholipid-derived signaling molecule, plays a fundamental role in modulating the gonadotropin-releasing hormone (GnRH) neuroendocrine system and in shaping the hypothalamus. In this review, after a brief historical overview, we highlight studies revealing that PGE2 released by glial cells such as astrocytes and tanycytes is intimately involved in the active control of GnRH neuronal activity and neurosecretion. Recent evidence suggests that hypothalamic astrocytes surrounding GnRH neuronal cell bodies may respond to neuronal activity with an activation of the erbB receptor tyrosine kinase signaling, triggering the release of PGE2 as a chemical transmitter from the glia themselves, and, in turn, leading to the feedback regulation of GnRH neuronal activity. At the GnRH neurohemal junction, in the median eminence of the hypothalamus, PGE2 is released by tanycytes in response to cell–cell signaling initiated by glial cells and vascular endothelial cells. Upon its release, PGE2 causes the retraction of the tanycyte end-feet enwrapping the GnRH nerve terminals, enabling them to approach the adjacent pericapillary space and thus likely facilitating neurohormone diffusion from these nerve terminals into the pituitary portal blood. In view of these new insights, we suggest that synaptically associated astrocytes and perijunctional tanycytes are integral modulatory elements of GnRH neuronal function at the cell soma/dendrite and nerve terminal levels, respectively. PMID:22649391

  1. Prostaglandin I2 Signaling Drives Th17 Differentiation and Exacerbates Experimental Autoimmune Encephalomyelitis

    PubMed Central

    Zhou, Weisong; Dowell, Dustin R.; Huckabee, Matthew M.; Newcomb, Dawn C.; Boswell, Madison G.; Goleniewska, Kasia; Lotz, Matthew T.; Toki, Shinji; Yin, Huiyong; Yao, Songyi; Natarajan, Chandramohan; Wu, Pingsheng; Sriram, Subramaniam; Breyer, Richard M.; FitzGerald, Garret A.; Peebles, R. Stokes

    2012-01-01

    Background Prostaglandin I2 (PGI2), a lipid mediator currently used in treatment of human disease, is a critical regulator of adaptive immune responses. Although PGI2 signaling suppressed Th1 and Th2 immune responses, the role of PGI2 in Th17 differentiation is not known. Methodology/Principal Findings In mouse CD4+CD62L+ naïve T cell culture, the PGI2 analogs iloprost and cicaprost increased IL-17A and IL-22 protein production and Th17 differentiation in vitro. This effect was augmented by IL-23 and was dependent on PGI2 receptor IP signaling. In mouse bone marrow-derived CD11c+ dendritic cells (BMDCs), PGI2 analogs increased the ratio of IL-23/IL-12, which is correlated with increased ability of BMDCs to stimulate naïve T cells for IL-17A production. Moreover, IP knockout mice had delayed onset of a Th17-associated neurological disease, experimental autoimmune encephalomyelitis (EAE), and reduced infiltration of IL-17A-expressing mononuclear cells in the spinal cords compared to wild type mice. These results suggest that PGI2 promotes in vivo Th17 responses. Conclusion The preferential stimulation of Th17 differentiation by IP signaling may have important clinical implications as PGI2 and its analogs are commonly used to treat human pulmonary hypertension. PMID:22590492

  2. Prostaglandin E2 inhibits collagen synthesis in dermal fibroblasts and prevents hypertrophic scar formation in vivo.

    PubMed

    Zhao, Jingling; Shu, Bin; Chen, Lei; Tang, Jinming; Zhang, Lijun; Xie, Julin; Liu, Xusheng; Xu, Yingbin; Qi, Shaohai

    2016-08-01

    Hypertrophic scarring is a common dermal fibroproliferative disorder characterized by excessive collagen deposition. Prostaglandin E2 (PGE2 ), an important inflammatory product synthesized via the arachidonic acid cascade, has been shown to act as a fibroblast modulator and to possess antifibroblastic activity. However, the mechanism underlying the antifibrotic effect of PGE2 remains unclear. In this study, we explored the effects of PGE2 on TGF-β1-treated dermal fibroblasts in terms of collagen production and to determine the regulatory pathways involved, as well as understand the antiscarring function of PGE2 in vivo. We found that PGE2 inhibited TGF-β1-induced collagen synthesis by regulating the balance of matrix metalloproteinases (MMPs) and tissue inhibitor of metalloproteinase (TIMP). It did so by upregulating cAMP through the E prostanoid (EP)2 receptor. We determined that inhibition of the TGF-β1/Smad pathway by PGE2 is associated with its ability to inhibit collagen synthesis. An in vivo study further confirmed that PGE2 inhibits hypertrophic scar formation by decreasing collagen production. Our results demonstrate that the novel anti-scarring function of PGE2 is achieved by balancing MMPs/TIMP expression and decreasing collagen production. PMID:26997546

  3. Prostaglandin D2 synthase/GPR44: a signaling axis in PNS myelination.

    PubMed

    Trimarco, Amelia; Forese, Maria Grazia; Alfieri, Valentina; Lucente, Alessandra; Brambilla, Paola; Dina, Giorgia; Pieragostino, Damiana; Sacchetta, Paolo; Urade, Yoshihiro; Boizet-Bonhoure, Brigitte; Martinelli Boneschi, Filippo; Quattrini, Angelo; Taveggia, Carla

    2014-12-01

    Neuregulin 1 type III is processed following regulated intramembrane proteolysis, which allows communication from the plasma membrane to the nucleus. We found that the intracellular domain of neuregulin 1 type III upregulated the prostaglandin D2 synthase (L-pgds, also known as Ptgds) gene, which, together with the G protein-coupled receptor Gpr44, forms a previously unknown pathway in PNS myelination. Neuronal L-PGDS is secreted and produces the PGD2 prostanoid, a ligand of Gpr44. We found that mice lacking L-PGDS were hypomyelinated. Consistent with this, specific inhibition of L-PGDS activity impaired in vitro myelination and caused myelin damage. Furthermore, in vivo ablation and in vitro knockdown of glial Gpr44 impaired myelination. Finally, we identified Nfatc4, a key transcription factor for myelination, as one of the downstream effectors of PGD2 activity in Schwann cells. Thus, L-PGDS and Gpr44 are previously unknown components of an axo-glial interaction that controls PNS myelination and possibly myelin maintenance.

  4. Effect of Prostaglandin E2 on Multidrug Resistance Transporters In Human Placental Cells

    PubMed Central

    Lee, Gene T.; Dong, Yafeng; Zhou, Helen; He, Lily; Weiner, Carl P.

    2014-01-01

    Prostaglandin (PG) E2, a major product of cyclooxygenase (COX)-2, acts as an immunomodulator at the maternal-fetal interface during pregnancy. It exerts biologic function through interaction with E-prostanoid (EP) receptors localized to the placenta. The activation of the COX-2/PGE2/EP signal pathway can alter the expression of the ATP-binding cassette (ABC) transporters, multidrug resistance protein 1 [P-glycoprotein (Pgp); gene: ABCB1], and breast cancer resistance protein (BCRP; gene: ABCG2), which function to extrude drugs and xenobiotics from cells. In the placenta, PGE2-mediated changes in ABC transporter expression could impact fetal drug exposure. Furthermore, understanding the signaling cascades involved could lead to strategies for the control of Pgp and BCRP expression levels. We sought to determine the impact of PGE2 signaling mechanisms on Pgp and BCRP in human placental cells. The treatment of placental cells with PGE2 up-regulated BCRP expression and resulted in decreased cellular accumulation of the fluorescent substrate Hoechst 33342. Inhibiting the EP1 and EP3 receptors with specific antagonists attenuated the increase in BCRP. EP receptor signaling results in activation of transcription factors, which can affect BCRP expression. Although PGE2 decreased nuclear factor κ-light chain-enhancer of activated B activation and increased activator protein 1, chemical inhibition of these inflammatory transcription factors did not blunt BCRP up-regulation by PGE2. Though PGE2 decreased Pgp mRNA, Pgp expression and function were not significantly altered. Overall, these findings suggest a possible role for PGE2 in the up-regulation of placental BCRP expression via EP1 and EP3 receptor signaling cascades. PMID:25261564

  5. Prostaglandin synthesis by chicken and rat lung microsomes

    SciTech Connect

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

    1986-03-01

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

  6. Determination of 6-keto prostaglandin F1α and its metabolites in human plasma by LC-MS/MS.

    PubMed

    Enzler, Mark; Schipp, Stefan; Nicolas, Laurent B; Dingemanse, Jasper; Siethoff, Christoph

    2012-07-15

    An HPLC-MS/MS method was developed and validated for the quantification of 6-keto prostaglandin F1α, the stable hydrolysis product of prostacyclin, and its metabolites 2,3-dinor-6-keto prostaglandin F1α and 6,15-diketo-13,14-dihydro prostaglandin F1α in human plasma. For sample preparation, a solid phase extraction step was combined with a column switching approach for analytes enrichment and further sample clean-up of the processed sample. The assay was validated in the concentration range 50.0-5000 pg/mL for 6-keto prostaglandin F1α and 6,15-diketo-13,14-dihydro prostaglandin F1α, and 100-10,000 pg/mL for 2,3-dinor-6-keto prostaglandin F1α. The inter-batch precision was better than 12.7%, 9.2%, and 9.4% for 6-keto prostaglandin F1α, 2,3-dinor-6-keto prostaglandin F1α, and 6,15-diketo-13,14-dihydro prostaglandin F1α, respectively. The inter-batch accuracy was between 97.3% and 100.8% for 6-keto prostaglandin F1α, between 97.5% and 103.0% for 2,3-dinor-6-keto prostaglandin F1α, and between 92.0% and 100.0% for 6,15-diketo-13,14-dihydro prostaglandin F1α. Further it has been demonstrated that the analytes were stable in plasma for 20 h at room temperature, during three freeze-and-thaw cycles, for 96 days at -25 °C storage temperature, and 50h in the autosampler tray at room temperature.

  7. Therapeutic targets in prostaglandin E2 signaling for neurologic disease

    PubMed Central

    Cimino, P.J.; Keene, C. Dirk; Breyer, Richard M.; Montine, Kathleen S.; Montine, Thomas J.

    2009-01-01

    Prostaglandins (PGs) are potent autocrine and paracrine oxygenated lipid molecules that contribute appreciably to physiologic and pathophysiologic responses in almost all organs, including brain. Emerging data indicate that the PGs, and more specifically PGE2, play a central role in brain diseases including ischemic injury and several neurodegenerative diseases. Given concerns over the potential toxicity from protracted use of cyclooxygenase inhibitors in the elderly, attention is now focused on blocking PGE2 signaling that is mediated by interactions with four distinct G protein-coupled receptors, EP1-4, which are differentially expressed on neuronal and glial cells throughout the central nervous system. EP1 activation has been shown to mediate Ca2+-dependent neurotoxicity in ischemic injury. EP2 activation has been shown to mediate microglial-induced paracrine neurotoxicity as well as suppress microglia internalization of aggregated neurotoxic peptides. Animal models support the potential efficacy of targeting specific EP receptor subtypes in Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and ischemic stroke. However promising these preclinical studies are, they have yet to be followed by clinical trials targeting any EP receptor in neurologic diseases. PMID:18691044

  8. Prostaglandin E2 Prevents Disuse-Induced Cortical Bone Loss

    NASA Technical Reports Server (NTRS)

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

    1992-01-01

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

  9. Prostaglandin F receptor expression in intrauterine tissues of pregnant rats

    PubMed Central

    Kanca, Halit; Yar, Atiye Seda; Helvacioğlu, Fatma; Menevşe, Sevda; Çalgüner, Engin; Erdoğan, Deniz

    2014-01-01

    In this investigation, we studied the expression and localization of rat prostaglandin F (FP) receptor in uterine tissues of rats on gestational Days 10, 15, 18, 20, 21, 21.5 and postpartal Days 1 and 3 using Western blotting analysis, real-time PCR, and immunohistochemistry. A high level of immunoreactivity was observed on gestational Days 20, 21, and 21.5 with the most significant signals found on Day 20. FP receptor protein was expressed starting on gestational Day 15, and a fluctuating unsteady increase was observed until delivery. Uterine FP receptor mRNA levels were low between Days 10 and 18 of gestation (p < 0.05). The transcript level increased significantly on Day 20 and peaked on Day 21.5 just before labor (p < 0.05). There was a positive correlation between FP receptor mRNA expression and serum estradiol levels (rs = 0.78; p < 0.01) along with serum estradiol/progesterone ratios (rs = 0.79; p < 0.01). In summary, we observed an increase FP receptor expression in rat uterus with advancing gestation, a marked elevation of expression at term, and a concominant decrease during the postpartum period. These findings indicate a role for uterine FP receptors in the mediation of uterine contractility at term. PMID:24136214

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

    SciTech Connect

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

    2005-09-30

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

  11. Prostaglandin E2 protects lower airways against bronchoconstriction.

    PubMed

    Hartney, John M; Coggins, Kenneth G; Tilley, Stephen L; Jania, Leigh A; Lovgren, Alysia Kern; Audoly, Laurent P; Koller, Beverly H

    2006-01-01

    Prostaglandin E2 (PGE2), similar to beta-adrenergic receptor agonists, can protect airways from bronchoconstriction and resulting increase in airway resistance induced by a number of agents, including cholinergic receptor agonists and antigen. We examined the impact of sustained alterations in PGE2 pathways on changes in airway resistance. Genetic methods were utilized to alter PGE2 metabolism and signal transduction in the murine lung. PGE2 levels were elevated by generating mice lacking 15-hydroxyprostaglandin (Hpgd-/-), the major catabolic enzyme of PGE2, and by generating a transgenic line in which mouse PGE2 synthase (Ptges) expression is driven by a human lung-specific promoter, hSP-C. Conversely, to determine the impact of loss of PGE2 on airway reactivity, we examined mice lacking this synthase (Ptges-/-) and receptors that mediate the actions of PGE2, particularly the PGE2 EP2 receptor (Ptger2). Diminished capacity to produce and respond to PGE2 did not alter the response of mice to cholinergic stimuli. In contrast, the responsiveness to cholinergic stimulation was dramatically altered in animals with elevated PGE2 levels. The Hpgd-/- and hSP-C-Ptges transgenic lines both showed attenuated airway responsiveness to methacholine as measured by lung resistance. Thus, whereas compromise of the Ptges/PGE2/Ptger2 pathway does not alter airway responsiveness, genetic modulation that elevates PGE2 levels in the lung attenuates airway responsiveness. PMID:16113047

  12. Hangover headache and prostaglandins: prophylactic treatment with tolfenamic acid.

    PubMed

    Kaivola, S; Parantainen, J; Osterman, T; Timonen, H

    1983-03-01

    Tolfenamic acid (TA), a potent inhibitor of prostaglandin (PG) biosynthesis and action, was tested prophylactically against hangover symptoms in 30 healthy volunteers in a double-blind cross-over study. One capsule of TA (200 mg) or placebo was taken before starting to drink alcohol and another before going to bed. The hangover symptoms were evaluated in the morning. TA was found significantly better than placebo in the subjective evaluation of drug efficacy (p less than 0.001) and in reducing the reported hangover symptoms in general (p less than 0.01). In the TA group, significantly lower symptom scores were obtained for headache (p less than 0.01), and for nausea, vomiting, irritation, tremor, thirst and dryness of mouth (all p less than 0.05). In a separate study with eight participants, plasma levels of PGs were followed during ingestion of alcohol with or without TA. The plasma concentrations of PGE2 and TXB2 (a metabolite of thromboxane A2) were lower in the TA group during alcohol ingestion, while PGF2 alpha and 6-keto-PGF1 alpha (a metabolite of prostacyclin) were unaffected. TXB2 correlated with blood alcohol levels in a U-shaped manner.

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

    PubMed Central

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

    2016-01-01

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

  14. Prostaglandin E2 promotes proliferation of skeletal muscle myoblasts via EP4 receptor activation.

    PubMed

    Mo, Chenglin; Zhao, Ruonan; Vallejo, Julian; Igwe, Orisa; Bonewald, Lynda; Wetmore, Lori; Brotto, Marco

    2015-01-01

    We recently demonstrated that conditioned media (CM) from osteocytes enhances myogenic differentiation of myoblasts, suggesting that signaling from bone may be important for skeletal muscle myogenesis. The effect of CM was closely mimicked by prostaglandin E2 (PGE2), a bioactive lipid mediator in various physiological or pathological conditions. PGE2 is secreted at high levels by osteocytes and such secretion is further enhanced under loading conditions. Although four types of receptors, EP1 to EP4, mediate PGE2 signaling, it is unknown whether these receptors play a role in myogenesis. Therefore, in this study, the expression of EPs in mouse primary myoblasts was characterized, followed by examination of their roles in myoblast proliferation by treating myoblasts with PGE2 or specific agonists. All four PGE2 receptor mRNAs were detectable by quantitative real-time PCR (qPCR), but only PGE2 and EP4 agonist CAY 10598 significantly enhance myoblast proliferation. EP1/EP3 agonist 17-phenyl trinor PGE2 (17-PT PGE2) and EP2 agonist butaprost did not have any significant effects. Moreover, treatment with EP4 antagonist L161,982 dose-dependently inhibited myoblast proliferation. These results were confirmed by cell cycle analysis and the gene expression of cell cycle regulators. Concomitant with the inhibition of myoblast proliferation, treatment with L161,982 significantly increased intracellular reactive oxygen species (ROS) levels. Cotreatment with antioxidant N-acetyl cysteine (NAC) or sodium ascorbate (SA) successfully reversed the inhibition of myoblast proliferation and ROS overproduction caused by L161,982. Therefore, PGE2 signaling via the EP4 receptor regulates myogenesis by promoting myoblast proliferation and blocking this receptor results in increased ROS production in myoblasts.

  15. Synthesis and reception of prostaglandins in corpora lutea of domestic cat and lynx.

    PubMed

    Zschockelt, Lina; Amelkina, Olga; Siemieniuch, Marta J; Kowalewski, Mariusz P; Dehnhard, Martin; Jewgenow, Katarina; Braun, Beate C

    2016-08-01

    Felids show different reproductive strategies related to the luteal phase. Domestic cats exhibit a seasonal polyoestrus and ovulation is followed by formation of corpora lutea (CL). Pregnant and non-pregnant cycles are reflected by diverging plasma progesterone (P4) profiles. Eurasian and Iberian lynxes show a seasonal monooestrus, in which physiologically persistent CL (perCL) support constantly elevated plasma P4 levels. Prostaglandins (PGs) represent key regulators of reproduction, and we aimed to characterise PG synthesis in feline CL to identify their contribution to the luteal lifespan. We assessed mRNA and protein expression of PG synthases (PTGS2/COX2, PTGES, PGFS/AKR1C3) and PG receptors (PTGER2, PTGER4, PTGFR), and intra-luteal levels of PGE2 and PGF2α Therefore, CL of pregnant (pre-implantation, post-implantation, regression stages) and non-pregnant (formation, development/maintenance, early regression, late regression stages) domestic cats, and prooestrous Eurasian (perCL, pre-mating) and metoestrous Iberian (perCL, freshCL, post-mating) lynxes were investigated. Expression of PTGS2/COX2, PTGES and PTGER4 was independent of the luteal stage in the investigated species. High levels of luteotrophic PGE2 in perCL might be associated with persistence of luteal function in lynxes. Signals for PGFS/AKR1C3 expression were weak in mid and late luteal stages of cats but were absent in lynxes, concomitant with low PGF2α levels in these species. Thus, regulation of CL regression by luteal PGF2α seems negligible. In contrast, expression of PTGFR was evident in nearly all investigated CL of cat and lynxes, implying that luteal regression, e.g. at the end of pregnancy, is triggered by extra-luteal PGF2α.

  16. Synthesis and reception of prostaglandins in corpora lutea of domestic cat and lynx.

    PubMed

    Zschockelt, Lina; Amelkina, Olga; Siemieniuch, Marta J; Kowalewski, Mariusz P; Dehnhard, Martin; Jewgenow, Katarina; Braun, Beate C

    2016-08-01

    Felids show different reproductive strategies related to the luteal phase. Domestic cats exhibit a seasonal polyoestrus and ovulation is followed by formation of corpora lutea (CL). Pregnant and non-pregnant cycles are reflected by diverging plasma progesterone (P4) profiles. Eurasian and Iberian lynxes show a seasonal monooestrus, in which physiologically persistent CL (perCL) support constantly elevated plasma P4 levels. Prostaglandins (PGs) represent key regulators of reproduction, and we aimed to characterise PG synthesis in feline CL to identify their contribution to the luteal lifespan. We assessed mRNA and protein expression of PG synthases (PTGS2/COX2, PTGES, PGFS/AKR1C3) and PG receptors (PTGER2, PTGER4, PTGFR), and intra-luteal levels of PGE2 and PGF2α Therefore, CL of pregnant (pre-implantation, post-implantation, regression stages) and non-pregnant (formation, development/maintenance, early regression, late regression stages) domestic cats, and prooestrous Eurasian (perCL, pre-mating) and metoestrous Iberian (perCL, freshCL, post-mating) lynxes were investigated. Expression of PTGS2/COX2, PTGES and PTGER4 was independent of the luteal stage in the investigated species. High levels of luteotrophic PGE2 in perCL might be associated with persistence of luteal function in lynxes. Signals for PGFS/AKR1C3 expression were weak in mid and late luteal stages of cats but were absent in lynxes, concomitant with low PGF2α levels in these species. Thus, regulation of CL regression by luteal PGF2α seems negligible. In contrast, expression of PTGFR was evident in nearly all investigated CL of cat and lynxes, implying that luteal regression, e.g. at the end of pregnancy, is triggered by extra-luteal PGF2α. PMID:27222595

  17. Prostaglandin F2α promotes angiogenesis and embryo-maternal interactions during implantation.

    PubMed

    Kaczynski, Piotr; Kowalewski, M P; Waclawik, Agnieszka

    2016-05-01

    Implantation in humans and other mammals is a critical period during which high embryonic mortality rates occur. Prostaglandins (PGs) are key mediators regulating interactions between the reproductive tract and the conceptus (embryo with extraembryonic membranes). Although the significance of PGF2α as a regulator of corpus luteum regression is well established, the role of its high amounts in the uterine lumen in most mammals, regardless of placentation type, during the implantation period remains unresolved. We hypothesized that PGF2α acting as an embryonic signal mediator contributes to pregnancy establishment. Using a porcine model, we demonstrated that the conceptus and its signal (estradiol-17β) elevated endometrial expression of PGF2α receptor (PTGFR) in vivo and in vitro PTGFR protein was expressed mainly in luminal epithelial (LE) and glandular epithelial cells and blood vessels in the endometrium. PGF2α stimulated the MAPK1/3 pathway in endometrial LE cells that coincided with elevated gene expression and secretion of endometrial vascular endothelial growth factor A (VEGFA) protein. PGF2α-PTGFR and adenylyl cyclase signaling were involved in this process. PGF2α-induced VEGFA acting through its receptors stimulated proliferation of endometrial endothelial cells. Moreover, PGF2α elevated gene expression of biglycan, matrix metalloproteinase 9, transforming growth factor β3, and interleukin 1α in the endometrium. In summary, our study indicates that PGF2α participates in pregnancy establishment by promoting angiogenesis and expression of genes involved in tissue remodeling and conceptus-maternal interactions in porcine endometrium during early pregnancy. PMID:26908918

  18. Selective Activation of the Prostaglandin E2 Circuit in Chronic Injury-Induced Pathologic Angiogenesis

    PubMed Central

    Liclican, Elvira L.; Nguyen, Van; Sullivan, Aaron B.

    2010-01-01

    Purpose. Cyclooxygenase (COX)-derived prostaglandin E2 (PGE2) is a prevalent and established mediator of inflammation and pain in numerous tissues and diseases. Distribution and expression of the four PGE2 receptors (EP1-EP4) can dictate whether PGE2 exerts an anti-inflammatory or a proinflammatory and/or a proangiogenic effect. The role and mechanism of endogenous PGE2 in the cornea, and the regulation of EP expression during a dynamic and complex inflammatory/reparative response remain to be clearly defined. Methods. Chronic or acute self-resolving inflammation was induced in mice by corneal suture or epithelial abrasion, respectively. Reepithelialization was monitored by fluorescein staining and neovascularization quantified by CD31/PECAM-1 immunofluorescence. PGE2 formation was analyzed by lipidomics and polymorphonuclear leukocyte (PMN) infiltration quantified by myeloperoxidase activity. Expression of EPs and inflammatory/angiogenic mediators was assessed by real-time PCR and immunohistochemistry. Mice eyes were treated with PGE2 (100 ng topically, three times a day) for up to 7 days. Results. COX-2, EP-2, and EP-4 expression was upregulated with chronic inflammation that correlated with increased corneal PGE2 formation and marked neovascularization. In contrast, acute abrasion injury did not alter PGE2 or EP levels. PGE2 treatment amplified PMN infiltration and the angiogenic response to chronic inflammation but did not affect wound healing or PMN infiltration after epithelial abrasion. Exacerbated inflammatory neovascularization with PGE2 treatment was independent of the VEGF circuit but was associated with a significant induction of the eotaxin-CCR3 axis. Conclusions. These findings place the corneal PGE2 circuit as an endogenous mediator of inflammatory neovascularization rather than general inflammation and demonstrate that chronic inflammation selectively regulates this circuit at the level of biosynthetic enzyme and receptor expression. PMID:20610836

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

    PubMed

    Fretland, D J; Cammarata, P S

    1984-04-01

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

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

    PubMed Central

    Bockman, R S

    1980-01-01

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

  1. ATP-induced vasodilation and purinergic receptors in the human leg: roles of nitric oxide, prostaglandins, and adenosine.

    PubMed

    Mortensen, Stefan P; González-Alonso, José; Bune, Laurids T; Saltin, Bengt; Pilegaard, Henriette; Hellsten, Ylva

    2009-04-01

    Plasma ATP is thought to contribute to the local regulation of skeletal muscle blood flow. Intravascular ATP infusion can induce profound limb muscle vasodilatation, but the purinergic receptors and downstream signals involved in this response remain unclear. This study investigated: 1) the role of nitric oxide (NO), prostaglandins, and adenosine as mediators of ATP-induced limb vasodilation and 2) the expression and distribution of purinergic P(2) receptors in human skeletal muscle. Systemic and leg hemodynamics were measured before and during 5-7 min of femoral intra-arterial infusion of ATP [0.45-2.45 micromol/min] in 19 healthy male subjects with and without coinfusion of N(G)-monomethyl-l-arginine (l-NMMA; NO formation inhibitor; 12.3 +/- 0.3 (SE) mg/min), indomethacin (INDO; prostaglandin formation blocker; 613 +/- 12 microg/min), and/or theophylline (adenosine receptor blocker; 400 +/- 26 mg). During control conditions, ATP infusion increased leg blood flow (LBF) from baseline conditions by 1.82 +/- 0.14 l/min. When ATP was coinfused with either l-NMMA, INDO, or l-NMMA + INDO combined, the increase in LBF was reduced by 14 +/- 6, 15 +/- 9, and 39 +/- 8%, respectively (all P < 0.05), and was associated with a parallel lowering in leg vascular conductance and cardiac output and a compensatory increase in leg O(2) extraction. Infusion of theophylline did not alter the ATP-induced leg hyperemia or systemic variables. Real-time PCR analysis of the mRNA content from the vastus lateralis muscle of eight subjects showed the highest expression of P(2Y2) receptors of the 10 investigated P(2) receptor subtypes. Immunohistochemistry showed that P(2Y2) receptors were located in the endothelium of microvessels and smooth muscle cells, whereas P(2X1) receptors were located in the endothelium and the sacrolemma. Collectively, these results indicate that NO and prostaglandins, but not adenosine, play a role in ATP-induced vasodilation in human skeletal muscle. The expression

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

    NASA Technical Reports Server (NTRS)

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

    1991-01-01

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

  3. Sensitivity of lymphocytes to prostaglandin E2 increases in subjects over age 70.

    PubMed Central

    Goodwin, J S; Messner, R P

    1979-01-01

    We examined the sensitivity of lymphocytes from different age groups to inhibition by prostaglandin E2. Phytohemagglutinin-stimulated cultures of peripheral blood mononuclear cells from 12 healthy subjects over the age of 70 were much more sensitive to inhibition by exogenously added prostaglandin E2 than were cells from 17 young controls (ID50 congruent to 10 nM for the subjects over 70 vs. greater than 3 micronM for the young controls). The more senstivie lymphocytes from a subject over 70 were to prostaglandin E2, the lower was his or her response to phytohemagglutinin (r = 0.75, P less than 0.01). The mean responses to phytohemagglutinin of the peripheral blood mononuclear cells from the subjects over 70 were significantly depressed compared to the young controls. Addition of indomethacin, a prostaglandin synthetase inhibitor, to the cultures resulted in an increase in [3H]thymidine incorporation of 140 +/- 16% in the cells of the subjects over 70 vs. a 36 +/- 3% increase in the young controls (mean +/- SEM, P less than 0.001). The mean phytohemagglutinin response of the subjects over 70 was 40% of the control response without indomethacin. With addition of indomethacin the response of subjects over 70 rose to 72% of control. Thus, increased sinsitivity to prostaglandin E2 appears to be responsible in part for the depressed mitogen response of peripheral blood mononuclear cells from healthy subjects over 70. PMID:457862

  4. Radiation-induced increases in sensitivity of cataleptic behavior to haloperidol: possible involvement of prostaglandins

    SciTech Connect

    Joseph, J.A.; Kandasamy, S.B.; Hunt, W.A.; Dalton, T.K.; Stevens, S.

    1988-02-01

    The effects of radiation exposure on haloperidol-induced catalepsy were examined in order to determine whether elevated prostaglandins, through an action on dopaminergic autoreceptors, could be involved in the radiation-induced increase in the potency of this neuroleptic. Cataleptic behavior was examined in animals irradiated with various doses of gamma photons (1-150 Gy) and pretreated with a subthreshold dose of haloperidol (0.1 mg/kg). This approach was chosen to maximize any synergistic effects of radiation and haloperidol. After irradiation with doses less than or equal to 30 Gy, the combined treatment of haloperidol and radiation produced catalepsy, whereas neither treatment alone had an effect. This observed catalepsy could be blocked with prior administration of indomethacin, a prostaglandin synthesis inhibitor. Animals exposed to doses of radiation less than or equal to 50 Gy and no haloperidol, however, displayed apparent catalepsy. This effect was also antagonized by indomethacin. Prostaglandins can induce catalepsy and when administered in subthreshold doses along with subthreshold doses of haloperidol, catalepsy was observed. In order to assess a possible action of prostaglandins and radiation on dopaminergic activity, the functioning of striatal dopaminergic autoreceptors was examined by determining the effects of varying concentrations of haloperidol on the K+-evoked release of dopamine from striatal slices obtained from parallel groups of animals treated as above. Results indicated that sensitivity to haloperidol increased (higher K+-evoked dopamine release) in slices from irradiated or prostaglandin-treated animals and that this increase in sensitivity was blocked by indomethacin.

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

    PubMed

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

    2015-10-12

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

  6. Metabolism of aromatic amines by prostaglandin H synthase.

    PubMed Central

    Boyd, J A; Eling, T E

    1985-01-01

    The metabolism of aromatic amines by the peroxidase activity of prostaglandin H synthase (PHS) has been studied in this laboratory by use of two model compounds, the carcinogenic primary amine 2-aminofluorene (2-AF) and the substituted amine aminopyrine (AP). 2-AF is oxidized by PHS to 2, 2-azobisfluorene, 2-aminodifluorenylamine, 2-nitrofluorene, polymeric material, and products covalently bound to macromolecules. In the presence of phenolic compounds, 2-AF oxidation results in the formation of amine/phenol adducts. The data are consistent with a one-electron mechanism of 2-AF oxidation by PHS; furthermore, an N-hydroxy intermediate is not involved in 2-AF metabolism by PHS. PHS also catalyzes the binding of 2-AF to DNA in vitro. Unique 2-AF/DNA adducts were isolated and are distinct from the N-(deoxyguanosin-8-yl)-2-AF adduct formed from the reaction of N-hydroxy-2-AF with DNA. These new adducts represent a marker unique to peroxidative activation of 2-AF. AP is oxidized by the peroxidase activity of PHS to the cation radical, with one molecule of hydroperoxy fatty acid reduced for every two molecules of AP free radical formed. The decay of the AP radical follows second order kinetics, supporting the proposed mechanism in which the AP radical disproportionates to an iminium cation, followed by hydrolysis of this species to the demethylated amine and formaldehyde. In the presence of glutathione, the cation radical is reduced to the parent amine, resulting in the formation of the glutathione thiyl radical. It thus appears that both primary and substituted aromatic amines may undergo one-electron oxidation by PHS. PMID:3938394

  7. Metabolism of aromatic amines by prostaglandin H synthase

    SciTech Connect

    Boyd, J.A.; Eling, T.E.

    1985-12-01

    The metabolism of aromatic amines by the peroxidase activity of prostaglandin H synthase (PHS) has been studied in this laboratory by use of two model compounds, the carcinogenic primary amine 2-aminofluorene (2-AF) and the substituted amine aminopyrine (AP). 2-AF is oxidized by PHS to 2, 2-azobisfluorene, 2-aminodifluorenylamine, 2-nitrofluorene, polymeric material, and products covalently bound to macromolecules. In the presence of phenolic compounds, 2-AF oxidation results in the formation of amine-phenol adducts. The data are consistent with a one-electron mechanism of 2-AF oxidation by PHS; furthermore, an N-hydroxy intermediate is not involved in 2-AF metabolism by PHS. PHS also catalyzes the binding of 2-AF to DNA in vitro. Unique 2-AF/DNA adducts were isolated and are distinct from the N-(deoxyguanosin-8-yl)-2-AF adduct formed from the reaction of N-hydroxy-2-AF with DNA. These new adducts represent a marker unique to peroxidative activation of 2-AF. AP is oxidized by the peroxidase activity of PHS to the cation radical, with one molecule of hydroperoxy fatty acid reduced for every two molecules of AP free radical formed. The decay of the AP radical follows second order kinetics, supporting the proposed mechanism in which the AP radical disproportionates to an iminium cation, followed by hydrolysis of this species to the demethylated amine and formaldehyde. In the presence of glutathione, the cation radical is reduced to the parent amine, resulting in the formation of the glutathione thiyl radical. It thus appears that both primary and substituted aromatic amines may undergo one-electron oxidation by PHS. 19 references.

  8. Opposing roles of Prostaglandin D2 receptors in ulcerative colitis

    PubMed Central

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

    2014-01-01

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

  9. Prostaglandin E2 inhibits NLRP3 inflammasome activation through EP4 receptor and intracellular cAMP in human macrophages

    PubMed Central

    Liu, Yueqin; Martinez-Anton, Asuncion; Qi, Hai-Yan; Logun, Carolea; Alsaaty, Sara; Park, Yong Hwan; Kastner, Daniel L.; Chae, Jae Jin; Shelhamer, James H.

    2015-01-01

    Prostaglandin E2 (PGE2) is a potent lipid mediator involved in maintaining homeostasis but also promotion of acute inflammation or immune suppression in chronic inflammation and cancer. NLRP3 inflammasome plays an important role in host defense. Uncontrolled activation of NLRP3 inflammasome, due to mutations in the NLRP3 gene causes cryopyrin-associated periodic syndromes (CAPS). Here, we showed that NLRP3 inflammasome activation is inhibited by PGE2 in human primary monocyte-derived macrophages. This effect was mediated through prostaglandin E receptor 4 (EP4) and an increase in intracellular cAMP, independently of protein kinase A (PKA) or exchange protein directly activated by cAMP (Epac). A specific agonist of EP4 mimicked, while its antagonist or EP4 knockdown reversed PGE2-mediated NLRP3 inhibition. PGE2 caused an increase in intracellular cAMP. Blockade of adenylate cyclase by its inhibitor reversed PGE2-mediated NLRP3 inhibition. Increase of intracellular cAMP by an activator of adenylate cyclase or an analog of cAMP, or a blockade of cAMP degradation by phosphodiesterase inhibitor decreased NLRP3 activation. PKA or Epac agonists did not mimic and their antagonists did not reverse PGE2-mediated NLRP3 inhibition. In addition, constitutive IL-1β secretion from LPS-primed PBMCs of CAPS patients was substantially reduced by high doses of PGE2. Moreover, blocking cytosolic phospholipase A2α by its inhibitor or siRNA or inhibiting cyclooxygenase 2, resulting in inhibition of endogenous PGE2 production, caused an increase in NLRP3 inflammasome activation. Our results suggest that PGE2 might play a role in maintaining homeostasis during the resolution phase of inflammation and might serve as an autocrine and paracrine regulator. PMID:25917098

  10. L-Citrulline dilates rat retinal arterioles via nitric oxide- and prostaglandin-dependent pathways in vivo.

    PubMed

    Mori, Asami; Morita, Masahiko; Morishita, Koji; Sakamoto, Kenji; Nakahara, Tsutomu; Ishii, Kunio

    2015-04-01

    L-Citrulline is an effective precursor of L-arginine produced by the L-citrulline/L-arginine cycle, and it exerts beneficial effects on the cardiovascular system by supporting enhanced nitric oxide (NO) production. NO dilates retinal blood vessels via the cyclooxygenase-mediated pathway. The purpose of this study was to examine the effects of L-citrulline on retinal circulation and to investigate the potential involvement of NO and prostaglandins in L-citrulline-induced responses in rats. L-Citrulline (10-300 μg kg(-1) min(-1), i.v.) increased the diameter of retinal arterioles without significantly changing mean blood pressure, heart rate, and fundus blood flow. The vasodilator response of retinal arterioles to l-citrulline was significantly diminished following treatment with N(G)-nitro-L-arginine methyl ester (30 mg/kg, i.v.), an NO synthase inhibitor, or indomethacin (5 mg/kg, i.v.), a cyclooxygenase inhibitor. In addition, α-methyl-dl-aspartic acid (147 mg/kg, i.v.), an inhibitor of argininosuccinate synthase, the rate-limiting enzyme for the recycling of l-citrulline to l-arginine, diminished the L-citrulline-induced retinal vasodilation. These results suggest that both NO- and prostaglandin-dependent pathways contribute to the L-citrulline-induced vasodilation of rat retinal arterioles. The L-citrulline/L-arginine recycling pathway may have more importance in regulating vascular tone in retinal blood vessels than in peripheral resistance vessels. PMID:25953269

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

    PubMed Central

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

    2016-01-01

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

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

    PubMed

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

    2016-01-01

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

  13. Effects of prostaglandin F2α on small intestinal interstitial cells of Cajal

    PubMed Central

    Park, Chan Guk; Kim, Young Dae; Kim, Man Yoo; Koh, Jae Woong; Jun, Jae Yeoul; Yeum, Cheol Ho; So, Insuk; Choi, Seok

    2011-01-01

    AIM: To explore the role of prostaglandin F2α (PGF2α)) on pacemaker activity in interstitial cells of Cajal (ICC) from mouse small intestine. METHODS: In this study, effects of PGF2α in the cultured ICC cells were investigated with patch clamp technology combined with Ca2+ image analysis. RESULTS: Externally applied PGF2α (10 μmol/L) produced membrane depolarization in current-clamp mode and increased tonic inward pacemaker currents in voltage-clamp mode. The application of flufenamic acid (a non-selective cation channel inhibitor) or niflumic acid (a Cl- channel inhibitor) abolished the generation of pacemaker currents but only flufenamic acid inhibited the PGF2α-induced tonic inward currents. In addition, the tonic inward currents induced by PGF2α were not inhibited by intracellular application of 5’-[-thio]diphosphate trilithium salt. Pretreatment with Ca2+ free solution, U-73122, an active phospholipase C inhibitor, and thapsigargin, a Ca2+-ATPase inhibitor in endoplasmic reticulum, abolished the generation of pacemaker currents and suppressed the PGF2α-induced tonic inward currents. However, chelerythrine or calphostin C, protein kinase C inhibitors, did not block the PGF2α-induced effects on pacemaker currents. When recording intracellular Ca2+ ([Ca2+]i) concentration using fluo-3/AM, PGF2α broadly increased the spontaneous [Ca2+]i oscillations. CONCLUSION: These results suggest that PGF2α can modulate pacemaker activity of ICC by acting non-selective action channels through phospholipase C-dependent pathway via [Ca2+]i regulation PMID:21448418

  14. Activated prostaglandin D2 receptors on macrophages enhance neutrophil recruitment into the lung

    PubMed Central

    Jandl, Katharina; Stacher, Elvira; Bálint, Zoltán; Sturm, Eva Maria; Maric, Jovana; Peinhaupt, Miriam; Luschnig, Petra; Aringer, Ida; Fauland, Alexander; Konya, Viktoria; Dahlen, Sven-Erik; Wheelock, Craig E.; Kratky, Dagmar; Olschewski, Andrea; Marsche, Gunther; Schuligoi, Rufina; Heinemann, Akos

    2016-01-01

    Background Prostaglandin (PG) D2 is an early-phase mediator in inflammation, but its action and the roles of the 2 D-type prostanoid receptors (DPs) DP1 and DP2 (also called chemoattractant receptor–homologous molecule expressed on TH2 cells) in regulating macrophages have not been elucidated to date. Objective We investigated the role of PGD2 receptors on primary human macrophages, as well as primary murine lung macrophages, and their ability to influence neutrophil action in vitro and in vivo. Methods In vitro studies, including migration, Ca2+ flux, and cytokine secretion, were conducted with primary human monocyte-derived macrophages and neutrophils and freshly isolated murine alveolar and pulmonary interstitial macrophages. In vivo pulmonary inflammation was assessed in male BALB/c mice. Results Activation of DP1, DP2, or both receptors on human macrophages induced strong intracellular Ca2+ flux, cytokine release, and migration of macrophages. In a murine model of LPS-induced pulmonary inflammation, activation of each PGD2 receptor resulted in aggravated airway neutrophilia, tissue myeloperoxidase activity, cytokine contents, and decreased lung compliance. Selective depletion of alveolar macrophages abolished the PGD2-enhanced inflammatory response. Activation of PGD2 receptors on human macrophages enhanced the migratory capacity and prolonged the survival of neutrophils in vitro. In human lung tissue specimens both DP1 and DP2 receptors were located on alveolar macrophages along with hematopoietic PGD synthase, the rate-limiting enzyme of PGD2 synthesis. Conclusion For the first time, our results show that PGD2 markedly augments disease activity through its ability to enhance the proinflammatory actions of macrophages and subsequent neutrophil activation. PMID:26792210

  15. Overexpressed TRPV3 ion channels in skin keratinocytes modulate pain sensitivity via prostaglandin E2

    PubMed Central

    Huang, Susan M.; Lee, Hyosang; Chung, Man-Kyo; Park, Una; Yu, Yin Yin; Bradshaw, Heather B.; Coulombe, Pierre A.; Walker, J. Michael; Caterina, Michael J.

    2009-01-01

    The ability to sense changes in the environment is essential for survival because it permits responses such as withdrawal from noxious stimuli and regulation of body temperature. Keratinocytes, which occupy much of the skin epidermis, are situated at the interface between the external environment and the body's internal milieu, and have long been appreciated for their barrier function against external insults. The recent discovery of temperature-sensitive TRPV ion channels in keratinocytes has raised the possibility that these cells also actively participate in acute temperature and pain sensation. To address this notion, we generated and characterized transgenic mice that overexpress TRPV3 in epidermal keratinocytes under the control of the keratin 14 promoter. Compared to wild-type controls, keratinocytes overexpressing TRPV3 exhibited larger currents as well as augmented prostaglandin E2 (PGE2) release in response to two TRPV3 agonists, 2-aminoethoxydiphenyl borate (2APB) and heat. Thermal selection behavior and heat-evoked withdrawal behavior of naïve mice overexpressing TRPV3 were not consistently altered. Upon selective pharmacological inhibition of TRPV1 with JNJ-7203212, however, the keratinocyte-specific TRPV3 transgenic mice showed increased escape responses to noxious heat relative to their wild-type littermates. Co-administration of the cyclooxygenase inhibitor, ibuprofen, with the TRPV1 antagonist decreased inflammatory thermal hyperalgesia in transgenic but not wild-type animals. Our results reveal a previously undescribed mechanism for keratinocyte participation in thermal pain transduction through keratinocyte TRPV3 ion channels and the intercellular messenger PGE2. PMID:19091963

  16. Prostaglandin E₂ increases fibroblast gene-specific and global DNA methylation via increased DNA methyltransferase expression.

    PubMed

    Huang, Steven K; Scruggs, Anne M; Donaghy, Jake; McEachin, Richard C; Fisher, Aaron S; Richardson, Bruce C; Peters-Golden, Marc

    2012-09-01

    Although alterations in DNA methylation patterns have been associated with specific diseases and environmental exposures, the mediators and signaling pathways that direct these changes remain understudied. The bioactive lipid mediator prostaglandin E(2) (PGE(2)) has been shown to exert a myriad of effects on cell survival, proliferation, and differentiation. Here, we report that PGE(2) also signals to increase global DNA methylation and DNA methylation machinery in fibroblasts. HumanMethylation27 BeadChip array analysis of primary fetal (IMR-90) and adult lung fibroblasts identified multiple genes that were hypermethylated in response to PGE(2). PGE(2), compared with nontreated controls, increased expression and activity (EC(50)∼10(7) M) of one specific isoform of DNA methyltransferase, DNMT3a. Silencing of DNMT3a negated the ability of PGE(2) to increase DNMT activity. The increase in DNMT3a expression was mediated by PGE(2) signaling via its E prostanoid 2 receptor and the second messenger cAMP. PGE(2), compared with the untreated control, increased the expression and activity of Sp1 and Sp3 (EC(50)∼3×10(7) M), transcription factors known to increase DNMT3a expression, and inhibition of these transcription factors abrogated the PGE(2) increase of DNMT3a expression. These findings were specific to fibroblasts, as PGE(2) decreased DNMT1 and DNMT3a expression in RAW macrophages. Taken together, these findings establish that DNA methylation is regulated by a ubiquitous bioactive endogenous mediator. Given that PGE(2) biosynthesis is modulated by environmental toxins, various disease states, and commonly used pharmacological agents, these findings uncover a novel mechanism by which alterations in DNA methylation patterns may arise in association with disease and certain environmental exposures.

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

    PubMed

    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.

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

    PubMed

    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.

  19. Prostaglandin synthesis genes are differentially transcripted in normal and pyometra endometria of bitches.

    PubMed

    Silva, E; Leitão, S; Ferreira-Dias, G; Lopes da Costa, L; Mateus, L

    2009-07-01

    Pro-inflammatory stimuli, such as endotoxins released by Gram-negative bacteria, are potent stimulators of prostaglandin (PG) synthesis. The aim of this study was to evaluate the gene transcription pattern of PG synthesis enzymes in normal (anestrous, n = 6 and diestrous, n = 8) and pyometra (n = 7) endometria of bitches. Uteri were collected during routine ovariohysterectomy, processed for histopathological evaluation and uterine contents cultured. Gene transcription of COX-1, COX-2, mPGES-1 and PGF-synthase (PGFS) were evaluated by relative real-time PCR and normalized with the ribosomal protein L27 (RPL27) housekeeping gene. Normal uteri had no histological abnormalities and were negative for bacteriology. All pyometra uteri were hyperplasic and Escherichia coli was the only isolated bacterium. Except for COX-1, gene transcription was significantly higher in pyometra than in normal endometria. No significant differences in gene transcription were observed between normal diestrous and anestrous endometria. COX-2 gene transcription was 19 and 69 times higher in pyometra than in diestrous and anestrous endometria (p < 0.001), while PGFS gene transcription had a 3- and 600-fold increase in pyometra endometria compared to normal diestrous and anestrous endometria (p < 0.001). Gene transcription of mPGES-1 was 9 times higher in pyometra than in normal uteri (p < 0.01). Based on these results, we suggest that pyometra-associated E. coli endotoxin release stimulates the up-regulation of COX-2 PGFS and mPGES-1 gene transcription in the endometrium. PMID:19754568

  20. Prostaglandin E2-dependent IL-23 production in aged murine dendritic cells

    PubMed Central

    Myer, Rebecca G.; Mezayen, Rabab El; High, Kevin P.

    2010-01-01

    CD4+ T cells of the Th17 subtype are over-represented in the aged immune system. Dendritic cells (DC) play a critical role in naive CD4+ T cell differentiation. However, expression of cytokines by aged DC that promote differentiation or survival of Th17 cells has not been extensively investigated. Using bone marrow-derived DC from C57BL/6 mice of different ages we compared cytokine production after DC activation by Toll-like receptor agonists for TLR4 and/or TLR7/8. DC-derived TNF-α and IL-12p70 production and expression of DC co-stimulatory molecules did not vary significantly by age indicating TLR expression, function and signal transduction were intact in aged DC. There were relatively minor age-related changes in TGF-β and IL-6 which promote Th17 differentiation, but IL-23, a Th17-suvival cytokine, increased more than 40-fold across the lifespan. DC-derived prostaglandin E2 (PGE2) also increased with age and the up-regulation of IL-23 expression by aged DC was blocked by indomethacin that prevents PGE2 production, and by antagonists of PGE2 receptors. Exogenous PGE2 added to DC cultures further enhanced IL-23 production from aged but not young DCs. These data indicate that age-related changes in DC PGE2 production are necessary, but not sufficient to induce DC IL-23 production. Such changes may play a role in the expansion of Th17 cells in the aged immune system. PMID:20600778

  1. Prostaglandin E2-mediated migration of human trophoblast requires RAC1 and CDC42.

    PubMed

    Nicola, Catalin; Lala, Peeyush K; Chakraborty, Chandan

    2008-06-01

    The invasion of maternal decidua and uterine spiral arteries by a trophoblast subpopulation called extravillous trophoblast (EVT) is essential for the establishment of a normal placenta and an adequate blood flow toward the fetus. Derangements in these processes underlie pregnancy-related diseases like preeclampsia and intrauterine growth restriction. Many growth factors, growth factor binding proteins, and extracellular matrix components can positively or negatively regulate the proliferation, migration, and/or invasiveness of these EVT cells. RHO GTPases, including RHOA, RAC1, and CDC42, are ubiquitous proteins that control cytoskeletal changes by forming stress fibers and projecting lamellipodia and filopodia during cellular migration. We had previously shown that prostaglandin (PG) E(2) produced in abundance by the decidua promotes the migration of first-trimester human EVTs by increasing the intracellular concentration of calcium and activating calpain. Using our well-characterized immortalized EVT cell line, HTR-8/SVneo, as well as villus explants from first-trimester placentae, this study examined the role of RHO GTPases RAC1 and CDC42 in PGE(2)-mediated migratory responses of these cells. Though a RAC1 inhibitor, NSC23766 as well as RAC1 knockdown by siRNA decreased the migration of HTR-8/SVneo cells in a Transwell migration assay, this inhibition could not be restored by PGE(2) or 17-phenyl trinor PGE(2) (PGE receptor PTGER1 agonist) or PGE(1) Alcohol (PGE receptor PTGER4 agonist). Similar results were noted for EVT cell spreading in villus explants. Furthermore, CDC42 silencing using siRNA inhibited PGE(2)-induced migration of HTR-8/SVneo cells. Finally, the treatment of EVT cells with PGE(2), PTGER1 agonist, or PTGER4 agonist activated RAC1 and CDC42 at 10 min, suggesting that RAC1 and CDC42 play an essential role in PGE(2)-mediated migration of human EVTs.

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

    PubMed

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

    2015-04-01

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

  3. TISSUE REGENERATION. Inhibition of the prostaglandin-degrading enzyme 15-PGDH potentiates tissue regeneration.

    PubMed

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

    2015-06-12

    Agents that promote tissue regeneration could be beneficial in a variety of clinical settings, such as stimulating recovery of the hematopoietic system after bone marrow transplantation. Prostaglandin PGE2, a lipid signaling molecule that supports expansion of several types of tissue stem cells, is a candidate therapeutic target for promoting tissue regeneration in vivo. Here, we show that inhibition of 15-hydroxyprostaglandin dehydrogenase (15-PGDH), a prostaglandin-degrading enzyme, potentiates tissue regeneration in multiple organs in mice. In a chemical screen, we identify a small-molecule inhibitor of 15-PGDH (SW033291) that increases prostaglandin PGE2 levels in bone marrow and other tissues. SW033291 accelerates hematopoietic recovery in mice receiving a bone marrow transplant. The same compound also promotes tissue regeneration in mouse models of colon and liver injury. Tissues from 15-PGDH knockout mice demonstrate similar increased regenerative capacity. Thus, 15-PGDH inhibition may be a valuable therapeutic strategy for tissue regeneration in diverse clinical contexts.

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

    NASA Technical Reports Server (NTRS)

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

    1990-01-01

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

  5. High-Throughput Quantification of Bioactive Lipids by MALDI Mass Spectrometry: Application to Prostaglandins

    PubMed Central

    Manna, Joseph D.; Reyzer, Michelle L.; Latham, Joey C.; Weaver, C. David; Marnett, Lawrence J.; Caprioli, Richard M.

    2011-01-01

    Analysis and quantification of analytes in biological systems is a critical component of metabolomic investigations of cell function. The most widely used methods employ chromatographic separation followed by mass spectrometric analysis, which requires significant time for sample preparation and sequential chromatography. We introduce a novel high-throughput, separation-free methodology based on MALDI mass spectrometry that allows for the parallel analysis of targeted metabolomes. Proof-of-concept is demonstrated by analysis of prostaglandins and glyceryl prostaglandins. Derivatization to incorporate a charged moiety into ketone-containing prostaglandins dramatically increases the signal-to-noise ratio relative to underivatized samples. This resulted in an increased dynamic range (15 fmol – 2000 fmol on plate) and improved linearity (r2= 0.99). The method was adapted for high-throughput screening methods for enzymology and drug discovery. Application to cellular metabolomics was also demonstrated. PMID:21770391

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

    PubMed Central

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

    2015-01-01

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

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

    PubMed

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

    2015-04-01

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

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

    Technology Transfer Automated Retrieval System (TEKTRAN)

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

  9. Curcumin blocks prostaglandin E2 biosynthesis through direct inhibition of the microsomal prostaglandin E2 synthase-1.

    PubMed

    Koeberle, Andreas; Northoff, Hinnak; Werz, Oliver

    2009-08-01

    Prostaglandin E(2) (PGE(2)) plays a crucial role in the apparent link between tumor growth and chronic inflammation. Cyclooxygenase (COX)-2 and microsomal PGE(2) synthase-1, which are overexpressed in many cancers, are functionally coupled and thus produce massive PGE(2) in various tumors. Curcumin, a polyphenolic beta-diketone from tumeric with anti-carcinogenic and anti-inflammatory activities, was shown to suppress PGE(2) formation and to block the expression of COX-2 and of microsomal PGE(2) synthase-1. Here, we identified microsomal PGE(2) synthase-1 as a molecular target of curcumin and we show that inhibition of microsomal PGE(2) synthase-1 activity is the predominant mechanism of curcumin to suppress PGE(2) biosynthesis. Curcumin reversibly inhibited the conversion of PGH(2) to PGE(2) by microsomal PGE(2) synthase-1 in microsomes of interleukin-1beta-stimulated A549 lung carcinoma cells with an IC(50) of 0.2 to 0.3 micromol/L. Closely related polyphenols (e.g., resveratrol, coniferyl alcohol, eugenol, rosmarinic acid) failed in this respect, and isolated ovine COX-1 and human recombinant COX-2 were not inhibited by curcumin up to 30 micromol/L. In lipopolysaccharide-stimulated human whole blood, curcumin inhibited COX-2-derived PGE(2) formation from endogenous or from exogenous arachidonic acid, whereas the concomitant formation of COX-2-mediated 6-keto PGF(1)alpha and COX-1-derived 12(S)-hydroxy-5-cis-8,10-trans-heptadecatrienoic acid was suppressed only at significant higher concentrations. Based on the key function of PGE(2) in inflammation and carcinogenesis, inhibition of microsomal PGE(2) synthase-1 by curcumin provides a molecular basis for its anticarcinogenic and anti-inflammatory activities.

  10. Reduced expression of 15-hydroxy prostaglandin dehydrogenase in chorion during labor is associated with decreased PRB and increased PRA and GR expression.

    PubMed

    Li, Yuan; He, Ping; Sun, Qianqian; Liu, Jie; Gao, Lu; You, Xingji; Gu, Hang; Ni, Xin

    2013-05-01

    The chorion laeve controls the levels of active prostaglandins within the uterus by NAD-dependent 15-hydroxy prostaglandin dehydrogenase (PGDH). The expression of PGDH in chorion is modulated by glucocorticoids and progesterone. In this study, we investigated glucocorticoid receptor (GR) and progesterone receptor A and B (PRA and PRB) in the regulation of PGDH expression in chorion, and we determined whether reduced PGDH expression in chorion during labor is associated with the changes in GR and PR expression by real-time RT-PCR and Western blot analysis. Dexamethasone (DEX) inhibited PGDH expression whereas progesterone stimulated PGDH expression in chorionic trophoblasts. DEX suppressed PGDH expression in GR overexpression and PR knockdown cells. The inhibitory effect of DEX did not occur in GR knockdown cells. Progesterone inhibited PGDH in GR overexpression and PR knockdown cells and it stimulated PGDH in PRB overexpression cells whereas it suppressed PGDH in PRA overexpression cells. Knockdown of c-Jun resulted in a loss of progesterone- and DEX-induced effects. PGDH was down-regulated in chorion tissues during labor. PRB was decreased whereas PRA and GR were increased in chorion during labor. Glucocorticoids inhibit PGDH expression via GR in chorionic trophoblasts. Progesterone enhances PGDH expression through PRB, whereas it inhibits PGDH expression via GR and PRA. Decreased PGDH expression is associated with increased GR and PRA, although decreased PRB, in chorion during labor.

  11. Arachidonoyl ethanolamide (AEA)-induced Apoptosis is Mediated by J-series Prostaglandins and is Enhanced by Fatty Acid Amide Hydrolase (FAAH) Blockade

    PubMed Central

    Kuc, Christian; Jenkins, Audrey; Van Dross, R. T.

    2011-01-01

    The endocannabinoid arachidonoyl ethanolamide (AEA) is a potent inducer of tumor cell apoptosis however its mechanism of cytotoxicity is unclear. A previous report from our laboratory showed that AEA induced cell death in a COX-2-dependent manner and in this report our data indicate that AEA-induced apoptosis is mediated by COX-2 metabolic products of the J-series. In experiments conducted with JWF2 keratinocytes which overexpress COX-2, AEA caused a concentration-regulated increase in J-series prostaglandin production and apoptosis. Similarly, cell treatment with exogenously added J-series prostaglandins (15-deoxy, Δ12,14 PGJ2 and PGJ2) induced apoptosis. AEA-induced apoptosis was inhibited by the antioxidant, N-acetyl cysteine, indicating that reactive oxygen species generation was required for apoptosis. Using antagonists of cannabinoid receptor 1, cannabinoid receptor 2, or TRPV1, it was observed that cannabinoid receptor inhibition did not block AEA-mediated cell death. In contrast, an inhibitor of fatty acid amide hydrolase (FAAH) potentiated AEA-induced J-series PG synthesis and apoptosis. These results suggest that the metabolism of AEA to J-series PGs regulates the induction of apoptosis in cells with elevated COX-2 levels. Our data further indicate that the proapoptotic activity of AEA can be enhanced by combining it with an inhibitor of FAAH. As such, AEA may be an effective agent to eliminate tumor cells that overexpress COX-2. PMID:21432910

  12. Interferon-γ stimulates human follicular dendritic cell-like cells to produce prostaglandins via the JAK-STAT pathway.

    PubMed

    Kim, Jini; Yoon, Yongdae; Jeoung, Dooil; Kim, Young-Myeong; Choe, Jongseon

    2015-08-01

    IFN-γ plays a critical role in the regulation of innate and adaptive immunity. Paying attention to the emerging role of prostaglandins (PGs) as immune regulators, we attempted to establish the effect of IFN-γ on PG production in human follicular dendritic cell-like HK cells and the underlying signaling pathway by using RNA interference technology. IFN-γ induced COX-2 protein expression in HK cells in a time- and dose-dependent manner, which was not observed in peripheral blood monocytes. Although IFN-γ induced phosphorylation of STAT1, STAT3, and STAT5, only STAT1 was essential for the COX-2 augmentation. The JAK kinases responsible for IFN-γ-triggered STAT1 phosphorylation were JAK1 and JAK2, which were also required for the COX-2 induction. The essential requirement of JAK1 and JAK2 was verified by confocal microscopic analysis, since STAT1 phosphorylation and nuclear translocation were impaired in HK cells with these two kinases knocked down. Finally, we demonstrated that JAK1, JAK2, and STAT1 were indispensable for the actual enhancement of PG production in response to IFN-γ stimulation. These results provide a novel insight into our understanding of IFN-γ under inflammatory conditions and support the emerging concept of PGs as important immune regulators.

  13. Effect of vasoactive agents on prostanoid synthesis in isolated rat glomeruli.

    PubMed

    Podjarny, E; Magen, H; Shapira, J; Rathaus, M; Bernheim, J

    1986-11-01

    We studied the influence of vasoactive substances (angiotensin II, epinephrine, norepinephrine and acetylcholine) on the synthesis of prostanoids in isolated rat glomeruli. A significant increase of prostaglandin E2, and of thromboxane B2, but not of prostaglandin F2 alpha synthesis was observed after the administration of angiotensin II at physiological doses. Neither catecholamines nor acetylcholine influenced prostaglandin synthesis. The stimulation of vasoactive prostaglandins by angiotensin II, may modify the hemodynamic status of the glomerulus.

  14. Foley catheter balloon vs locally applied prostaglandins for cervical ripening and labor induction: a systematic review and metaanalysis.

    PubMed

    Vaknin, Zvi; Kurzweil, Yaffa; Sherman, Dan

    2010-11-01

    We performed a metaanalysis of publications comparing the efficacy and safety of cervical ripening and labor induction by Foley catheter balloon (FCB) vs locally applied prostaglandins (LAPG) in the third trimester of pregnancy. Twenty-seven randomized controlled trials (1966-2008; 3532 participants) were selected from MEDLINE, EMBASE, and CENTRAL searches. There was no significant difference between FCB and LAPG in cesarean delivery rates. LAPG had a significantly increased risk of excessive uterine activity (P = .001). FCB had a significantly higher risk of oxytocin induction/augmentation during labor (P = .0002). Cervical prostaglandin-E2 was less effective (P = .04), and vaginal prostaglandin-E1 bore a significantly higher risk of excessive uterine activity (P < .0001) and meconium staining (P = .04). We concluded that FCB and LAPG result in similar cesarean delivery rates, that FCB bears a higher risk of oxytocin use for labor induction and/or augmentation, and that LAPG carries a higher risk of contraction abnormalities.

  15. Morphologic study of changes of collagenous tissue in the amnion and cervix during prostaglandin-induced abortion and delivery.

    PubMed

    Manabe, Y; Yoshida, Y

    1990-07-01

    Marked dissociation of the cervical collagenous tissue during prostaglandin-induced abortion is well recognized, but the response of collagenous tissue of the amnion to prostaglandin treatment is not known. A morphologic study of amniotic collagenous tissue was performed after prostaglandin-induced abortion and prostaglandin-induced term delivery. The collagenous fibers of the amnion were found to be closely packed with no ground substances and formed in a thick layer. Cervical collagenous tissue of the same patients showed a marked dissociation of fibers and abundant ground substance. The fetus was often delivered within a complete sac at midtrimester. These findings suggest differences in collagenous tissue responses to prostaglandin treatment between the amnion and cervix. PMID:2375370

  16. [Role of interstitial cells in prostaglandin synthesis in the kidney medulla].

    PubMed

    Sokolova, R I; Vikhert, A M

    1976-01-01

    An electron-microscopic study of the interstitial cells of the medulla of the kidneys was carried out after the administration of the inhibitor of prostaglandine synthesis -- indometacine. Under these conditions the amount of lipid granules in the interstitial cells increased significantly. The authors consider the results of study to be an evident proof of participation of lipid granules in the synthetic function of the interstitial cells as a "depôt" of a chemical precursor of prostaglandines synthesized by the interstitial cells.

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

    PubMed Central

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

    1990-01-01

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

  18. [Methods of artificial termination of pregnancy with special consideration of the use of prostaglandin (author's transl)].

    PubMed

    Kepp, R

    1976-09-01

    For termination of a pregnancy up until the 12th week, the method of choice is suction curettage. The dilation of the cervical canal is made easier and sometimes the embryo is aborted if a viscid preparation containing Prostaglandin F 22 is injected intracervically 12 hours prior to the scheduled procedure. For termination of pregnancy after the 14th week, prostaglandin is superior to all other methods. It can be used intraamnially, extra-amnially or intravenously. Not enough information and experience is available in Europe regarding the intravaginal application.

  19. The influence of pre-induction vaginal prostaglandin E2 gel upon subsequent labour.

    PubMed

    Mackenzie, I Z; Embrey, M P

    1978-09-01

    Eight hundred and three patients with singleton viable pregnancies and fetal cephalic presentation were given prostaglandin E2 in viscous gel by intravaginal instillation the evening before planned surgical induction. When the cervix was 'ripe', surgical induction was avoided in 65.9 per cent of primigravidae and 87.5 per cent of multigravidae; the administration of epidural analgesia was less frequent, the rate of spontaneous vaginal delivery greater, the Caesarean section rate lower, and the state of the newborn at delivery better than in those patients who required surgical induction. Side effects attributable to the prostaglandin gel were rare as were complications.

  20. Protection of Hippocampal Neurogenesis from Toll-Like Receptor 4-Dependent Innate Immune Activation by Ablation of Prostaglandin E2 Receptor Subtype EP1 or EP2

    PubMed Central

    Keene, C. Dirk; Chang, Rubens; Stephen, Christina; Nivison, Mary; Nutt, Samuel E.; Look, Amy; Breyer, Richard M.; Horner, Phillip J.; Hevner, Robert; Montine, Thomas J.

    2009-01-01

    Prostaglandin E2 is one of several eicosanoid products of the cyclooxygenase isozymes and is a key regulator of innate immune responses; it also possesses paracrine effects on mature neurons. The prostaglandin E2 receptor family consists of four subtypes of which EP1 and EP2 are known to be expressed by microglia. Lipopolysaccharide (LPS)-induced innate immune activation leads to the degeneration of intermediate progenitor cells (IPCs) that are destined for neuronal maturation in the hippocampal subgranular zone (SGZ); these cells can be identified by the expression of the transcription factor T-box brain gene 2 (Tbr2). Importantly, depletion of LPS-induced IPCs from the SGZ is suppressed by cyclooxygenase inhibitors. We therefore tested the hypothesis that either EP1 or EP2 is critical to LPS-induced depletion of Tbr2+ IPCs from the SGZ. Expression of either EP1 or EP2 was necessary for Toll-like receptor 4-dependent innate immune-mediated depletion of these Tbr2+ IPCs in mice. Moreover, EP1 activation was directly toxic to murine adult hippocampal progenitor cells; EP2 was not expressed by these cells. Finally, EP1 modulated the response of murine primary microglia cultures to LPS but in a manner distinct from EP2. These results indicate that prostaglandin E2 signaling via either EP1 or EP2 is largely to completely necessary for Toll-like receptor 4-dependent depletion of IPCs from the SGZ and suggest further pharmacological strategies to protect this important neurogenic niche. PMID:19389932

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

    PubMed Central

    Rafique, Nazmi; Goodman, Michael Christopher; Idborg, Helena; Bergqvist, Filip; Jakobsson, Per-Johan

    2016-01-01

    Introduction 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. Aim The objective of this study was to investigate which amino acids play a key role in the catalytic mechanism of MPGES1. Materials and Methods 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. Results and Conclusions 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. PMID:27684486

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

    PubMed Central

    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

  3. The role of synthetic prostaglandines in the induction of therapeutical miscarriage.

    PubMed

    Rolfini, G; Rolfini, E; Letta, C

    1995-01-01

    The Authors tell about their experience on the use of prostaglandins in patients admitted to the fourth Division of the II Institute of the Maternity Home of the Umberto I General Hospital in Rome, suffering from fetal pathologies not compatible with an autonomous life. They describe the effects of the drugs used, underlying their effectiveness in the induction of therapeutical miscarriage.

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

    Technology Transfer Automated Retrieval System (TEKTRAN)

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

  5. Prostaglandin E2 inhibits tumor necrosis factor-alpha RNA through PKA type I.

    PubMed

    Stafford, Jennifer B; Marnett, Lawrence J

    2008-02-01

    Tumor necrosis factor-alpha (TNF-alpha) is a cytokine that may contribute to the pathogenesis of septic shock, rheumatoid arthritis, cancer, and diabetes. Prostaglandins endogenously produced by macrophages act in an autocrine fashion to limit TNF-alpha production. We investigated the timing and signaling pathway of prostaglandin-mediated inhibition of TNF-alpha production in Raw 264.7 and J774 macrophages. TNF-alpha mRNA levels were rapidly modulated by PGE(2) or carbaprostacylin. PGE(2) or carbaprostacyclin prevented and rapidly terminated on-going TNF-alpha gene transcription within 15 min of prostaglandin treatment. Selective activation of PKA type I, but not PKA type II or Epac, with chemical analogs of cAMP was sufficient to inhibit LPS-induced TNF-alpha mRNA levels. The mechanisms by which prostaglandins limit TNF-alpha mRNA levels may underlie endogenous regulatory mechanisms that limit inflammation, and may have important implications for understanding chronic inflammatory disease pathogenesis. PMID:18060853

  6. Use of Prostaglandin E2 in the Management of Missed Abortion, Missed Labour, and Hydatidiform Mole

    PubMed Central

    Karim, S. M. M.

    1970-01-01

    Treatment of six cases of missed abortion and one case of hydatidiform mole with intravenous infusion of prostaglandin E2 resulted in complete abortion in all cases. Of 15 patients with missed labour, 14 were delivered successfully with similar treatment. The technique appears to be a safe, reliable, and rapid method of managing missed abortion, missed labour, and hydatidiform mole. PMID:5448780

  7. Interaction among beta-endorphin, nitric oxide and prostaglandins during ovulation in rats.

    PubMed

    Faletti, A G; Mohn, C; Farina, M; Lomniczi, A; Rettori, V

    2003-04-01

    The aim of this study was to investigate the relationship between beta-endorphin and nitric oxide (NO) during the ovulatory process in rats. Immature rats were treated with equine chorionic gonadotrophin-hCG to induce ovulation. An intrabursal injection of beta-endorphin stimulated nitric oxide synthase (NOS) activity. This effect was completely reversed when naltrexone was co-injected with beta-endorphin. The stimulatory action of beta-endorphin on NOS activity was studied to determine whether it was exerted via prostaglandins. Treatment with prostaglandin E(2) (PGE(2)) completely reversed the beta-endorphin-induced stimulation of NOS activity. Moreover, intrabursal injection of meloxicam, an inhibitor of cyclooxygenase 2, increased NOS activity, but this effect was not altered by co-injection with beta-endorphin. The presence of both endothelial NOS (eNOS) and inducible NOS (iNOS) in the ovary at 10 h after hCG treatment was studied by western blot analysis. Local administration of beta-endorphin inhibited the expression of eNOS protein, whereas expression of iNOS protein was not detectable. Ovarian beta-endorphin content was diminished at 10 h after hCG injection. Treatment with prostaglandin synthesis inhibitors in vivo augmented the ovarian beta-endorphin content. In conclusion, these results indicate that beta-endorphin stimulates the activity of ovarian NOS indirectly by inhibiting prostaglandin production. PMID:12683918

  8. Modulation of lipocalin-type prostaglandin D2 synthase expression in catfish seminal vesicles by thyroid disrupting agents and hormones.

    PubMed

    Sreenivasulu, Gunti; Pavani, Ayinampudi; Sudhakumari, Cheni-Chery; Dutta-Gupta, Aparna; Senthilkumaran, Balasubramanian

    2013-11-01

    Thyroid hormones play crucial role in several biological processes including reproduction. Disruption of normal thyroid status by environmental contaminants can cause severe impairment in reproductive functions. In our previous study, we reported down-regulation of a protein in seminal vesicular fluid of air-breathing catfish, Clarias gariepinus during experimentally induced hyperthyroidism. N-terminal amino acid sequence analysis followed by search in sequence database denoted it to be lipocalin-type prostaglandin D2 synthase (ptgds-b). In the present study, we cloned full-length cDNA of ptgds-b based on the N-terminal amino acid sequence. Surprisingly, Northern blot as well as RT-PCR analysis demonstrated the presence of ptgds-b transcript predominantly in seminal vesicles and developing testis. Further, ptgds-b mRNA significantly decreased in seminal vesicles following L-thyroxine overdose while there was an increased expression of ptgds-b after depletion of thyroid hormone by thiourea and withdrawal of the treatments reverted this effect. Treatment of catfish with human chorionic gonadotropin and estradiol significantly reduced ptgds-b expression. Taken together, we report ptgds-b as a thyroid hormone regulated protein in the seminal vesicles in addition to gonadotropin and estradiol. Further studies might explain the exclusive presence of ptgds-b in seminal vesicles and developing testis yet present data evaluated it as a putative biomarker for thyroid hormone disruption.

  9. Long-chain acyl-CoA synthetase 4 modulates prostaglandin E2 release from human arterial smooth muscle cells

    PubMed Central

    Golej, Deidre L.; Askari, Bardia; Kramer, Farah; Barnhart, Shelley; Vivekanandan-Giri, Anuradha; Pennathur, Subramaniam; Bornfeldt, Karin E.

    2011-01-01

    Long-chain acyl-CoA synthetases (ACSLs) catalyze the thioesterification of long-chain FAs into their acyl-CoA derivatives. Purified ACSL4 is an arachidonic acid (20:4)-preferring ACSL isoform, and ACSL4 is therefore a probable regulator of lipid mediator production in intact cells. Eicosanoids play important roles in vascular homeostasis and disease, yet the role of ACSL4 in vascular cells is largely unknown. In the present study, the ACSL4 splice variant expressed in human arterial smooth muscle cells (SMCs) was identified as variant 1. To investigate the function of ACSL4 in SMCs, ACSL4 variant 1 was overexpressed, knocked-down by small interfering RNA, or its enzymatic activity acutely inhibited in these cells. Overexpression of ACSL4 resulted in a markedly increased synthesis of arachidonoyl-CoA, increased 20:4 incorporation into phosphatidylethanolamine, phosphatidylinositol, and triacylglycerol, and reduced cellular levels of unesterified 20:4. Accordingly, secretion of prostaglandin E2 (PGE2) was blunted in ACSL4-overexpressing SMCs compared with controls. Conversely, acute pharmacological inhibition of ACSL4 activity resulted in increased release of PGE2. However, long-term downregulation of ACSL4 resulted in markedly reduced PGE2 secretion. Thus, ACSL4 modulates PGE2 release from human SMCs. ACSL4 may regulate a number of processes dependent on the release of arachidonic acid-derived lipid mediators in the arterial wall. PMID:21242590

  10. Opposing roles of TGF-β in prostaglandin production by human follicular dendritic cell-like cells.

    PubMed

    Choe, Jongseon; Park, Jihoon; Lee, Seungkoo; Kim, Young-Myeong; Jeoung, Dooil

    2016-08-01

    Prostaglandins (PGs) are recognized as important immune regulators. Using human follicular dendritic cell (FDC)-like HK cells, we have investigated the immunoregulatory role of PGs and their production mechanisms. The present study was aimed at determining the role of TGF-β in IL-1β-induced cyclooxygenase-2 (COX-2) expression by immunoblotting. COX-2 is the key enzyme responsible for PG production in HK cells. TGF-β, when added simultaneously with IL-1β, gave rise to an additive effect on COX-2 expression in a dose-dependent manner. However, TGF-β inhibited IL-1β-stimulated COX-2 expression when it was added at least 12h before IL-1β addition. The inhibitory effect of TGF-β was specific to IL-1β-induced COX-2 expression in HK cells. The stimulating and inhibitory effects of TGF-β were reproduced in IL-1β-stimulated PG production. Based on our previous results of the essential requirement of ERK and p38 MAPKs in TGF-β-induced COX-2 expression, we examined whether the differential activation of these MAPKs would underlie the opposing activities of TGF-β. The phosphorylation of ERK and p38 MAPKs was indeed enhanced or suppressed by the simultaneous treatment or pre-treatment, respectively. These results suggest that TGF-β exerts opposing effects on IL-1β-induced COX-2 expression in HK cells by differentially regulating activation of ERK and p38 MAPKs.

  11. Prostaglandin E receptor 4 (PTGER4) involved in host protection against immune challenge in oyster, Crassostrea hongkongensis.

    PubMed

    Qu, Fufa; Xiang, Zhiming; Wang, Fuxuan; Qi, Lin; Xu, Fengjiao; Xiao, Shu; Yu, Ziniu

    2015-02-01

    Prostaglandin E receptor 4 (PTGER4) is an essential receptor that can detect various physiological and pathological stimuli and has been implicated in a wide variety of biological processes, including the regulation of immune responses, cytokine production, and apoptosis. In this report, the first mollusk PTGER4, referred to as ChPTGER4, was cloned and characterized from the Hong Kong oyster Crassostrea hongkongensis. Its full-length cDNA is 1734 bp in length, including 5'- and 3'-untranslated region (UTRs) of 354 bp and 306 bp, respectively, and an open reading frame (ORF) of 1074 bp. ChPTGER4 comprises 357 amino acids and shares significant homology with its vertebrate homologs. The results of phylogenetic analysis revealed that ChPTGER4 clusters with PTGER4 from the Pacific oyster. In addition, quantitative real-time PCR analysis revealed that ChPTGER4 was constitutively expressed in all tissues examined and that its expression was significantly up-regulated in hemocytes and gills following challenge by pathogens (Vibrio alginolyticus, Staphylococcus haemolyticus and Saccharomyces cerevisiae) and pathogen-associated molecular patterns (PAMPs: lipopolysaccharide (LPS) and peptidoglycan (PGN). Moreover, fluorescence microscopy analysis revealed that ChPTGER4 localized to the membrane, and its overexpression significantly enhanced NF-κB reporter gene activation in the HEK293T cell line. In summary, this study provides the first experimental evidence of a functional PTGER4 in mollusks, which suggests its involvement in the innate immune response in oyster.

  12. The endometrial expression of prostaglandin cascade components in lactating dairy cows fed different polyunsaturated fatty acids.

    PubMed

    Dirandeh, E; Towhidi, A; Pirsaraei, Z Ansari; Saberifar, T; Akhlaghi, A; Roodbari, A Rezaei

    2015-01-15

    Feeding n-6 polyunsaturated fatty acids (PUFA) increases the endometrial percentages of linoleic and arachidonic acids (AA), enhances the synthesis of prostaglandin F2α (PGF2α), and improves uterine health. In contrary, the n-3 PUFA, eicosapentaenoic acid, and docosahexaenoic acid may play pivotal roles by suppressing the synthesis of uterine PGF2α, a component being centrally involved in the control of the bovine estrous cycle and in early embryo survival. The objectives of the present study were to determine the effect of feeding a diet enriched in either α-linolenic acid (n-3) or linolenic acid (n-6) on the uterine expression of genes related to prostaglandin cascade and uterine release of PGF2α (measured as 13, 14-dihydro-15-keto PGF2α [PGFM]). From calving to 60 days in milk, cows (n = 24) were fed isonitrogenous, isocaloric, and isolipidic diets that differed in the ratio of n-3/n-6 PUFA. Treatments including palm oil ([PLM]; saturated FA, n = 8), soybean whole roast ([SOY]; n-6, n = 8), and linseed extruded ([LIN]; n-3, n = 8). At 30 days in milk, the ovulatory cycles of cows were synchronized using 2 injections of PGF2α with a 14-day interval. On day 15 postovulation, cows were injected with oxytocin and blood samples were collected to monitor the uterine release of PGF2α (measured as PGFM) and uterine endometrial biopsies were prepared to evaluate the expression of genes related to prostaglandin cascade (prostaglandin F synthase [PGFS], prostaglandin E synthase [PGES], prostaglandin endoperoxide synthase-2 [PGHS-2]), phospholipase A2 (PLA2), peroxisome proliferator-activated receptors [PPAR]). Results showed that uterine endometrial PPAR-δ genes were higher in cows fed LIN (3.17-fold) compared with cows fed PLM or SOY (P < 0.05). The messenger RNA (mRNA) level of PGES in the LIN group was threefold as high as those found in SOY and PLM diets (P < 0.05). The mean relative gene expression of PLA2 and PGFS was increased in animals fed the SOY diet (2

  13. Peptide-induced prostaglandin biosynthesis in the renal-vein-constricted kidney

    PubMed Central

    Myers, Stuart I.; Zipser, Robert; Needleman, Philip

    1981-01-01

    The ipsilateral kidney was removed from a rabbit 48h after unilateral partial renal-vein-constriction and was perfused with Krebs–Henseleit media at 37°C. Hourly administration of a fixed dose of bradykinin to the renal-vein-constricted kidney demonstrated a marked time-dependent increase in the release of bioassayable prostaglandin E2 and thromboxane A2 into the venous effluent as compared with the response of the contralateral control kidney. The renal-vein-constricted kidney produced up to 60 times more prostaglandin E2 in response to bradykinin after 6h of perfusion as compared with the contralateral kidney; thromboxane A2 was not demonstratable in the contralateral kidney. Inhibition of protein synthesis de novo in the perfused renal-vein-constricted kidney with cycloheximide lessened the hormone-stimulated increase in prostaglandin E2 by 94% and in thromboxane A2 by 90% at 6h of perfusion. Covalent acetylation of the renal cyclo-oxygenase by prior oral administration of aspirin to the rabbit inhibited initial bradykinin-stimulated prostaglandin E2 biosynthesis 71% at 1h of perfusion. However, there was total recovery from aspirin in the renal-vein-constricted kidney by 2h of perfusion after bradykinin stimulation. Total cyclo-oxygenase activity as measured by [14C]arachidonate metabolism to labelled prostaglandins by renal cortical and renal medullary microsomal fractions prepared from 6h-perfused kidneys demonstrated that renal-vein-constricted kidney-cortical cyclo-oxygenase activity was significantly greater than the contralateral-kidney-cortical conversion, whereas medullary arachidonate metabolism was comparable in both the renal-vein-constricted kidney and contralateral kidney. These data suggest that perfusion of a renal-vein-constricted kidney initiates a time-dependent induction of synthesis of prostaglandin-producing enzymes, which appear to be primarily localized in the renal cortex. The presence of the synthetic capacity to generate very potent

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

    PubMed Central

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

    2016-01-01

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

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

    PubMed Central

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

    2015-01-01

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

  16. In vivo glucocorticoids regulate cyclooxygenase-2 but not cyclooxygenase-1 in peritoneal macrophages.

    PubMed

    Masferrer, J L; Reddy, S T; Zweifel, B S; Seibert, K; Needleman, P; Gilbert, R S; Herschman, H R

    1994-09-01

    Acute inflammatory stimuli elevate both the production of prostaglandins and the synthesis and activity of prostaglandin synthase/cyclooxygenase enzyme (COX) in murine peritoneal macrophages. Adrenalectomy also elevates prostaglandin production, COX synthesis and COX activity in these cells. We have utilized cDNA probes and antisera specific for the products of the prostaglandin synthase/cyclooxygenase-1 (COX-1) and TIS10/prostaglandin synthase-2/cyclooxygenase-2 (COX-2) genes to demonstrate that adrenalectomy causes elevation of mRNA and protein from the COX-2 gene, but not from the COX-1 gene, in peritoneal macrophages. Dexamethasone replacement suppressed the elevation of COX-2 mRNA message, COX-2 protein and the increased COX enzyme activity observed in adrenalectomized animals. In contrast, both COX-1 message and COX-1 protein levels were unaffected either by adrenalectomy or by dexamethasone administration. Thus, under normal physiological conditions, tonic glucocorticoid inhibition appears to play a major role in the in vivo regulation of the COX-2 gene. These data are consistent with COX-1 being the constitutive, housekeeping enzyme in macrophages in normal physiological conditions and with the enhanced prostaglandin synthesis seen after an inflammatory stimulus resulting from the rapid induction and activity of COX-2.

  17. In vivo activation of N-methyl-D-aspartate receptors in the rat hippocampus increases prostaglandin E(2) extracellular levels and triggers lipid peroxidation through cyclooxygenase-mediated mechanisms.

    PubMed

    Pepicelli, O; Fedele, E; Bonanno, G; Raiteri, M; Ajmone-Cat, M A; Greco, A; Levi, G; Minghetti, L

    2002-06-01

    Cyclooxygenases (COX) are a family of enzymes involved in the biosynthesis of prostaglandin (PG) and thromboxanes. The inducible enzyme cyclooxygenase-2 (COX-2) is the major isoform found in normal brain, where it is constitutively expressed in neurons and is further up-regulated during several pathological events, including seizures and ischaemia. Emerging evidence suggests that COX-2 is implicated in excitotoxic neurodegenerative phenomena. It remains unclear whether PGs or other products associated to COX activity take part in these processes. Indeed, it has been suggested that reactive oxygen species, produced by COX, could mediate neuronal damage. In order to obtain direct evidence of free radical production during COX activity, we undertook an in vivo microdialysis study to monitor the levels of PGE(2) and 8-epi-PGF(2alpha) following infusion of N-methyl-D-aspartate (NMDA). A 20-min application of 1 mm NMDA caused an immediate, MK-801-sensitive increase of both PGE(2) and 8-epi-PGF(2alpha) basal levels. These effects were largely prevented by the specific cytosolic phospholipase A(2) (cPLA(2) ) inhibitor arachidonyl trifluoromethyl ketone (ATK), by non- selective COX inhibitors indomethacin and flurbiprofen or by the COX-2 selective inhibitor NS-398, suggesting that the NMDA-evoked prostaglandin synthesis and free radical-mediated lipid peroxidation are largely dependent on COX-2 activity. As several lines of evidence suggest that prostaglandins may be potentially neuroprotective, our findings support the hypothesis that free radicals, rather than prostaglandins, mediate the toxicity associated to COX-2 activity.

  18. 15-deoxy prostaglandin J2, the nonenzymatic metabolite of prostaglandin D2, induces apoptosis in keratinocytes of human hair follicles: a possible explanation for prostaglandin D2-mediated inhibition of hair growth.

    PubMed

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

    2016-07-01

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

  19. The role of prostaglandin E2 in the immunopathogenesis of experimental pulmonary tuberculosis

    PubMed Central

    Moreno, Javier Rangel; García, Iris Estrada; de la Luz García Hernández, María; Leon, Diana Aguilar; Marquez, Ricardo; Pando, Rogelio Hernández

    2002-01-01

    Prostaglandins (PG) are potent mediators of intercellular communication, and PGE2 at high concentration is immunosuppressive for T-cell-mediated immunity. We studied the kinetics of PGE2 production and the expression of the enzymes related to its synthesis during the course of experimental pulmonary tuberculosis. Secondly, we analysed the pathological and immunological changes produced by the pharmacological suppression of PG production. In BALB/c mice infected via the trachea with Mycobacterium tuberculosis H37Rv there is an initial phase of partial resistance, dominated by type 1 cytokines plus tumour necrosis factor-α (TNF-α) and expression of the inducible form of nitric oxide synthase (iNOS), followed by a phase of progressive disease. During the early phase of the infection some activated macrophages located in the alveolar-capillary interstitium and in granulomas showed strong PGE2 immunostaining. However, PGE2 concentrations were relatively low and stable. Animals in this early phase of infection were treated with niflumic acid, a potent and specific blocker of cyclo-oxygenase 2, the rate-limiting enzyme of PG production. In comparison with control animals, the suppression of PG synthesis produced higher inflammation and expression of TNF-α, interleukin-1α and interferon-γ (IFN-γ), but almost complete disappearance of iNOS expression, which coexisted with a significant increment of bacterial load. The late progressive phase in this experimental model is characterized by progressive pneumonia, small granulomas and diminished expression of IFN-γ, TNF-α and iNOS in coexistence with high expression of IL-4. Strong PGE2 immunostaining was seen in foamy macrophages localized in the pneumonic areas, and the PGE2 concentration was four-fold higher in this late phase of infection than during the early phase. When PG production was suppressed in animals suffering advanced phase infection, a significant reduction of pneumonia and bacillus load with striking

  20. Molecular characterization of prostaglandin F receptor (FP) and E receptor subtype 3 (EP3) in chickens.

    PubMed

    Kwok, Amy H Y; Wang, Yajun; Leung, Frederick C

    2012-10-01

    Prostaglandin E and F regulate diverse physiological functions including gastrointestinal motility, fever induction and reproduction. This multitude of biological effects is mediated via their four E receptor subtypes (EP(1), EP(2), EP(3) and EP(4)) and F receptor (FP), respectively. Majority of these studies was performed in mammalian species, while investigations on their roles were impeded by inadequate information on their receptors in avian species. In present study, full-length cDNAs of chicken EP(3) (cEP(3)) and two isoforms of FP - cFPa and cFPb - were cloned from adult hen ovary. The putative cEP(3) and cFPa share high amino acid sequence identity with their respective orthologs, while the predicted cFPb is a novel middle-truncated splice variant which lacks 107 amino acids between transmembrane domains 4 and 6. RT-PCR showed that cEP(3), cFPa and cFPb are widely expressed in adult tissues examined, including ovary and oviduct. Using a pGL3-CRE luciferase reporter system, cEP(3)-expressing DF1 cells inhibited forskolin-induced luciferase activity (EC(50): <1.9 pM) upon PGE(2) treatment, suggesting that cEP(3) may functionally couple to Gi protein. Upon PGF(2α) addition, cFPa was shown to potentially couple to intracellular Ca(2+)-signaling pathway by pGL3-NFAT-RE reporter assay (EC(50): 2.9 nM), while cFPb showed no response. Using a pGL4-SRE reporter system, both cEP(3) and cFPa exhibited potential MAPK activation by PGE(2) and PGF(2α) at EC(50) 0.34 and 13 nM, respectively. Molecular characterization of these receptors paved the road to the better understanding of PGE(2) and PGF(2α) roles in avian physiology and comparative endocrinology studies. PMID:22885557

  1. Identification of Francisella novicida mutants that fail to induce prostaglandin E2 synthesis by infected macrophages

    PubMed Central

    Woolard, Matthew D.; Barrigan, Lydia M.; Fuller, James R.; Buntzman, Adam S.; Bryan, Joshua; Manoil, Colin; Kawula, Thomas H.; Frelinger, Jeffrey A.

    2013-01-01

    Francisella tularensis is the causative agent of tularemia. We have previously shown that infection with F. tularensis Live Vaccine Strain (LVS) induces macrophages to synthesize prostaglandin E2 (PGE2). Synthesis of PGE2 by F. tularensis infected macrophages results in decreased T cell proliferation in vitro and increased bacterial survival in vivo. Although we understand some of the biological consequences of F. tularensis induced PGE2 synthesis by macrophages, we do not understand the cellular pathways (neither host nor bacterial) that result in up-regulation of the PGE2 biosynthetic pathway in F. tularensis infected macrophages. We took a genetic approach to begin to understand the molecular mechanisms of bacterial induction of PGE2 synthesis from infected macrophages. To identify F. tularensis genes necessary for the induction of PGE2 in primary macrophages, we infected cells with individual mutants from the closely related strain F. tularensis subspecies novicida U112 (U112) two allele mutant library. Twenty genes were identified that when disrupted resulted in U112 mutant strains unable to induce the synthesis of PGE2 by infected macrophages. Fourteen of the genes identified are located within the Francisella pathogenicity island (FPI). Genes in the FPI are required for F. tularensis to escape from the phagosome and replicate in the cytosol, which might account for the failure of U112 with transposon insertions within the FPI to induce PGE2. This implies that U112 mutant strains that do not grow intracellularly would also not induce PGE2. We found that U112 clpB::Tn grows within macrophages yet fails to induce PGE2, while U112 pdpA::Tn does not grow yet does induce PGE2. We also found that U112 iglC::Tn neither grows nor induces PGE2. These findings indicate that there is dissociation between intracellular growth and the ability of F. tularensis to induce PGE2 synthesis. These mutants provide a critical entrée into the pathways used in the host for PGE2

  2. TGF-beta 1 inhibits both endotoxin-induced prostaglandin synthesis and expression of the TIS10/prostaglandin synthase 2 gene in murine macrophages.

    PubMed

    Reddy, S T; Gilbert, R S; Xie, W; Luner, S; Herschman, H R

    1994-02-01

    Activated macrophages produce substantial quantities of paracrine mediators, including cytokines, nitric oxide, and prostaglandins. Transforming growth factor beta 1 (TGF-beta) is a potent modulator of immune function. TGF-beta inhibits the cytotoxic activity of endotoxin/lipopolysaccharide (LPS)-activated macrophage cell lines and primary macrophage cultures, reducing their expression of cytokines and nitric oxide. In this report we demonstrate that TGF-beta also attenuates the LPS-induced synthesis and secretion of prostaglandin E2 in murine RAW 264.7 macrophage cells. Macrophage activation also induces accumulation of the recently described ligand-responsive prostaglandin synthase (PGS) TIS10/PGS-2. While TGF-beta alone has no effect on expression from the TIS10/PGS-2 gene, this cytokine inhibits LPS-induced TIS10/PGS-2 protein accumulation and synthesis, as well as LPS-induced TIS10/PGS-2 message accumulation in RAW 264.7 cells. TGF-beta concentrations in the range of 0.1-1.0 ng/ml (4-40 pM) maximally inhibit LPS-induced TIS10/PGS-2 message accumulation. In contrast, neither LPS nor TGF-beta has any effect on the level of PGS-1 (EC 1.14.99.1) message. TGF-beta also attenuates LPS-induced accumulation of unspliced TIS10/PGS-2 transcripts in RAW 264.7 cells, suggesting that this cytokine exerts its effects on TIS10/PGS-2 expression at the transcriptional level. TGF-beta inhibits the LPS-induced accumulation of TIS10/PGS-2 protein and message in cultured murine peritoneal macrophages, as well as in macrophage cell lines.

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

    PubMed Central

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

    2013-01-01

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

  4. [Changes in prostaglandin systhetase activity in mouse tissues as affected by S-[N-(3-aminopropyl)-2-aminoethyl] thiophosphoric acid].

    PubMed

    Prianishnikova, E N; Zhulanova, Z I; Romantsev, E F

    1980-01-01

    Effect of various concentrations of a radioprotector S-[N-(3 aminopropyl)-2-aminoethyl] thiophosphoric acid on the activity of prostaglandine synthetase was studied in mouse liver microsomes as well as in the soluble fractions of testicules and brain in vitro. The activity of prostaglandine synthetase was estimated by monitoring the formation of labelled PGF2 alpha and PGE2 from I-14C-arachidonic acid. The radioprotector at concentration 1.66 mg/ml stimulated formation of PGF2 alpha in all the tissues studied. At the lower concentrations of the radioprotector only slight stimulation of the biosynthesis of prostaglandines in testicules was noted. No effect on their synthesis in the brain soluble fraction could be observed while in the liver microsomes it was inhibited. The radioprotective substance studied apparently affected the cyclooxygenase activity, which is a key enzyme in the prostaglandine-synthesizing system.

  5. [Cerebral malaria with renal insufficiency in a 5 months pregnant woman. The use of prostaglandines for delivery (author's transl)].

    PubMed

    Thonnier, C; Bruneu, A; Valmary, J; Capdevielle, P; Delprat, J

    1979-01-01

    Report of a typical case of cerebral malaria with coma during 3 days, pneumopathy and renal insufficiency with failure of concentration. The delivery of a dead foetus has been started by prostaglandines.

  6. Implication of prostaglandins and histamine H1 and H2 receptors in radiation-induced temperature responses of rats

    SciTech Connect

    Kandasamy, S.B.; Hunt, W.A.; Mickley, G.A.

    1988-04-01

    Exposure of rats to 1-15 Gy gamma radiation (/sup 60/Co) induced hyperthermia, whereas 20-200 Gy induced hypothermia. Exposure either to the head or to the whole body to 10 Gy induced hyperthermia, while body-only exposure produced hypothermia. This observation indicates that radiation-induced fever is a result of a direct effect on the brain. The hyperthermia due to 10 Gy was significantly attenuated by the pre- or post-treatment with a cyclooxygenase inhibitor, indomethacin. Hyperthermia was also altered by the central administration of a mu-receptor antagonist naloxone but only at low doses of radiation. These findings suggest that radiation-induced hyperthermia may be mediated through the synthesis and release of prostaglandins in the brain and to a lesser extent to the release of endogenous opioid peptides. The release of histamine acting on H1 and H2 receptors may be involved in radiation-induced hypothermia, since both the H1 receptor antagonist, mepyramine, and H2 receptor antagonist, cimetidine, antagonized the hypothermia. The results of these studies suggest that the release of neurohumoral substances induced by exposure to ionizing radiation is dose dependent and has different consequences on physiological processes such as the regulation of body temperature. Furthermore, the antagonism of radiation-induced hyperthermia by indomethacin may have potential therapeutic implications in the treatment of fever resulting from accidental irradiations.

  7. Implication of prostaglandins and histamine h1 and h2 receptors in radiation-induced temperature responses of rats

    SciTech Connect

    Kandasamy, S.B.; Hunt, W.A.; Mickley, G.A .

    1988-01-01

    Exposure of rats to 1-15 Gy cobalt 60 gamma radiation induced hyperthermia, whereas 20-200 Gy induced hypothermia. Exposure either to the head or to the whole body to 10 Gy induced hyperthermia, while body-only exposure produced hypothermia. This observation indicates that radiation-induced fever is a result of a direct effect on the brain. The hyperthermia due to 10 Gy was significantly attenuated by the pre- or post-treatment with a cyclooxgenase inhibitor, indomethacin. Hyperthermia was also altered by the central administration of a mu receptor antagonist naloxone but only at low doses of radiation. These findings suggest that radiation-induced hyperthermia may be mediated through the synthesis and release of prostaglandins in the brain and to a lesser extent to the release of endogenous opioid peptides. The release of histamine acting on H(1) and H(2) receptors may be involved in radiation-induced hypothermia since both the H(1) receptor antagonist, mepyramine, and H(2) receptor antagonist, cimetidine, antagonized the hypothermia. The results of these studies suggested that the release of neurohumoral substances induced by exposure to ionizing radiation is dose dependent and has different consequences on physiological processes such as the regulation of body temperature. Furthermore, the antagonism of radiation-induced hyperthermia by indomethacin may have potential therapeutic implications in the treatment of fever resulting from accidental irradiations.

  8. Ethanol extract of Angelica gigas inhibits croton oil-induced inflammation by suppressing the cyclooxygenase - prostaglandin pathway.

    PubMed

    Shin, Sunhee; Joo, Seong Soo; Park, Dongsun; Jeon, Jeong Hee; Kim, Tae Kyun; Kim, Jeong Seon; Park, Sung Kyeong; Hwang, Bang Yeon; Kim, Yun-Bae

    2010-03-01

    The anti-inflammatory effects of an ethanol extract of Angelica gigas (EAG) were investigated in vitro and in vivo using croton oil-induced inflammation models. Croton oil (20 microg/mL) up-regulated mRNA expression of cyclooxygenase (COX)-I and COX-II in the macrophage cell line, RAW 264.7, resulting in the release of high concentrations of prostaglandin E(2) (PGE(2)). EAG (1 approximately 10 microg/mL) markedly suppressed croton oil-induced COX-II mRNA expression and PGE(2) production. Application of croton oil (5% in acetone) to mouse ears caused severe local erythema, edema and vascular leakage, which were significantly attenuated by oral pre-treatment with EAG (50 approximately 500 mg/kg). Croton oil dramatically increased blood levels of interleukin (IL)-6 and PGE(2) without affecting tumor-necrosis factor (TNF)-alpha and nitric oxide (NO) levels. EAG pre-treatment remarkably lowered IL-6 and PGE(2), but did not alter TNF-alpha or NO concentrations. These results indicate that EAG attenuates inflammatory responses in part by blocking the COX - PGE(2) pathway. Therefore, EAG could be a promising candidate for the treatment of inflammatory diseases.

  9. Ethanol extract of Angelica gigas inhibits croton oil-induced inflammation by suppressing the cyclooxygenase - prostaglandin pathway

    PubMed Central

    Shin, Sunhee; Joo, Seong Soo; Park, Dongsun; Jeon, Jeong Hee; Kim, Tae Kyun; Kim, Jeong Seon; Park, Sung Kyeong

    2010-01-01

    The anti-inflammatory effects of an ethanol extract of Angelica gigas (EAG) were investigated in vitro and in vivo using croton oil-induced inflammation models. Croton oil (20 µg/mL) up-regulated mRNA expression of cyclooxygenase (COX)-I and COX-II in the macrophage cell line, RAW 264.7, resulting in the release of high concentrations of prostaglandin E2 (PGE2). EAG (1~10 µg/mL) markedly suppressed croton oil-induced COX-II mRNA expression and PGE2 production. Application of croton oil (5% in acetone) to mouse ears caused severe local erythema, edema and vascular leakage, which were significantly attenuated by oral pre-treatment with EAG (50~500 mg/kg). Croton oil dramatically increased blood levels of interleukin (IL)-6 and PGE2 without affecting tumor-necrosis factor (TNF)-α and nitric oxide (NO) levels. EAG pre-treatment remarkably lowered IL-6 and PGE2, but did not alter TNF-α or NO concentrations. These results indicate that EAG attenuates inflammatory responses in part by blocking the COX-PGE2 pathway. Therefore, EAG could be a promising candidate for the treatment of inflammatory diseases. PMID:20195064

  10. Prostaglandin D2 signaling mediated by the CRTH2 receptor is involved in MK-801-induced cognitive dysfunction.

    PubMed

    Onaka, Yusuke; Shintani, Norihito; Nakazawa, Takanobu; Kanoh, Takuya; Ago, Yukio; Matsuda, Toshio; Hashimoto, Ryota; Ohi, Kazutaka; Hirai, Hiroyuki; Nagata, Kin-Ya; Nakamura, Masataka; Kasai, Atsushi; Hayata-Takano, Atsuko; Nagayasu, Kazuki; Takuma, Kazuhiro; Ogawa, Asao; Baba, Akemichi; Hashimoto, Hitoshi

    2016-11-01

    Chemoattractant receptor-homologous molecule expressed on T helper type 2 cells (CRTH2), which is a second receptor for prostaglandin (PG) D2, is involved in inflammatory responses in peripheral tissue; however, its role in cognitive function remains unclear. Here, we demonstrate that CRTH2 is involved in cognitive function using a well-established animal model of cognitive dysfunction induced by MK-801, an N-methyl-d-aspartate receptor antagonist. Genetic deletion and pharmacological inhibition of CRTH2 suppressed MK-801-induced cognitive dysfunction. Pharmacological inhibition of cyclooxygenase-1, a rate-limiting enzyme in PG synthesis, also suppressed MK-801-induced cognitive dysfunction. Moreover, an MK-801-induced increase in c-Fos expression in the paraventricular nucleus (PVN) was abolished in the CRTH2-deficient mice. Together, these results suggest that PGD2-CRTH2 signaling is involved in both MK-801-induced cognitive dysfunction and neuronal activity regulation in the PVN. Furthermore, genetic association studies suggest that CRTH2 is weakly associated with cognitive function in humans. Our study provides evidence that PGD2-CRTH2 signaling is involved in cognitive function and may represent a potential therapeutic target for cognitive dysfunction in patients with psychiatric disorders.

  11. Mechanism of inhibitory action of prostaglandins on the growth of human gastric carcinoma cell line KATO III.

    PubMed

    Nakamura, A; Yamatani, T; Fujita, T; Chiba, T

    1991-10-01

    Prostaglandins (PGs) play important roles in the regulation of various gastric functions. In this study, the effects of various PGs on the growth of the human gastric carcinoma cell line KATO III were investigated. All the PGs tested inhibited KATO III cell growth with a relative potency order of PGE2 greater than PGE1 greater than 17S,20-dimethyl-6-oxo PGE1-methyl ester (ornoprostil) greater than PGF2 alpha. This inhibition was accompanied by an increase of cyclic adenosine monophosphate production. Furthermore, in the presence of guanosine triphosphate, these PGs stimulated adenylate cyclase activity in the plasma membrane of KATO III cells, followed by enhancement of membrane guanosine triphosphatase activity. The relative potencies of these PGs for increasing cyclic adenosine monophosphate levels, activating adenylate cyclase, and enhancing guanosine triphosphatase activity were all comparable to those for inhibiting cell growth. On the other hand, the proliferation of KATO III cells was also inhibited by forskolin as well as dibutyryl cyclic adenosine monophosphate, whereas none of the agents that did not increase cyclic adenosine monophosphate levels had any effect. These results suggest that PGs inhibit KATO III cell growth by stimulating cyclic adenosine monophosphate production via a guanosine triphosphate-dependent process, suggesting the involvement of guanosine triphosphate-binding stimulatory protein, probably coupled to PGE2 receptors, in the action of PGs. PMID:1653751

  12. Prostaglandin E2 promotes Na1.8 trafficking via its intracellular RRR motif through the protein kinase A pathway.

    PubMed

    Liu, Chao; Li, Qian; Su, Yuanyuan; Bao, Lan

    2010-03-01

    Voltage-gated sodium channels (Na(v)) are essential for the initiation and propagation of action potentials in neurons. Na(v)1.8 activity is regulated by prostaglandin E(2) (PGE(2)). There is, however, no direct evidence showing the regulated trafficking of Na(v)1.8, and the molecular and cellular mechanism of PGE(2)-induced sodium channel trafficking is not clear. Here, we report that PGE(2) regulates the trafficking of Na(v)1.8 through the protein kinase A (PKA) signaling pathway, and an RRR motif in the first intracellular loop of Na(v)1.8 mediates this effect. In rat dorsal root ganglion (DRG) neurons, prolonged PGE(2) treatment enhanced Na(v)1.8 currents by increasing the channel density on the cell surface. Activation of PKA by forskolin had the same effect on DRG neurons and human embryonic kidney 293T cells expressing Na(v)1.8. Inhibition of PKA completely blocked the PGE(2)-promoted effect on Na(v)1.8. Mutation of five PKA phosphorylation sites or the RRR motif in the first intracellular loop of Na(v)1.8 abolished the PKA-promoted Na(v)1.8 surface expression. Furthermore, a membrane-tethered peptide containing the intracellular RRR motif disrupted the PGE(2)-induced promotion of the Na(v)1.8 current in DRG neurons. Our data indicate that PGE(2) promotes the surface expression of Na(v)1.8 via an intracellular RRR motif, and provide a novel mechanism for functional modulation of Na(v)1.8 by hyperalgesic agents. PMID:20028484

  13. Modulation of endothelin-1 in normal human keratinocytes by UVA1/B radiations, prostaglandin E2 and peptidase inhibitors.

    PubMed

    Pernet, I; Mayoux, C; Trompezinski, S; Schmitt, D; Viac, J

    2000-12-01

    In the skin, keratinocytes synthesize and secrete endothelin-(ET-1), a potent vasoconstrictor peptide which acts also as a growth factor for most skin cells. The aim of the study was to test the effects of UVA1 and the associations UVA1/B on the expression of ET-1 in normal human keratinocytes and to determine whether exogenously added prostaglandin E2 (PGE2) regulated ET-1 expression. As ET-1 is susceptible to degradation, we also evaluated whether ET-1 secretion was modulated by peptidase inhibitors. Our results showed that UVA1 (365 nm) did not modify the levels of preproET-1 mRNA and protein. Moreover, the associations UVA1+UVB or UVB+UVA1 down-regulated the overexpression of secreted ET-1 induced by UVB alone. PGE2 at 10(-5) M reduced the expression of ET-1 at the mRNA and protein levels but did not exert any significant modification at lower concentrations from 10(-10) to 10(6) M. Phosphoramidon, an endothelin converting enzyme (ECE) inhibitor, drastically decreased the amount of ET-1 accumulating in the culture medium in basal conditions or after UVB irradiation. Conversely, thiorphan, a specific inhibitor of neutral endopeptidase (NEP), rather increased the levels of ET-1 secretion mainly after UVB irradiation. Taken together, the results showed that normal human keratinocytes secrete and partly degrade ET-1 through ECE and NEP pathways and pointed out a differential regulation of ET-1 by UVB and UVA1 radiations without any noticeable role for PGE2.

  14. Mechanical stimulation of skeletal muscle generates lipid-related second messengers by phospholipase activation

    NASA Technical Reports Server (NTRS)

    Vandenburgh, Herman H.; Shansky, Janet; Karlisch, Patricia; Solerssi, Rosa Lopez

    1991-01-01

    Repetitive mechanical stimulation of cultured avian skeletal muscle increases the synthesis of prostaglandins E2 and F2(alpha) which regulate protein turnover rates and muscle cell growth. Mechnical stimulation significantly increases the breakdown rate of (3)H-arachidonic acid labelled phospholipids, releasing free (3)H-arachidonic acid, and the rate-limiting precursor of prostaglandin synthesis. Mechanical stimulation also significantly increases (3)H-arachidonic acid labelled diacylglycerol formation and intracellular levels of inositol phosphates from myo-2-(3)H inositol labelled phospholipids. Phospholipase A2, phosphatidylinositol-specific phospholipase C (PLC), and phospholipase D (PLD) are activated by stretch. The lipase inhibitors bromophenacylbromide and RHC80267 together reduce stretch-induced prostaglandin production by 73-83 percent. The stretch-induced increases in prostaglandin production, (3)H-arachidonic acid labelled phospholipid breakdown, and (3)H-arachidonic acid labelled diacylglycerol formation occur independently of cellular electrical activity (tetrodotoxin insensitive) whereas the formation of inositol phosphates from myo-2-(3)H inositol labelled phospholipids are dependent on cellular electrical activity. These results indicate that mechanical stimulation increases the lipid-related second messengers arachidonic acid, diacylglycerol, and prostaglandins through activation of specific phospholipases such as PLA2 and PLD, but not by activation of phosphatidylinositol-specific PLC.

  15. Influence of Epilobium extracts on prostaglandin biosynthesis and carrageenin induced oedema of the rat paw.

    PubMed

    Hiermann, A; Juan, H; Sametz, W

    1986-08-01

    Epilobium species have been used as remedies in folk-medicine for the treatment of pathophysiological processes of the prostata. In this paper the influence of extracts of Herba Epilobii angustifolii L. and Herba Epilobii parviflori Schreb. on prostaglandin biosynthesis and the carrageenin rat paw oedema is described. Aqueous extracts of Herba E. angustifolii reduced the release of prostaglandins I2, E2 and D2 (in the perfused rabbit ear) approximately 5 times more effectively than did similar extracts of Herba E. parviflori. Methanolic extracts were inactive. The aqueous extract of E. angustifolium strongly reduced the carrageenin-induced rat paw oedema whereas that of E. parviflorum was inactive. The chemical nature of the active compound(s) is as yet unknown but flavonoids and sitosterol derivatives can be excluded. PMID:3099091

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

    PubMed

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

    2015-03-01

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

  17. Ursolic acid from Plantago major, a selective inhibitor of cyclooxygenase-2 catalyzed prostaglandin biosynthesis.

    PubMed

    Ringbom, T; Segura, L; Noreen, Y; Perera, P; Bohlin, L

    1998-10-01

    A hexane extract of Plantago major was investigated by bioactivity-directed fractionation, using an in vitro cyclooxygenase-2 (COX-2) catalyzed prostaglandin biosynthesis inhibition assay, and resulted in the isolation of ursolic acid (1). This triterpenoid showed a significant COX-2 inhibitory effect, directly on the enzyme activity, with an IC50 value of 130 microM and a COX-2/COX-1 selectivity ratio of 0.6. The structural isomer oleanolic acid (2) was found to be less active than 1, with an IC50 value of 295 microM, but showed a similar selectivity ratio (0.8). Furthermore, no significant inhibition on COX-2 or COX-1 was observed by the triterpenoid, 18beta-glycyrrhetinic acid (3). The direct inhibitory effect of 1 and 2 on COX-2 catalyzed prostaglandin biosynthesis increased with preincubation, indicating a time-dependent inhibition, while the effect on COX-1 was found to be independent of preincubation time.

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

    PubMed Central

    Nieves, Ashley; Garza, Luis A.

    2014-01-01

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

  19. [Vasodilation effects of prostaglandin E1 in patients with precapillary pulmonary hypertension].

    PubMed

    Munclinger, M; Kautzner, J; Serf, B

    1990-04-01

    Prostaglandin E1. (Prostavasin, Schwarz, FRG) was administered in a short-term infusion, 5-30 ng/kg/min., to five patients with precapillary pulmonary hypertension associated with lung disease. Significant pulmonary vasodilatation characterized by a drop of the median pressure in the pulmonary artery by 15% and of the pulmonary vascular resistance by 31% was achieved only in two patients. The authors observed a minimal incidence of side-effects; systemic hypotension observed in three patients was an undesirable manifestaútion. Prostaglandin E1 extends possibilities of a vasodilatating influence on precapillary pulmonary hypertension in lung disease. With regard to the different individual reactivity of patients it should be administered in this indication only under conditions of haemodynamic monitoring.

  20. High-quality crystals of human haematopoietic prostaglandin D synthase with novel inhibitors.

    PubMed

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

    2010-07-01

    Human haematopoietic prostaglandin D synthase (H-PGDS; EC 5.3.99.2) produces prostaglandin D(2), an allergic and inflammatory mediator, in mast cells and Th2 cells. H-PGDS has been crystallized with novel inhibitors with half-maximal inhibitory concentrations (IC(50)) in the low nanomolar range by the counter-diffusion method onboard the Russian Service Module on the International Space Station. The X-ray diffraction of a microgravity-grown crystal of H-PGDS complexed with an inhibitor with an IC(50) value of 50 nM extended to 1.1 A resolution at 100 K using SPring-8 synchrotron radiation, which is one of the highest resolutions obtained to date for this protein.

  1. Synthesis of prostaglandin analogues, latanoprost and bimatoprost, using organocatalysis via a key bicyclic enal intermediate.

    PubMed

    Prévost, Sébastien; Thai, Karen; Schützenmeister, Nina; Coulthard, Graeme; Erb, William; Aggarwal, Varinder K

    2015-02-01

    Two antiglaucoma drugs, bimatoprost and latanoprost, which are analogues of the prostaglandin, PGF2α, have been synthesized in just 7 and 8 steps, respectively. The syntheses employ an organocatalytic aldol reaction that converts succinaldehyde into a key bicyclic enal intermediate, which is primed for attachment of the required lower and upper side chains. By utilizing the crystalline lactone, the drug molecules were prepared in >99% ee.

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

    PubMed Central

    Özyol, Pelin; Özyol, Erhan; Baldemir, Ercan

    2016-01-01

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

  3. [Concentration of prostaglandins and cyclic adenosine-3',5'-monophosphate in the tissues of rats].

    PubMed

    Komissarenko, V P; Slavnov, V N; Epsheĭn, E V; Malinkovich, V D

    1977-04-01

    The content of prostaglandines (PG) and cyclic 3',5'-adenosine monphosphate (cAMP) was investigated in rat tissues by the radioisotopic method of competitive binding. Maximum quantities of both PG and cAMP were revealed in the same most actively functioning organs: the brain, incretory glands, small intestine. Fatty tissue showed minimum quantities of these substances. Results indicate a close functional relationship between the PG synthesis and adenylatecyclase activity in the body tissues.

  4. Evaluation of prostaglandin biosynthetic activity in canine basilar artery following subarachnoid injection of blood.

    PubMed

    Sasaki, T; Murota, S I; Wakai, S; Asano, T; Sano, K

    1981-11-01

    Transformation of arachidonic acid into prostaglandins was investigated in the basilar artery by incubating sections of artery with carbon-14-labeled arachidonic acid. Thin-layer radiochromatography revealed that, in normal canine basilar arteries, 14C-arachidonic acid was transformed mainly to 6-keto-prostaglandin (PG)F1 alpha, a spontaneous metabolite of prostacyclin (PGI2). Among other prostaglandins, only a small amount of PGF2 alpha was detected, whereas PGD2, PGE2, and thromboxane B2 were not. Arteries removed on Days 3 and 8 after subarachnoid blood injection showed a prostaglandin synthesis profile similar to that in the normal cerebral artery. In borate-buffered saline (0.1M borate buffer, pH 9.0/0.15M NaCl = 1:9, vol/vol), canine basilar artery produced a PGI2-like substance that inhibited adenosine diphosphate (ADP)-induced platelet aggregation. Its anti-aggregatory activity was completely abolished by acidification. Aspirin likewise inhibited production of the anti-aggregatory substance. From these results, it was concluded that the anti-aggregatory activity was due solely to the production of PGI2 by the arterial specimen. Based on the above results, PGI2 biosynthetic activity in the cerebral artery exposed to subarachnoid blood injection was bioassayed by measuring the inhibitory activity of the incubation product upon ADP-induced platelet aggregation following incubation of the arteries in borate-buffered saline for 5 to 30 minutes at 20 degrees C, using synthetic PGI2-Na as a standard. The synthetic activity of PGI2 in the artery exposed to subarachnoid blood injection had diminished remarkably by Days 3 and 8. This diminution of PGI2 synthesis in the cerebral artery may be involved in the pathogenesis of cerebral vasospasm.

  5. Prostaglandin synthesis inhibitors reduce Cannabis and restraint stress induced increase in rat brain serotonin concentrations.

    PubMed

    Bhattacharya, S K; Bhattacharya, D

    1983-01-01

    Cannabis resin (CI) produced a dose-related increase in rat brain serotonin concentrations, whereas restraint stress produced maximal rise of the neurotransmitter concentrations at 1 h, followed by a tendency to normalise by 4 h. The prostaglandin (PG) synthesis inhibitors, diclofenac and paracetamol, antagonized CI and restraint stress induced rise in serotonin concentrations. The findings lend credence to earlier reports that PG synthesis inhibitors antagonize serotonin-mediated neuropharmacological actions of CI and restraint stress in rats.

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

    PubMed Central

    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

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

    NASA Technical Reports Server (NTRS)

    Chromiak, Joseph A.; Vandenburgh, Herman H.

    1993-01-01

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

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

    PubMed

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

    2011-01-01

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

  9. Oral E2 prostaglandins affect endocrine cell populations in the gastric antrum of the rat.

    PubMed

    Uribe, A; Grimelius, L; Theodorsson, L E; Riis-Angelo, L; Johansson, C

    1989-04-01

    The aim of the present study was to investigate antral endocrine cell populations and tissue and circulating hormone levels following a 4-week oral regimen with prostaglandin E2 (25, 250 and 5000 micrograms/kg-1 b.i.d.) or a stable methyl analogue (5 and 50 micrograms kg-1 b.i.d.). Epithelial hyperplasia of the gastric antrum was observed with the highest dose of prostaglandin E2 and both doses of the analogue, as evaluated by stereological methods and conventional cell count. The treatments significantly affected the endocrine cell population. Somatostatin-immunoreactive cells were increased in proportion to the increased epithelial cellularity and plasma levels of somatostatin were increased in parallel. The tissue content of somatostatin-like immunoreactivity differed according to the extraction procedure used, and was significantly higher than controls in specimens extracted in neutral water. In the neutral extracts an immunoreactive somatostatin of unidentified molecular structure dominated quantitatively over somatostatin 14 and 28, which were the major components in acetic acid extracts. The serotonin-immunoreactive cell population was also significantly increased by natural prostaglandin E2 and the analogue but the gastrin cell population was not significantly affected by treatments. Accordingly, no significant changes were observed in tissue or plasma gastrin levels. It is concluded that the epithelial hyperplasia of the antral epithelia produced by E2 prostaglandins is associated with selective changes of endocrine cell populations. The changes were proportional to the increases of epithelial cellularity and required quantitative determination of the total antral volume to be detected.(ABSTRACT TRUNCATED AT 250 WORDS)

  10. Positive correlation between patency and mRNA levels for cyclooxygenase-2 and prostaglandin E synthase in the uterine cervix of bitches with pyometra

    PubMed Central

    TAMADA, Hiromichi; ADACHI, Nahoko; KAWATE, Noritoshi; INABA, Toshio; HATOYA, Shingo; SAWADA, Tsutomu

    2015-01-01

    Factors involved in patency of uterine cervices in the bitch with pyometra remain to be clarified. This study examined relationship between patency and mRNA levels for inducible nitric oxide synthase (iNOS), cyclooxygenase (COX)-1, COX-2 and prostaglandin E synthase (PGES) in the uterine cervix of bitches with pyometra. Cervical patency was measured by inserting the stainless steel rods with different diameter into cervical canals. Levels of mRNA expression were determined by semi-quantitative reverse transcription-polymerase chain reaction. The cervical patency was positively correlated with mRNA levels for COX-2 and PGES, but not those for iNOS and COX-1. The results suggest that gene expression of COX-2 and PGES may be involved in the regulation of patency in the uterine cervix of bitches with pyometra. PMID:26596635

  11. Role of IL-1 beta and prostaglandins in beta 2-microglobulin-induced bone mineral dissolution.

    PubMed

    Moe, S M; Hack, B K; Cummings, S A; Sprague, S M

    1995-02-01

    beta 2-microglobulin (beta 2m) induces an osteoclast-mediated net calcium efflux from neonatal mouse calvariae which occurs only after 48 hours of incubation, suggesting that beta 2m acts via other growth factors. To further test this hypothesis, calvariae were incubated with and without beta 2m in the presence of the prostaglandin inhibitor indomethacin, anti-interleukin-1 beta antibody (anti-IL-1 beta), or interleukin-1 beta receptor antagonist (IL-1 beta RA). The addition of beta 2m to the culture medium stimulated, whereas indomethacin inhibited basal calcium efflux following 48 hours. However, the difference (delta) between the calcium efflux induced in calvariae incubated with and without beta 2m in basal medium and that in calvariae incubated with and without beta 2m in indomethacin supplemented medium was similar, suggesting a prostaglandin independent mechanism. There was a time dependent increase in PGE2 in basal medium which was unaffected by beta 2m. In contrast, pre-incubating calvariae with either anti-IL-1 beta or IL-1 beta RA did not alter basal calcium efflux but completely blocked the beta 2m induced calcium efflux. Anti-IL-1 beta had no effect on the basal release of beta-glucuronidase but partially blocked the beta 2m induced release of beta-glucuronidase. Thus, the beta 2m-induced calcium efflux observed in neonatal mouse calvariae is dependent on interleukin-1 beta but not prostaglandins.

  12. The identification of prostaglandins E2, F2α and A2 from rabbit kidney medulla

    PubMed Central

    Lee, J. B.; Crowshaw, K.; Takman, B. H.; Attrep, Katherine A.; Gougoutas, J. Z.

    1967-01-01

    Rabbit kidney medulla (10kg.) was homogenized in 5mm-disodium hydrogen phosphate and deproteinized with ethanol, and the concentrated supernatant solution was extracted at pH8 with light petroleum and at pH2 with chloroform. The acidic lipids present in the chloroform phase were separated on silicic acid columns into three biologically active fractions. The first fraction contained only vasodepressor activity; the second fraction contained both vasodepressor and non-vascular-smooth-muscle-stimulating activity; the third fraction contained both vasopressor and non-vascular-smooth-muscle-stimulating activity. Purification of each fraction by reversed-phase partition and thick-layer chromatography yielded three pure acids. Thin-layer chromatographic, spectroscopic and mass-spectral analysis of the acids and their methyl esters established their structures as prostaglandins E2, F2α and A2. Evidence is presented demonstrating that part or all of the prostaglandin A2 is formed during the isolation procedures from endogenous prostaglandin E2. PMID:16742553

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

    PubMed Central

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

    2014-01-01

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

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

    PubMed Central

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

    2015-01-01

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

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

    PubMed

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

    2016-04-01

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

  16. CRTH2, a prostaglandin D2 receptor, mediates depression-related behavior in mice.

    PubMed

    Onaka, Yusuke; Shintani, Norihito; Nakazawa, Takanobu; Haba, Ryota; Ago, Yukio; Wang, Hyper; Kanoh, Takuya; Hayata-Takano, Atsuko; Hirai, Hiroyuki; Nagata, Kin-Ya; Nakamura, Masataka; Hashimoto, Ryota; Matsuda, Toshio; Waschek, James A; Kasai, Atsushi; Nagayasu, Kazuki; Baba, Akemichi; Hashimoto, Hitoshi

    2015-05-01

    Depression is a complex neuropsychiatric disorder with an unclear molecular etiology. Inflammatory cytokines and molecular intermediates (including prostaglandins) are suggested to be involved in depression; however, the roles of prostaglandins and their respective receptors are largely unknown in depression. Using genetic and pharmacological approaches, we show here that chemoattractant receptor-homologous molecule expressed on T helper type 2 cells (CRTH2), a second receptor for prostaglandin D2 (PGD2), mediates depression-related behavior in mice. CRTH2-deficient (CRTH2(-/-)) mice showed antidepressant-like activity in a chronic corticosterone treatment-induced depression. Consistent with this observation, the pharmacological inhibition of CRTH2 via the clinically available drug ramatroban also rescued abnormal social interaction and depression-related behavior in well-established models, including chronic corticosterone-, lipopolysaccharide-, and tumor-induced pathologically relevant depression models. Importantly, chronic stress via corticosterone treatment increased mRNA levels in PGD2-producing enzymes, such as cyclooxygenase-2 and lipocalin-type PGD2 synthase, in the brain. Furthermore, the activity of the hippocampal noradrenergic system but not the dopaminergic or serotonergic systems was increased in CRTH2(-/-) mice. Together with the observation that untreated CRTH2(-/-) mice showed antidepressant-like activity in the forced swim test, these results provide evidence that central CRTH2-mediated signaling is critically involved in depression-related behavior. PMID:25698598

  17. PPADS does not block contraction-induced prostaglandin E2 synthesis in cat skeletal muscle

    PubMed Central

    McCord, Jennifer L.; Hayes, Shawn G.; Kaufman, Marc P.

    2008-01-01

    Pyridoxal-phosphate-6-azophenyl-2′-4-disulfonate (PPADS), a purinergic 2 (P2) receptor antagonist, has been shown to attenuate the exercise pressor reflex in cats. In vitro, however, PPADS has been shown to block the production of prostaglandins, some of which play a role in evoking the exercise pressor reflex. Thus the possibility exists that PPADS blocks the exercise pressor reflex through a reduction in prostaglandin synthesis rather than through the blockade of P2 receptors. Using microdialysis, we collected interstitial fluid from skeletal muscle to determine prostaglandin E2 (PGE2) concentrations during the intermittent contraction of the triceps surae muscle before and after a popliteal arterial injection of PPADS (10 mg/kg). We found that the PGE2 concentration increased in response to the intermittent contraction before and after the injection of PPADS (both, P < 0.05). PPADS reduced the pressor response to exercise (P < 0.05) but had no effect on the magnitude of PGE2 production during contraction (P = 0.48). These experiments demonstrate that PPADS does not block the exercise pressor reflex through a reduction in PGE2 synthesis. We suggest that PGE2 and P2 receptors play independent roles in stimulating the exercise pressor reflex. PMID:18790832

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

    PubMed

    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.

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

    NASA Technical Reports Server (NTRS)

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

    2001-01-01

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

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

    PubMed

    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.

  1. Methylmercury Alters the Activities of Hsp90 Client Proteins, Prostaglandin E Synthase/p23 (PGES/23) and nNOS

    PubMed Central

    Caito, Samuel; Zeng, Heng; Aschner, Judy L.; Aschner, Michael

    2014-01-01

    Methylmercury (MeHg) is a persistent pollutant with known neurotoxic effects. We have previously shown that astrocytes accumulate MeHg and play a prominent role in mediating MeHg toxicity in the central nervous system (CNS) by altering glutamate signaling, generating oxidative stress, depleting glutathione (GSH) and initiating lipid peroxidation. Interestingly, all of these pathways can be regulated by the constitutively expressed, 90-kDa heat shock protein, Hsp90. As Hsp90 function is regulated by oxidative stress, we hypothesized that MeHg disrupts Hsp90-client protein functions. Astrocytes were treated with MeHg and expression of Hsp90, as well as the abundance of complexes of Hsp90-neuronal nitric oxide synthase (nNOS) and Hsp90-prostaglandin E synthase/p23 (PGES/p23) were assessed. MeHg exposure decreased Hsp90 protein expression following 12 h of treatment while shorter exposures had no effect on Hsp90 protein expression. Interestingly, following 1 or 6 h of MeHg exposure, Hsp90 binding to PGES/p23 or nNOS was significantly increased, resulting in increased prostaglandin E2 (PGE2) synthesis from MeHg-treated astrocytes. These effects were attenuated by the Hsp90 antagonist, geldanmycin. NOS activity was increased following MeHg treatment while cGMP formation was decreased. This was accompanied by an increase in •O2− and H2O2 levels, suggesting that MeHg uncouples NO formation from NO-dependent signaling and increases oxidative stress. Altogether, our data demonstrates that Hsp90 interactions with client proteins are increased following MeHg exposure, but over time Hsp90 levels decline, contributing to oxidative stress and MeHg-dependent excitotoxicity. PMID:24852575

  2. Comprehensive analysis of prostaglandin metabolic enzyme expression during pregnancy and the characterization of AKR1B1 as a prostaglandin F synthase at the maternal-conceptus interface in pigs.

    PubMed

    Seo, Heewon; Choi, Yohan; Shim, Jangsoo; Yoo, Inkyu; Ka, Hakhyun

    2014-05-01

    Prostaglandins (PGs) are important lipid mediators regulating various reproductive processes in many species. In pigs, the expression pattern of PGE2 and PGF2α metabolic enzymes and the regulatory mechanism controlling PGE2 and PGF2α levels in the uterus during pregnancy are not completely understood. This study determined endometrial expression of the genes (PLA2G4A, PTGS1, PTGS2, PTGES, PTGES2, PTGES3, AKR1B1, CBR1, and HPGD) involved in PGE2 and PGF2α metabolism during the estrous cycle and pregnancy and measured levels of PGE2 and PGF2α in uterine endometrial tissues and uterine flushings at the time of conceptus implantation in pigs. Except PTGES3, expression of the genes studied changed in a pregnancy-stage-specific manner, and localization of PTGES, AKR1B1, CBR1, and HPGD mRNAs were cell-type specific in the uterine endometrium. Levels of both PGE2 and PGF2α in uterine endometrial tissues and uterine lumen were higher on Day 12 of pregnancy than those of the estrous cycle and affected by different morphology of spherical and filamentous conceptuses. Furthermore, we determined that endometrial expression of AKR1B1, known to encode a PGF2α synthase in other species, was increased by estrogen and interleukin-1beta and that AKR1B1 exhibited PGF2α synthase activity in the porcine uterine endometrium. These results in pigs indicate that the PGE2 and PGF2α metabolic enzymes are expressed stage specifically in the endometrium during pregnancy and regulate the abundance of PGE2 and PGF2α in the uterus at the time of implantation and that AKR1B1 may act as a major PGF synthase in the endometrium during early pregnancy.

  3. Comprehensive analysis of prostaglandin metabolic enzyme expression during pregnancy and the characterization of AKR1B1 as a prostaglandin F synthase at the maternal-conceptus interface in pigs.

    PubMed

    Seo, Heewon; Choi, Yohan; Shim, Jangsoo; Yoo, Inkyu; Ka, Hakhyun

    2014-05-01

    Prostaglandins (PGs) are important lipid mediators regulating various reproductive processes in many species. In pigs, the expression pattern of PGE2 and PGF2α metabolic enzymes and the regulatory mechanism controlling PGE2 and PGF2α levels in the uterus during pregnancy are not completely understood. This study determined endometrial expression of the genes (PLA2G4A, PTGS1, PTGS2, PTGES, PTGES2, PTGES3, AKR1B1, CBR1, and HPGD) involved in PGE2 and PGF2α metabolism during the estrous cycle and pregnancy and measured levels of PGE2 and PGF2α in uterine endometrial tissues and uterine flushings at the time of conceptus implantation in pigs. Except PTGES3, expression of the genes studied changed in a pregnancy-stage-specific manner, and localization of PTGES, AKR1B1, CBR1, and HPGD mRNAs were cell-type specific in the uterine endometrium. Levels of both PGE2 and PGF2α in uterine endometrial tissues and uterine lumen were higher on Day 12 of pregnancy than those of the estrous cycle and affected by different morphology of spherical and filamentous conceptuses. Furthermore, we determined that endometrial expression of AKR1B1, known to encode a PGF2α synthase in other species, was increased by estrogen and interleukin-1beta and that AKR1B1 exhibited PGF2α synthase activity in the porcine uterine endometrium. These results in pigs indicate that the PGE2 and PGF2α metabolic enzymes are expressed stage specifically in the endometrium during pregnancy and regulate the abundance of PGE2 and PGF2α in the uterus at the time of implantation and that AKR1B1 may act as a major PGF synthase in the endometrium during early pregnancy. PMID:24695626

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

    SciTech Connect

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

    2015-01-02

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

  5. Prostaglandin transporters ABCC4 and SLCO2A1 in the uterine endometrium and conceptus during pregnancy in pigs.

    PubMed

    Seo, Heewon; Choi, Yohan; Shim, Jangsoo; Yoo, Inkyu; Ka, Hakhyun

    2014-05-01

    Prostaglandins (PGs) are involved in many reproductive activities including luteolysis, maternal recognition of pregnancy, endometrial gene expression, conceptus development, and parturition in domestic animals. However, mechanisms by which PGE2 and PGF2alpha are modulated in the uterine endometrium and expression of ABCC4 and SLCO2A1, responsible for efficient transport of PGs across the cell membrane, in the endometrium during the estrous cycle and pregnancy are not fully understood in pigs. Therefore, we determined expression of ABCC4 and SLCO2A1, genes involved in transport of PGE2 and PGF2alpha in the uterine endometrium during the estrous cycle and pregnancy in pigs. ABCC4 and SLCO2A1 mRNAs were expressed in the uterine endometrium, most abundantly on Day 12 of pregnancy and during late pregnancy. Expression of ABCC4 mRNA and protein was localized mainly to uterine luminal epithelial (LE) and glandular epithelial (GE) cells, and expression of SLCO2A1 mRNA and protein was expressed primarily in uterine LE and blood vessels. Expression of ABCC4 and SLCO2A1 mRNAs was also detected in conceptuses during early pregnancy. In addition, explant culture experiments showed that increasing doses of interleukin 1B (IL1B) with estrogen and progesterone increased levels of ABCC4 and SLCO2A1 mRNAs in the uterine endometrium. These results indicate that expression of genes responsible for transport of PGE2 and PGF2alpha are dynamically regulated in the uterine endometrium during pregnancy and that ABCC4 and SLCO2A1 play critical roles in supporting the establishment and maintenance of pregnancy by regulating PG transport at the maternal-fetal interface in pigs.

  6. Anti-inflammatory activity of Nerium indicum by inhibition of prostaglandin E2 in murine splenic lymphocytes

    PubMed Central

    Dey, Priyankar; Chaudhuri, Tapas Kumar

    2015-01-01

    Objective: Nerium indicum Mill (syn. N. oleander L. and N. odorum Aiton; family: Apocynaceae) is a medicinal plant, used in the treatment of diverse ailments including various chronic inflammatory diseases in traditional medicine. We have previously demonstrated the immunomodulatory activity of a bioactive fraction of Nerium indicum leaf (NILE) by studying up-regulation of interleukin-2 (IL-2), IL-10, interferon-gamma and down regulation of IL-4, tumor necrosis factor-alpha (TNF-α), nitric oxide, cyclooxygenase-1 (COX-1) and COX-2 activities. Therefore, this study aimed to confirm the anti-inflammatory activity of NILE by inhibition of prostaglandin E2 (PGE2) activity in murine splenic lymphocytes in vitro. Materials and Methods: Murine lymphocytes were isolated from spleen and stimulated with 5 ΅g/mL concanavalin A in RPMI-1640, supplemented with 50 U/mL penicillin, 50 U/mL streptomycin, 50 U/mL nystatin and 10% fetal bovine serum. Different concentrations (0–80 μg/mL) of NILE were added and the cells were cultured for 48 h. The culture supernatants were thereafter collected by centrifugation and assayed for expression of PGE2 level. The data were analyzed statistically. Results: The results demonstrated a 2.26-fold inhibition of PGE2 level at 80 μg/mL of NILE. Half maximum inhibitory concentration (IC50) was calculated to be 44.95 ± 0.45 ΅g/mL. Linear correlation analysis of the dose-dependent PGE2 inhibition with other pro- and anti-inflammatory mediators demonstrated high inter-correlation between the parameters. Conclusions: Thus, the present study remains in accordance with our previous report and confirms the anti-inflammatory claim of N. indicum, mentioned in the traditional medicine. PMID:26288481

  7. Aldose reductases influence prostaglandin F2α levels and adipocyte differentiation in male mouse and human species.

    PubMed

    Pastel, Emilie; Pointud, Jean-Christophe; Loubeau, Gaëlle; Dani, Christian; Slim, Karem; Martin, Gwenaëlle; Volat, Fanny; Sahut-Barnola, Isabelle; Val, Pierre; Martinez, Antoine; Lefrançois-Martinez, Anne-Marie

    2015-05-01

    Aldose reductases (AKR1B) are widely expressed oxidoreductases whose physiological function remains elusive. Some isoforms are genuine prostaglandin F2α (PGF2α) synthases, suggesting they might influence adipose homeostasis because PGF2α inhibits adipogenesis. This was shown by Akr1b7 gene ablation in the mouse, which resulted in increased adiposity related to a lower PGF2α content in fat. Yet humans have no ortholog gene for Akr1b7, so the role of aldose reductases in human adipose homeostasis remains to be explored. We analyzed expression of genes encoding human and mouse aldose reductase isoforms in adipose tissues and differentiating adipocytes to assess conserved mechanisms regulating PGF2α synthesis and adipogenesis. The Akr1b3 gene encoded the most abundant isoform in mouse adipose tissue, whereas Akr1b7 encoded the only isoform enriched in the stromal vascular fraction. Most mouse aldose reductase gene expression peaked in early adipogenesis of 3T3-L1 cells and diminished with differentiation. In contrast with its mouse ortholog Akr1b3, AKR1B1 expression increased throughout differentiation of human multipotent adipose-derived stem cells, paralleling PGF2α release, whereas PGF2α receptor (FP) levels collapsed in early differentiation. Pharmacological inhibition of aldose reductase using Statil altered PGF2α production and enhanced human multipotent adipose-derived stem adipocyte differentiation. As expected, the adipogenic effects of Statil were counteracted by an FP agonist (cloprostenol). Thus, in both species aldose reductase-dependent PGF2α production could be important in early differentiation to restrict adipogenesis. PGF2α antiadipogenic signaling could then be toned down through the FP receptor or aldose reductases down-regulation in human and mouse cells, respectively. Our data suggest that aldose reductase inhibitors could have obesogenic potential.

  8. Induction of cyclo-oxygenase-2 mRNA by prostaglandin E2 in human prostatic carcinoma cells

    NASA Technical Reports Server (NTRS)

    Tjandrawinata, R. R.; Dahiya, R.; Hughes-Fulford, M.

    1997-01-01

    Prostaglandins are synthesized from arachidonic acid by the enzyme cyclo-oxygenase. There are two isoforms of cyclooxygenases: COX-1 (a constitutive form) and COX-2 (an inducible form). COX-2 has recently been categorized as an immediate-early gene and is associated with cellular growth and differentiation. The purpose of this study was to investigate the effects of exogenous dimethylprostaglandin E2 (dmPGE2) on prostate cancer cell growth. Results of these experiments demonstrate that administration of dmPGE2 to growing PC-3 cells significantly increased cellular proliferation (as measured by the cell number), total DNA content and endogenous PGE2 concentration. DmPGE2 also increased the steady-state mRNA levels of its own inducible synthesizing enzyme, COX-2, as well as cellular growth to levels similar to those seen with fetal calf serum and phorbol ester. The same results were observed in other human cancer cell types, such as the androgen-dependent LNCaP cells, breast cancer MDA-MB-134 cells and human colorectal carcinoma DiFi cells. In PC-3 cells, the dmPGE2 regulation of the COX-2 mRNA levels was both time dependent, with maximum stimulation seen 2 h after addition, and dose dependent on dmPGE2 concentration, with maximum stimulation seen at 5 microg ml(-1). The non-steroidal anti-inflammatory drug flurbiprofen (5 microM), in the presence of exogenous dmPGE2, inhibited the up-regulation of COX-2 mRNA and PC-3 cell growth. Taken together, these data suggest that PGE2 has a specific role in the maintenance of human cancer cell growth and that the activation of COX-2 expression depends primarily upon newly synthesized PGE2, perhaps resulting from changes in local cellular PGE2 concentrations.

  9. Genetic variability in key genes in prostaglandin E2 pathway (COX-2, HPGD, ABCC4 and SLCO2A1) and their involvement in colorectal cancer development.

    PubMed

    Pereira, Carina; Queirós, Sara; Galaghar, Ana; Sousa, Hugo; Pimentel-Nunes, Pedro; Brandão, Catarina; Moreira-Dias, Luís; Medeiros, Rui; Dinis-Ribeiro, Mário

    2014-01-01

    The pro-carcinogenic effects of prostaglandin E2 (PGE2) in colonic mucosa are not only regulated by the rates between Cyclooxygenase-2 (COX-2) biosynthesis and 15-Hydroxyprostaglandin Dehydrogenase (15-PGDH)-dependent degradation but also the steady-state levels of PGE2 in extracellular microenvironment, maintained by key specific prostaglandin transporters, the Multidrug Resistance Protein (MRP4) (efflux carrier) and Prostaglandin Transporter (PGT) (influx carrier). To understand the contribution of genetic variability in genes coding for COX-2/15-PGDH/MRP4/PGT proteins in CRC development, we conducted a hospital-based case-control study involving 246 CRC patients and 480 cancer-free controls. A total of 51 tagSNPs were characterized using the Sequenom platform through multiplexed amplification followed by mass-spectrometric product separation or allelic discrimination using real-time PCR. Seven tagSNPs were implicated in CRC development: the rs689466 in COX-2 gene, the rs1346271 and rs1426945 in 15-PGDH, the rs6439448 and rs7616492 in PGT and rs1751051 and rs1751031 in MRP4 coding genes. Upon a stratified analysis a measurable gene-environment interaction was noticed between rs689466 and smoking habits, with individuals ever-smokers carriers of rs689466 GG homozygous genotype having a nearly 6-fold increased susceptibility for CRC onset (95%CI: 1.49-22.42, P = 0.011). Furthermore, the multifactor dimensionality reduction (MDR) analysis identified an overall four-factor best gene-gene interactive model, including the rs1426945, rs6439448, rs1751051 and rs1751031 polymorphisms. This model had the highest cross-validation consistency (10/10, P<0.0001) and an accuracy of 0.6957 and was further associated with a 5-fold increased risk for CRC development (95%CI: 3.89-7.02, P<0.0001). In conclusion, specific low penetrance genes in the pro-carcinogenic PGE2 pathway appear to modulate the genetic susceptibility for CRC development. A clearer understanding on CRC

  10. The Prostaglandin F Synthase Activity of the Human Aldose Reductase AKR1B1 Brings New Lenses to Look at Pathologic Conditions

    PubMed Central

    Bresson, Eva; Lacroix-Pépin, Nicolas; Boucher-Kovalik, Sofia; Chapdelaine, Pierre; Fortier, Michel A.

    2012-01-01

    Prostaglandins are important regulators of female reproductive functions to which aldose reductases exhibiting hydroxysteroid dehydrogenase activity also contribute. Our work on the regulation of reproductive function by prostaglandins (PGs), lead us to the discovery that AKR1B5 and later AKR1B1were highly efficient and physiologically relevant PGF synthases. PGE2 and PGF2α are the main prostanoids produced in the human endometrium and proper balance in their relative production is important for normal menstruation and optimal fertility. Recent evidence suggests that PGE2/EP2 and PGF2α/FP may constitute a functional dyad with physiological relevance comparable to the prostacyclin-thromboxane dyad in the vascular system. We have recently reported that AKR1B1 was expressed and modulated in association with PGF2α production in response to IL-1β in the human endometrium. In the present study, we show that the human AKR1B1 (gene ID: 231) also known as ALDR1 or ALR2 is a functional PGF2α synthase in different models of living cells and tissues. Using human endometrial cells, prostate, and vascular smooth muscle cells, cardiomyocytes and endothelial cells we demonstrate that IL-1β is able to up regulate COX-2 and AKR1B1 proteins as well as PGF2α production under normal glucose concentrations. We show that the promoter activity of AKR1B1 gene is increased by IL-1β particularly around the multiple stress response region containing two putative antioxidant response elements adjacent to TonE and AP1. We also show that AKR1B1 is able to regulate PGE2 production through PGF2α acting on its FP receptor and that aldose reductase inhibitors like alrestatin, Statil (ponalrestat), and EBPC exhibit distinct and characteristic inhibition of PGF2α production in different cell models. The PGF synthase activity of AKR1B1 represents a new and important target to regulate ischemic and inflammatory responses associated with several human pathologies. PMID:22654757

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

    PubMed

    Siljehav, Veronica; Shvarev, Yuri; Herlenius, Eric

    2014-11-01

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

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

    PubMed

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

    2013-01-01

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

  13. Recombinant interleukin-1β dilates steelhead trout coronary microvessels: effect of temperature and role of the endothelium, nitric oxide and prostaglandins

    PubMed Central

    Costa, Isabel A. S. F.; Hein, Travis W.; Secombes, Christopher J.; Gamperl, A. Kurt

    2015-01-01

    ABSTRACT Interleukin (IL)-1β is associated with hypotension and cardiovascular collapse in mammals during heat stroke, and the mRNA expression of this pro-inflammatory cytokine increases dramatically in the blood of Atlantic cod (Gadus morhua) at high temperatures. These data suggest that release of IL-1β at high temperatures negatively impacts fish cardiovascular function and could be a primary determinant of upper thermal tolerance in this taxa. Thus, we measured the concentration-dependent response of isolated steelhead trout (Oncorhynchus mykiss) coronary microvessels (<150 μm in diameter) to recombinant (r) IL-1β at two temperatures (10 and 20°C). Recombinant IL-1β induced a concentration-dependent vasodilation with vessel diameter increasing by approximately 8 and 30% at 10−8 and 10−7 mol l−1, respectively. However, this effect was not temperature dependent. Both vessel denudation and cyclooxygenase blockade (by indomethacin), but not the nitric oxide (NO) antagonist L-NIO, inhibited the vasodilator effect of rIL-1β. In contrast, the concentration-dependent dilation caused by the endothelium-dependent calcium ionophore A23187 was completely abolished by L-NIO and indomethacin, suggesting that both NO and prostaglandin signaling mechanisms exist in the trout coronary microvasculature. These data: (1) are the first to demonstrate a functional link between the immune and cardiovascular systems in fishes; (2) suggest that IL-1β release at high temperatures may reduce systemic vascular resistance, and thus, the capacity of fish to maintain blood pressure; and (3) provide evidence that both NO and prostaglandins play a role in regulating coronary vascular tone, and thus, blood flow. PMID:26026045

  14. Signaling of Prostaglandin E Receptors, EP3 and EP4 Facilitates Wound Healing and Lymphangiogenesis with Enhanced Recruitment of M2 Macrophages in Mice

    PubMed Central

    Hosono, Kanako; Isonaka, Risa; Kawakami, Tadashi; Narumiya, Shuh; Majima, Masataka

    2016-01-01

    Lymphangiogenesis plays an important role in homeostasis, metabolism, and immunity, and also occurs during wound-healing. Here, we examined the roles of prostaglandin E2 (PGE2) receptor (EP) signaling in enhancement of lymphangiogenesis in wound healing processes. The hole-punch was made in the ears of male C57BL/6 mice using a metal ear punch. Healing process and lymphangiogenesis together with macrophage recruitment were analyzed in EP knockout mice. Lymphangiogenesis was up-regulated in the granulation tissues at the margins of punched-hole wounds in mouse ears, and this increase was accompanied by increased expression levels of COX-2 and microsomal prostaglandin E synthase-1. Administration of celecoxib, a COX-2 inhibitor, suppressed lymphangiogenesis in the granulation tissues and reduced the induction of the pro-lymphangiogenic factors, vascular endothelial growth factor (VEGF) -C and VEGF-D. Topical applications of selective EP receptor agonists enhanced the expressions of lymphatic vessel endothelial hyaluronan receptor-1 and VEGF receptor-3. The wound-healing processes and recruitment of CD11b-positive macrophages, which produced VEGF-C and VEGF-D, were suppressed under COX-2 inhibition. Mice lacking either EP3 or EP4 exhibited reduced wound-healing, lymphangiogenesis and recruitment of M2 macrophages, compared with wild type mice. Proliferation of cultured human lymphatic endothelial cells was not detected under PGE2 stimulation. Lymphangiogenesis and recruitment of M2 macrophages that produced VEGF-C/D were suppressed in mice treated with a COX-2 inhibitor or lacking either EP3 or EP4 during wound healing. COX-2 and EP3/EP4 signaling may be novel targets to control lymphangiogenesis in vivo. PMID:27711210

  15. Myeloid Cell Prostaglandin E2 Receptor EP4 Modulates Cytokine Production but Not Atherogenesis in a Mouse Model of Type 1 Diabetes

    PubMed Central

    Vallerie, Sara N.; Kramer, Farah; Barnhart, Shelley; Kanter, Jenny E.; Breyer, Richard M.; Andreasson, Katrin I.; Bornfeldt, Karin E.

    2016-01-01

    Type 1 diabetes mellitus (T1DM) is associated with cardiovascular complications induced by atherosclerosis. Prostaglandin E2 (PGE2) is often raised in states of inflammation, including diabetes, and regulates inflammatory processes. In myeloid cells, a key cell type in atherosclerosis, PGE2 acts predominately through its Prostaglandin E Receptor 4 (EP4; Ptger4) to modulate inflammation. The effect of PGE2-mediated EP4 signaling specifically in myeloid cells on atherosclerosis in the presence and absence of diabetes is unknown. Because diabetes promotes atherosclerosis through increased arterial myeloid cell accumulation, we generated a myeloid cell-targeted EP4-deficient mouse model (EP4M-/-) of T1DM-accelerated atherogenesis to investigate the relationship between myeloid cell EP4, inflammatory phenotypes of myeloid cells, and atherogenesis. Diabetic mice exhibited elevated plasma PGE metabolite levels and elevated Ptger4 mRNA in macrophages, as compared with non-diabetic littermates. PGE2 increased Il6, Il1b, Il23 and Ccr7 mRNA while reducing Tnfa mRNA through EP4 in isolated myeloid cells. Consistently, the stimulatory effect of diabetes on peritoneal macrophage Il6 was mediated by PGE2-EP4, while PGE2-EP4 suppressed the effect of diabetes on Tnfa in these cells. In addition, diabetes exerted effects independent of myeloid cell EP4, including a reduction in macrophage Ccr7 levels and increased early atherogenesis characterized by relative lesional macrophage accumulation. These studies suggest that this mouse model of T1DM is associated with increased myeloid cell PGE2-EP4 signaling, which is required for the stimulatory effect of diabetes on IL-6, markedly blunts the effect of diabetes on TNF-α and does not modulate diabetes-accelerated atherogenesis. PMID:27351842

  16. Leptin protection of salivary gland acinar cells against ethanol cytotoxicity involves Src kinase-mediated parallel activation of prostaglandin and constitutive nitric oxide synthase pathways.

    PubMed

    Slomiany, B L; Slomiany, A

    2008-04-01

    Leptin, a pleiotropic cytokine secreted by adipocytes but also identified in salivary glands and saliva, is recognized as an important element of oral mucosal defense. Here, we report that in sublingual salivary glands leptin protects the acinar cells of against ethanol cytotoxicity. We show that ethanol- induced cytotoxicity, characterized by a marked drop in the acinar cell capacity for NO production, arachidonic acid release and prostaglandin generation, was subject to suppression by leptin. The loss in countering capacity of leptin on the ethanol-induced cytotoxicity was attained with cyclooxygenase inhibitor, indomethacin and nitric oxide synthase (cNOS) inhibitor, L-NAME, as well as PP2, an inhibitor of Src kinase. Indomethacin, while not affecting leptin-induced arachidonic acid release, caused the inhibition in PGE2 generation, pretreatment with L-NAME led to the inhibition in NO production, whereas PP2 exerted the inhibitory effect on leptin-induced changes in NO, arachidonic acid, and PGE2. The leptin-induced changes in arachidonic acid release and PGE2 generation were blocked by ERK inhibitor, PD98059, but not by PI3K inhibitor, wortmannin. Further, leptin suppression of ethanol cytotoxicity was reflected in the increased Akt and cNOS phosphorylation that was sensitive to PP2. Moreover, the stimulatory effect of leptin on the acinar cell cNOS activity was inhibited not only by PP2, but also by Akt inhibitor, SH-5, while wortmannin had no effect. Our findings demonstrate that leptin protection of salivary gland acinar cells against ethanol cytotoxicity involves Src kinase-mediated parallel activation of MAPK/ERK and Akt that result in up-regulation of the respective prostaglandin and nitric oxide synthase pathways.

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

    PubMed Central

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

    1992-01-01

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

  18. Effects of ethanol on synthesis of prostaglandin F2α in bovine females.

    PubMed

    De Barros, F R O; Bertan, C M; Dias, L O P; Fantini, D A; Ayres, G R; Marques, V B; Miguez, P H P; Binelli, M

    2010-10-01

    Ethanol stimulates the production of prostaglandins in many species. The purpose of this study was to verify the effect of ethanol on the production of prostaglandin F2α (PGF2α) and luteolysis in bovine females. In the first experiment, Holstein cows at day 17 of the oestrous cycle were treated with 100% ethanol (0.05 ml/kg of body weight, IV; n = 5), saline (0.05 ml/kg of body weight, IV; n = 4) or synthetic prostaglandin (150 μg of D-cloprostenol/cow, IM; n = 4). The plasma concentrations of 13, 14-dihydro-15-keto PGF2α (PGFM; the main metabolite of PGF2α measured in the peripheral blood) were assessed by radioimmunoassay (RIA). There was an acute release of PGFM in response to ethanol comparing to other treatments (p ≤ 0.05). However, only cows treated with PGF2α underwent luteolysis. In the second experiment, endometrial explants of cross-bred beef cows (n = 4) slaughtered at day 17 of the oestrous cycle were cultured for 4 h. During the last 3 h, the explants were cultured with medium supplemented with 0, 0.1, 1, 10 or 100 μl of 100% ethanol/ml. Medium samples were collected at hours 1 and 4 and concentrations of PGF2α were measured by RIA. Ethanol did not induce PGF2α production by the endometrium. In conclusion, ethanol does not cause luteolysis in cows because it stimulates production of PGF2α in extra-endometrial tissues.

  19. Stimulation of intestinal mucosal adenyl cyclase by cholera enterotoxin and prostaglandins

    PubMed Central

    Kimberg, Daniel V.; Field, Michael; Johnson, Judith; Henderson, Antonia; Gershon, Elaine

    1971-01-01

    The effects of several prostaglandins (PG) and a highly purified preparation of cholera enterotoxin (CT) on intestinal mucosal adenyl cyclase activity and the effect of CT on intestinal mucosal cyclic 3′,5′-adenosine monophosphate concentration were determined in guinea pig and rabbit small intestine and were correlated with the effects of the same agents on ion transport. Adenyl cyclase activity, measured in a crude membrane fraction of the mucosa, was found at all levels of the small intestine with the highest activity per milligram protein in the duodenum. The prostaglandins, when added directly to the assay, increased adenyl cyclase activity; the greatest effect (2-fold increase) was obtained with PGE1 (maximal effect at 0.03 mM) and PGE2. The prostaglandins also increased short-circuit current (SCC) in isolated guinea pig ileal mucosa, with PGE1 and PGE2 again giving the greatest effects. The prior addition of theophylline (10 mM) reduced the subsequent SCC response to PGE1 and vice versa. It was concluded, therefore, that the SCC response to PGE1, like the response to theophylline, represented active Cl secretion. CT increased adenyl cyclase activity in guinea pig and rabbit ileal mucosa when preincubated with the mucosa from 1 to 2.5 hr in vitro or for 2.5 hr in vivo but not when added directly to the assay. The increments in activity caused by PGE1 and NaF were the same in CT-treated and control mucosa. Cyclic 3′,5′-AMP concentration in rabbit ileal mucosa was increased 3.5-fold after a 2 hr preincubation with CT in vitro. Phosphodiesterase activity in the crude membrane fraction of the mucosa was unaffected by either CT or PGE1. A variety of other agents including insulin, glucagon, parathormone, thyroid-stimulating hormone, L-thyroxine, thyrocalcitonin, vasopressin, and epinephrine all failed to change adenyl cyclase activity. It is concluded that CT and certain prostaglandins produce small intestinal fluid secretion by increasing mucosal adenyl

  20. Structures of prostaglandin F synthase from the protozoa Leishmania major and Trypanosoma cruzi with NADP.

    PubMed

    Moen, Spencer O; Fairman, James W; Barnes, Steve R; Sullivan, Amy; Nakazawa-Hewitt, Stephen; Van Voorhis, Wesley C; Staker, Bart L; Lorimer, Donald D; Myler, Peter J; Edwards, Thomas E

    2015-05-01

    The crystal structures of prostaglandin F synthase (PGF) from both Leishmania major and Trypanosoma cruzi with and without their cofactor NADP have been determined to resolutions of 2.6 Å for T. cruzi PGF, 1.25 Å for T. cruzi PGF with NADP, 1.6 Å for L. major PGF and 1.8 Å for L. major PGF with NADP. These structures were determined by molecular replacement to a final R factor of less than 18.6% (Rfree of less than 22.9%). PGF in the infectious protozoa L. major and T. cruzi is a potential therapeutic target.

  1. Molecular characterization of prostaglandin F receptor (FP) and E receptor subtype 1 (EP₁) in zebrafish.

    PubMed

    Kwok, Amy H Y; Wang, Yajun; Leung, Frederick C

    2012-09-01

    Prostaglandins E (PGE) and F (PGF) mediate diverse physiological functions via their cell surface receptors - prostaglandin E receptor (EP) subtypes 1, 2, 3 and 4 (EP(1); EP(2); EP(3); EP(4)) and F receptor (FP). In teleost fishes, PGE was implicated in gill epithelium ion transport, while both PGE and PGF were involved in oocyte maturation, follicular rupture and coordination of reproductive behaviors. However, little is known about the mechanisms behind their actions. In present study, we first identified the full-length ORF cDNA clones of three zebrafish prostaglandin E receptor subtype 1 (zEP(1)) isoforms - zEP(1a), zEP(1b) and zEP(1c) - and FP (zFP) from adult ovary. RT-PCR showed that zEP(1a), zEP(1b) and zFP are widely expressed in adult tissues, while zEP(1c) mRNA expression is mainly confined in brain and kidney. Using a pGL3-NFAT-RE luciferase reporter system, both zEP(1a) and zEP(1b) expressed in DF-1 cells were shown to be activated by PGE(2) potently while zEP(1c) and zFP were activated by PGF(2a) effectively, suggesting that the four receptors are functionally coupled to intracellular Ca(2+)-signaling pathway. Furthermore, EP1a and EP1b, but not EP1c were suggested to couple to cAMP-PKA signaling pathway using a pGL3-CRE luciferase reporter assay. Although zEP(1c) might originate as a paralog to zEP(1a) and zEP(1b), its functional coupling to PGF(2α) instead of PGE(2) suggested that zEP(1) isoforms might have sub-functionalized in their ligand binding and G protein coupling specificity, in addition to differential tissue distribution. Characterization of these receptors undoubtedly furthered our understanding on the diverse yet highly target-specific responses of prostaglandins in teleosts. PMID:22617193

  2. Inhibition of gonadotropin and prostaglandin stimulation of testicular steroidogenesis in malnourished rats.

    PubMed

    Nduka, E U; Dada, O A

    1984-01-01

    The effect of human chorionic gonadotropin (hCG) and prostaglandin E1 (PGE1) on testicular steroidogenesis in protein-deficient and refed rats was studied in vitro. The malnourished, refed, and control rats were found to secret testosterone in response to hCG and PGE1 stimulation. There was a significant reduction in the basal level of secretion in the malnourished rat testis (1.0 +/- 0.4 nMol/3 hr./Testis). Malnourished rats refed with adequate protein diet responded to hCG and PGE1 stimulation in a similar manner to normally-fed adult rats. PMID:6541885

  3. Effects of altering dietary fatty acid composition on prostaglandin synthesis and fertility.

    PubMed

    Abayasekara, D R; Wathes, D C

    1999-11-01

    Several studies over the past 20 years have demonstrated that subjects on diets composed of substances with high levels of n-3 polyunsaturated fatty acids (PUFAs) (e.g. fish) have a decreased incidence of heart disease. On this basis, a recent report from the Department of Health has advised UK consumers to decrease the proportion of saturated as opposed to unsaturated fats in their diet and to increase the ratio of n-3 to n-6 PUFAs. This could be achieved by altering the amounts of these constituents in milk and meat. n-3 Fatty acids can most easily be added to animal feed as either fish oil or linseed oil and can be increased in the blood and milk of ruminants following protection to avoid hydrogenation in the rumen. In western countries the ratio of consumption of n-6 to n-3 PUFAs is greater than 10 and current evidence tends to suggest that a ratio nearer 5 would be more desirable and compatible with cardiovascular well being. As fertility in the UK dairy herd is already poor, it is important to establish whether alterations in dietary n-3 and n-6 PUFAs affects herd fertility before widespread changes in animal diets are recommended. Therefore, this review considers the role played by PUFAs and eicosanoids in fertility, with particular reference to the implications for farm livestock production. The evidence reviewed shows that alteration of the concentration and ratio of n-6 and n-3 PUFAs in feeds can influence prostaglandin synthesis/metabolism in a number of mammalian systems. The changed patterns of prostaglandin synthesis can as a consequence, affect the diverse functions (e.g. hormone secretion) that are normally mediated via prostaglandins. Similarly, changes in prostaglandin synthesis effected through manipulation of PUFAs has a major bearing on fertility (as PGs affect many reproductive parameters, e.g. ovulation). Several studies in cattle and other mammals, show that feeding or infusing different types of fat with varying PUFA content to females can

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

    PubMed

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

    2009-12-01

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

  5. Definition of Prostaglandin E2-EP2 Signals in the Colon Tumor Microenvironment That Amplify Inflammation and Tumor Growth.

    PubMed

    Ma, Xiaojun; Aoki, Tomohiro; Tsuruyama, Tatsuaki; Narumiya, Shuh

    2015-07-15

    Inflammation in the colon contributes significantly to colorectal cancer development. While aspirin reduces the colorectal cancer risk, its action mechanism, especially in inflammation in tumor microenvironment, still remains obscure. Here, we examined this issue by subjecting mice deficient in each prostaglandin (PG) receptor to colitis-associated cancer model. Deficiency of PGE receptor subtype EP2 selectively reduced, and deficiency of EP1 and EP3 enhanced, the tumor formation. EP2 is expressed in infiltrating neutrophils and tumor-associated fibroblasts in stroma, where it regulates expression of inflammation- and growth-related genes in a self-amplification manner. Notably, expression of cytokines such as TNFα and IL6, a chemokine, CXCL1, a PG-producing enzyme, COX-2, and Wnt5A was significantly elevated in tumor lesions of wild-type mice but this elevation was significantly suppressed in EP2-deficient mice. Intriguingly, EP2 stimulation in cultured neutrophils amplified expression of TNFα, IL6, CXCL1, COX-2, and other proinflammatory genes synergistically with TNFα, and EP2 stimulation in cultured fibroblasts induced expression of EP2 itself, COX-2, IL6, and Wnt genes. EP2 expression in infiltrating neutrophils and tumor-associated fibroblasts was also found in clinical specimen of ulcerative colitis-associated colorectal cancer. Bone marrow transfer experiments suggest that EP2 in both cell populations is critical for tumorigenesis. Finally, administration of a selective EP2 antagonist potently suppressed tumorigenesis in this model. Our study has thus revealed that EP2 in neutrophils and tumor-associated fibroblasts promotes colon tumorigenesis by amplifying inflammation and shaping tumor microenvironment, and suggests that EP2 antagonists are promising candidates of aspirin-alternative for chemoprevention of colorectal cancer.

  6. Prostaglandin E2 Prevents Hyperosmolar-Induced Human Mast Cell Activation through Prostanoid Receptors EP2 and EP4

    PubMed Central

    Torres-Atencio, Ivonne; Ainsua-Enrich, Erola; de Mora, Fernando; Picado, César; Martín, Margarita

    2014-01-01

    Background Mast cells play a critical role in allergic and inflammatory diseases, including exercise-induced bronchoconstriction (EIB) in asthma. The mechanism underlying EIB is probably related to increased airway fluid osmolarity that activates mast cells to the release inflammatory mediators. These mediators then act on bronchial smooth muscle to cause bronchoconstriction. In parallel, protective substances such as prostaglandin E2 (PGE2) are probably also released and could explain the refractory period observed in patients with EIB. Objective This study aimed to evaluate the protective effect of PGE2 on osmotically activated mast cells, as a model of exercise-induced bronchoconstriction. Methods We used LAD2, HMC-1, CD34-positive, and human lung mast cell lines. Cells underwent a mannitol challenge, and the effects of PGE2 and prostanoid receptor (EP) antagonists for EP1–4 were assayed on the activated mast cells. Beta-hexosaminidase release, protein phosphorylation, and calcium mobilization were assessed. Results Mannitol both induced mast cell degranulation and activated phosphatidyl inositide 3-kinase and mitogen-activated protein kinase (MAPK) pathways, thereby causing de novo eicosanoid and cytokine synthesis. The addition of PGE2 significantly reduced mannitol-induced degranulation through EP2 and EP4 receptors, as measured by beta-hexosaminidase release, and consequently calcium influx. Extracellular-signal-regulated kinase 1/2, c-Jun N-terminal kinase, and p38 phosphorylation were diminished when compared with mannitol activation alone. Conclusions Our data show a protective role for the PGE2 receptors EP2 and EP4 following osmotic changes, through the reduction of human mast cell activity caused by calcium influx impairment and MAP kinase inhibition. PMID:25329458

  7. Oxidative Stress-Dependent Cyclooxygenase-2-Derived Prostaglandin F2α Impairs Endothelial Function in Renovascular Hypertensive Rats

    PubMed Central

    Tian, Xiao Yu; Leung, Fung Ping; Zhang, Yang; Wang, Yi-Xiang; Lee, Hung Kay; Ng, Chi Fai; Chen, Zhen Yu; Yao, Xiaoqiang; Au, Chak Leung; Lau, Chi Wai; Vanhoutte, Paul M.; Cooke, John P.

    2012-01-01

    Abstract Aims: The role of endothelium-derived contracting factors (EDCFs) in regulating renovascular function is yet to be elucidated in renovascular hypertension (RH). The current study investigated whether oxidative stress-dependent cyclooxygenase (COX)-2-derived prostaglandin F2α (PGF2α) impairs endothelial function in renal arteries of renovascular hypertensive rats (RHR). Results: Renal hypertension was induced in rats by renal artery stenosis of both kidneys using the 2-kidney 2-clip model. Acute treatment with reactive oxygen species (ROS) scavengers, COX-2 inhibitors, and thromboxane-prostanoid receptor antagonists, but not COX-1 inhibitors, improved endothelium-dependent relaxations and eliminated endothelium-dependent contractions in RHR renal arteries. Five weeks of treatment with celecoxib or tempol reduced blood pressure, increased renal blood flow, and restored endothelial function in RHRs. Increased ROS production in RHR arteries was inhibited by ROS scavengers, but unaffected by COX-2 inhibitors; whereas increased PGF2α release was reduced by both ROS scavengers and COX-2 inhibitors. ROS also induced COX-2-dependent contraction in RHR renal arteries, which was accompanied by the release of COX-2-derived PGF2α. Further, chronic tempol treatment reduced COX-2 and BMP4 upregulation, p38MAPK phosphorylation, and the nitrotyrosine level in RHR renal arteries. Conclusion: These findings demonstrate the functional importance of oxidative stress, which serves as an initiator of increased COX-2 activity, and that COX-2-derived PGF2α plays an important role in mediating endothelial dysfunction in RH. Innovation: The current study, thus, suggests that drugs targeting oxidative stress-dependent COX-2-derived PGF2α may be useful in the prevention and management of RH. Antioxid. Redox Signal. 16, 363–373. PMID:21951274

  8. Oestrous cycle-related changes in production of Toll-like receptors and prostaglandins in the canine endometrium.

    PubMed

    Silva, E; Henriques, S; Brito, S; Ferreira-Dias, G; Lopes-da-Costa, L; Mateus, L

    2012-12-01

    The objectives of this study were to evaluate the following events in the canine endometrium over the course of the oestrous cycle: (i) the transcriptional profiles of genes encoding the Toll-like receptors (TLR1-TLR7 and TLR9); (ii) the transcription and protein expression levels of TLR2 and TLR4; (iii) the gene transcription profile of prostaglandin synthesis enzymes (PTGS2, PGES and PGFS); (iv) the response pattern of PGF(2α) and PGE(2) following exposure of endometrial explants to LPS and LTA. TLR1-TLR7 and TLR9 genes were transcribed in the endometrium of bitches throughout the oestrous cycle, which indicates that TLR-mediated immune surveillance is an important component of the defence mechanisms within the uterus. Canine endometrial mRNA and protein expression of TLR2 and TLR4 was up-regulated at the late dioestrus and anoestrus and was the lowest in the follicular phase and early dioestrus. The decreased mRNA and protein levels observed at early dioestrus may favour implantation, but may also be linked to the high prevalence of pyometra at this stage of the oestrous cycle. After LPS and LTA stimulation, endometrial explants produced more PGF(2α) than PGE(2), which may be related to the early demise of the corpus luteum observed in vivo in canine pyometra cases. Overall, these results indicate that TLRs are involved in the activation of the inflammatory response associated with pyometra in the bitch. TLRs may therefore be therapeutic targets for the control of uterine bacterial infections in the bitch and potentially in other species. PMID:22959486

  9. Peripheral plasma levels of progesterone in pregnant goats and in pregnant goats treated with prostaglandin F2a.

    PubMed

    Bosu, W T; Serna Garibay, J A; Barker, C A

    1979-02-01

    Prostaglandin or prostaglandin analogues have been shown to be luteolytic in the pregnant goat. In this study the temporal changes in the plasma concentrations of progesterone during pregnancy and after administration of PGF2a to pregnant goats are described. PGF2a administration to pregnant goats at 30 and 65 days after breeding induced abortion within 34 to 75 hours. These abortions were accompanied by estrus and profuse muco-hemorrhagic discharges. When PGF2a was administered to pregnant goats 140 or 142 days after breeding, premature parturition occurred within 42 to 76 hours. Live kids were delivered in all cases. The plasma levels of progesterone in all pregnant goats showed dramatic decreases within 24 hours after the prostaglandin injections and continued to decrease gradually until abortions or premature parturition. Thereafter, the progesterone levels remained low for several days. PMID:16725398

  10. Distribution of Prostaglandin E2 in Gastric and Duodenal Mucosa: Possible Role in the Pathogenesis of Peptic Ulcer

    PubMed Central

    Park, Sill Moo; Yoo, Byung Chul; Lee, Hyo Rang; Chung, Hyuk; Lee, Young Soon

    1992-01-01

    Background Prostaglandin E which is present abundantly in the gastric mucosa is a powerful inhibitor of gastric acid secretion and a stimulus to gastric mucus production. In addition, prostaglandin E2 inhibits ulcer formation in animals, and the synthetic analogues of prostaglandin E have successfully been used in the treatment of patients with gastric and duodenal ulcer disease. To evaluate the role of endogenous prostaglandin E2 in the pathogenesis of the peptic ulcer disease, we measured mucosal prostaglandin E2 levels in patients with gastric and duodenal ulcer disease and compared with that of non-ulcer control persons. Methods The study population was made up of 44 non-ulcer persons, 36 patients with a benign gastric ulcer, and 48 with a duodenal ulcer. Every mucosai specimen, taken from the antrum and from the duodenal bulb, were homogenized, mixed with 1 M HCI, and centrifuged. After removal of the supernatant, precipitate was eluted with ethyl acetate in the Amprep C18 minicolumn. Then the extracted prostaglandin E2 in the ethyl acetate fractions was converted into its methyl oximate derivatives, and the prostaglandin E2 level was measured by radioimmunoassay. During the procedure any homogenized specimen which was looking grossly bloody was removed from the assay in order to avoid any possible contamination or prostaglandin E2 in blood. Results In non-ulcer persons, the mean values was 258.17±127.03 pg/mg. tissue in antrum and 121.07±67.46 pg/mg. tissue in duodenal bulb. The corresponding values were 186.42±70.51 pg/mg. tissue, 79.44±39.04 pg/mg. tissue in gastric ulcer patients and 204. 94 92.03 pg/mg. tissue, 99.66±56.10 pg/mgl. tissue in duodenal ulcer patients respectively. Gastric ulcer patients have the significantly lower level of the antral and duodenal prostaglandin E2 (p<0.005). Those levels of duodenal ulcer patients were also significantly lower than those of non-ulcer persons (p<0.025 & 0.05). Antral prostaglandin E2 level increased to

  11. Mutations in the prostaglandin transporter encoding gene SLCO2A1 cause primary hypertrophic osteoarthropathy and isolated digital clubbing.

    PubMed

    Seifert, Wenke; Kühnisch, Jirko; Tüysüz, Beyhan; Specker, Christof; Brouwers, Ad; Horn, Denise

    2012-04-01

    Digital clubbing is usually secondary to different acquired diseases. Primary hypertrophic osteoarthropathy (PHO) is a rare hereditary disorder with variable digital clubbing as the most prominent feature, subperiosteal new bone formation, and arthropathy. Recently, mutations in the 15-hydroxy-prostaglandin dehydrogenase (15-PGDH) encoding gene HPGD were found to cause PHO. Here, we identified three unrelated families with different mutations in the prostaglandin transporter (PGT) encoding gene SLCO2A1 which presumably result in reduced metabolic clearance by 15-PGDH due to diminished cellular uptake of prostaglandin E(2) (PGE(2)) by mutant PGT. In two consanguineous families, homozygous mutations, an intragenic deletion that results in frameshift and a missense mutation, are associated with a severe PHO phenotype. In a third family, a heterozygous carrier of a stop mutation presents with isolated digital clubbing. Thus, our study further supports the importance of PGE(2) metabolism in the pathogenesis of digital clubbing and PHO. PMID:22331663

  12. Bromoenol Lactone, an Inhibit