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Sample records for prostaglandin f2alpha regulates

  1. Expression and regulation of the messenger ribonucleic acid encoding the prostaglandin F(2alpha) receptor in the rat myometrium during pregnancy and labor.

    PubMed

    Ou, C W; Chen, Z Q; Qi, S; Lye, S J

    2000-04-01

    We examined expression of messenger ribonucleic acid encoding the prostaglandin F(2alpha) receptor in the rat myometrium throughout late gestation and its regulation by progesterone and mechanical stretch. Normal pregnant rats were killed on gestational day 15, 22, or 23 (during labor) or 1 day post partum. The effects of progesterone on prostaglandin F(2alpha) receptor messenger ribonucleic acid levels were investigated by daily injections of progesterone (4 mg) from day 20 of normal gestation or from day 17 in rats bilaterally ovariectomized on day 17. To investigate the effects of myometrial stretch, unilaterally pregnant rats underwent either sham surgery or placement of a polyvinyl tube 3 mm in diameter in the nongravid uterine horn on day 15 or 18 and were killed 5 days later. Prostaglandin F(2alpha) receptor messenger ribonucleic acid levels in the myometrium were determined by a semiquantitative reverse transcription-polymerase chain reaction method. Myometrial prostaglandin F(2alpha) receptor messenger ribonucleic acid levels significantly increased during both term and ovariectomy-induced preterm labor. This increase was blocked by progesterone. In rats with unilateral pregnancies prostaglandin F(2alpha) receptor messenger ribonucleic acid levels in the nongravid horns were similar to those in the contralateral gravid horns on day 20 and during labor regardless of whether they were stretched by a 3-mm tube. Increased myometrial expression of prostaglandin F(2alpha) receptor messenger ribonucleic acid during term and preterm labor is temporally associated with progesterone withdrawal but is not dependent on mechanical stretch of the myometrium.

  2. Regulation of pulsatile secretion of prostaglandin F2 alpha from the ovine uterus by ovarian steroids.

    PubMed

    Silvia, W J; Raw, R E

    1993-07-01

    Two experiments were conducted to determine how progesterone and oestradiol regulate pulsatile secretion of PGF2 alpha from the ovine uterus. In Expt 1, ovariectomized ewes received: (1) no treatment, (2) oestradiol, (3) progesterone, or (4) oestradiol and progesterone (n = 5 ewes per treatment group) to approximate the changes in steroids that occur during the oestrous cycle. Jugular venous blood samples were collected at 30 min intervals for 48 h beginning at 08:00 on day 14 of steroid replacement. Blood samples were collected from five intact ewes at a comparable time of the oestrous cycle for comparison. The number and magnitude of pulses in 13,14-dihydro-15-keto-PGF2 alpha (PGFM) in jugular venous blood samples were used to assess uterine secretion of PGF2 alpha. Experiment 2 was conducted as Expt 1, except that the progesterone replacement protocol was modified to duplicate more closely the temporal pattern of progesterone observed in intact ewes. Results were similar in both experiments. Intact ewes averaged 4.4 +/- 0.6 pulses per 48 h blood sampling period. The frequency of pulses was less in ovariectomized ewes (P < 0.05). The number of pulses was increased by progesterone treatment (P < 0.01); the number of pulses in ovariectomized ewes receiving progesterone replacement was similar to that observed in intact ewes. There was a tendency for oestradiol to have a positive effect on the number of pulses (P = 0.12). The magnitude of pulses in intact ewes averaged 419 +/- 38 pg ml-1 and was much less in ovariectomized ewes (P < 0.05) than in intact ewes.(ABSTRACT TRUNCATED AT 250 WORDS)

  3. 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.

  4. Prostaglandin F2 alpha as the luteolysin in swine: VI. Hormonal regulation of the movement of exogenous PGF2 alpha from the uterine lumen into the vasculature.

    PubMed

    Marengo, S R; Bazer, F W; Thatcher, W W; Wilcox, C J; Wetteman, R P

    1986-03-01

    To test the endocrine-exocrine theory of maternal recognition of pregnancy in the pig 16 gilts were assigned randomly to a 2 X 2 factorial involving pretreatment with sesame oil (SO) or estradiol valerate (5 mg; EV) injected on Days 11 through 14 of the estrous cycle and an intrauterine injection of saline (5 ml; SA) or prostaglandin F2 alpha (50 micrograms; PGF) on Day 14. Peripheral blood samples were collected for 120 min postinjection and analyzed for 15-keto-13,14-dihydro-PGF2 alpha (PGFM). PGFM concentrations were lower in EV than SO gilts (438 vs. 844 pg/ml; p less than 0.05). There was heterogeneity of regression between EV and SO gilts (p less than 0.01), with EV gilts having a slower release of PGF from the uterine lumen into the vasculature. Prostaglandin F2 alpha did not increase mean PGFM concentrations (p greater than 0.10), but resulted in an altered temporal pattern of PGFM (p less than 0.05) compared to SA gilts. There was an interaction between the two treatments over time, with EV-PGF gilts demonstrating a slower, more gradual release of PGFM than SO-PGF gilts. To test whether prostaglandins of the E series were involved in this mechanism, gilts were assigned to two 4 X 4 latin squares balanced for residual effects and treated with saline or flunixen meglumine (Banamine). Each gilt was treated with four PGE:PGF infusion sequences (SEQ) in each uterine horn: phosphate-buffered saline (PBS; PBS-SEQ), PGE1 (50 micrograms), PGE2 (50 micrograms), and PGE1 (25 micrograms) + PGE2 (25 micrograms) (PGE-SEQ), with each infusion followed 15 min later by PGF (25 micrograms).(ABSTRACT TRUNCATED AT 250 WORDS)

  5. The possible mode of action of prostaglandins: XVI. A study to assess the local effect of prostaglandins E1, E2 or F2 alpha in the regulation of male fertility.

    PubMed

    Rej, S K; Chatterjee, A

    1980-06-01

    A single intratesticular injection of prostaglandin E1 (PGE1) or prostaglandin E2 (PGE2) at a dose of 2.5 mg/kg was found to interfere with the fertilizing ability of epididymal spermatozoa of the test animals both in the injected and contralateral control sides. Prostaglandin F2 alpha, conversely, was found to be ineffective in terms of fertility of the test animals in the same experimental model. The beneficial effect of testosterone therapy concurrently with either of the PGE1 or PGE2 in maintaining the fertility of the animals has been recorded and discussed in terms of the mode of action of prostaglandins.

  6. Prostaglandin F2alpha produced by inducible cyclooxygenase may contribute to the resolution of inflammation.

    PubMed

    Colville-Nash, Paul R; Gilroy, Derek W; Willis, Dean; Paul-Clark, Mark J; Moore, Adrian R; Willoughby, Derek A

    2005-01-01

    Cyclooxygenase-2 may play a role in resolution of carrageenan-induced pleurisy in rats by generating anti-inflammatory prostanoids. Here, we show exudate prostaglandin F2alpha concentrations rise during resolution of this model. These were reduced by the selective cyclooxygenase-2 inhibitor NS-398, which exacerbated inflammation. Concomitant treatment with NS-398 and the synthetic FP receptor agonist fluprostenol reversed this exacerbation. This suggests prostaglandin F2alpha produced by cyclooxygenase-2 contributes to resolution of this inflammatory reaction.

  7. 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.

  8. Estrus synchronization and controlled breeding in goats using prostaglandin F(2)alpha.

    PubMed

    Ogunbiyi, P O; Molokwu, E C; Sooriyamoorthy, T

    1980-04-01

    Estrus synchronization in the goat employing the double injection regimen of 7.5 mg of prostaglandin F(2)alpha (Lutalyse) at each injection, resulted in 64% and 84% synchronization at first and second injections, respectively. Breeding at estrus induced by the second injection resulted in 90% conception. Kidding at the end of the gestation period was spread over a 17-day period. The first and the last does had 141 and 158 days of gestation, respectively. The findings of this study indicate that two injections of prostaglandin F(2)alpha 10 days apart is superior to a single injection for estrus synchronization in the goat. Breeding following the second injection resulted in high conception rate. Due to individual differences in gestational lengths, estrus synchronization with prostaglandin F(2)alpha cannot be depended upon for synchrony of kidding.

  9. 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.

  10. Preliminary experience with 15 (S) 15-methyl prostaglandin F2 alpha for midtrimester abortion.

    PubMed

    Greer, B E; Droegemueller, W; Engel, T

    1975-02-15

    Twenty-six women received intramuscular or intra-amniotic 15 (S) 15-methyl prostaglandin F2 alpha to induce midtrimester abortion. The median initial injection-abortion interval was 10 hours and 25 minutes. The advantages of intramuscular analogue are somnolence and reduced discomfort during labor. Disadvantages include severe gastrointestinal toxicity in the majority of patients and symptoms of acute respiratory distress in two patients.

  11. Prostaglandin F2 alpha synthesis and metabolism by luteal phase endometrium in vitro.

    PubMed

    Brumsted, J R; Chapitis, J; Deaton, J L; Riddick, D H; Gibson, M

    1989-11-01

    Differences in prostaglandin (PG) F2 alpha synthesis and degradation were sought between early luteal endometrium (histology day 15 to 22, n = 6) and late luteal endometrium (histology day 23 to 28, n = 6). In addition, alterations in PGF2 alpha synthesis and degradation in response to 17 beta-estradiol (E2) and progesterone (P) were examined to clarify the mechanism of steroid modulation of endometrial PG production (n = 12). Endometrium was maintained in tissue culture and the concentration of PGF2 alpha and 13,14 dehydro-15 keto F2 alpha (DHKF2 alpha) was determined in spent media by radioimmunoassay. Prostaglandin F2 alpha and DHKF2 alpha output from luteal endometrium exposed to P and E2 + P were both significantly reduced when compared with no addition or E2 treatments. This implies that the modulation of PGF2 alpha output by P in vitro is secondary to altered synthesis. There was an increase in PGF2 alpha output from late luteal endometrium when compared with early luteal endometrium in the P and E2 + P treatments, but DHKF2 alpha remained unchanged. These data imply that the temporal increase in PGF2 alpha output is the result of alterations in both PG synthesis and catabolism.

  12. Vasoconstrictor effects of iso-prostaglandin F2alpha type-III (8-iso-prostaglandin F2alpha) on human saphenous veins.

    PubMed

    Gardan, B; Cracowski, J L; Sessa, C; Hunt, M; Stanke-Labesque, F; Devillier, P; Bessard, G

    2000-05-01

    Free radical generation can initiate the peroxidation of arachidonic acid, resulting in a non-cyclooxygenase-dependent production of bioactive prostaglandin F2-like compounds. We have investigated the effects of iso-prostaglandin F2alpha type III, (iPF2alpha-III, formerly named 8-iso prostaglandin F2alpha) on human saphenous veins, and characterized the underlying mechanisms. In organ baths, the contractile effects of iPF2alpha-III were tested on saphenous vein rings coming from 22 patients. iPF2alpha-III induced concentration-dependent contractions of isolated human saphenous veins. The maximal contraction did not differ significantly from that of prostaglandin F2alpha (PGF2alpha). The pD2 values for iPF2alpha-III, PGF2alpha, endothelin-1 (ET-1), and U46619 (a stable thromboxane A2 mimetic) were 6.31+/-0.12, 5.66+/-0.13, 7.37+/-0.08, and 7.99+/-0.31, respectively (p < 0.001 for U46619 vs. iPF2alpha-III and PGF2alpha; and ET-1 vs. PGF2alpha). Emax values of iPF2alpha-III, PGF2alpha, ET-1, and U46619 were 137.7+/-24.3%, 145.9+/-7.5%, 92.9+/-16.8%, and 238.7+/-23.7%, respectively (p < 0.001 for U46619 vs. iPF2alpha-III, PGF2alpha and ET-1; and for PGF2alpha vs. ET-1). The responses to iPF2alpha-III were inhibited by GR 32191 10(-7) M, a TP-receptor antagonist, without affecting the maximal response (pD2 values were 5.98+/-0.06 in the absence, and 5.22+/-0.05 in the presence of GR32191; p < 0.001). Concentration-effect curves to iPF2alpha-III were not affected by phosphoramidon 10(-5) M (an endothelin converting enzyme inhibitor), BQ123 10(-6) M (a selective ET(A)-receptor antagonist), BQ788 10(-6) M (a selective ET(B)-receptor antagonist), and indomethacin 10(-5) M (a cyclooxygenase inhibitor). Finally, the contractile response of iPF2alpha-III did not involve the release of thromboxane B2 and ET-1, measured using enzyme immunoassays. This study demonstrates that iPF2alpha-III is a vasoconstrictor of human saphenous veins, with a potency fourfold greater than that of

  13. Comparison of prostaglandin F2alpha and hypertonic saline for induction of midtrimester abortion.

    PubMed

    Lauersen, N H; Wilson, K H; Beling, C G; Fuchs, F

    1974-12-01

    20 healthy women between 18-20 weeks of gestation and seeking abortion were studied to compare the effects of prostaglandin F2alpha (PGF2) with those of instillation of saline solution and intravenous oxytocin. 9 out of 10 patients in the prostaglandin group aborted completely in about 15.16 hours. In only one of the prostaglandin patients did abortion have to be completed surgically. All of the 10 patients in the saline solution-oxytocin group also aborted completely, but with a mean time of 22.34 hours, a difference not statistically significant. The complication rate was higher in patients aborted with PGF2, including postabortion lactation and gastrointestinal effects, especially vomiting. In terms of hormonal changes, the similarities between the 2 groups were more numerous than the differences, suggesting that the 2 mechanics of abortion may not be totally different. Comparative studies on a much larger group of patients are desirable.

  14. 8-Iso-prostaglandin f(2alpha) reduces trophoblast invasion and matrix metalloproteinase activity.

    PubMed

    Staff, A C; Ranheim, T; Henriksen, T; Halvorsen, B

    2000-06-01

    Preeclampsia is a common pregnancy complication in the latter half of gestation diagnosed by hypertension and proteinuria. A key feature of preeclampsia is an altered placentation with reduced trophoblast invasion. Normal placentation requires controlled invasion of trophoblasts into the maternal uterine wall, with secretion of specific proteolytic enzymes able to degrade basement membranes and extracellular matrix, such as the matrix metalloproteinases (MMPs). 8-Iso-prostaglandin F(2alpha) (8-iso-PGF(2alpha)) is a marker of oxidative stress in vivo and is biologically active. We have recently reported an elevated content of free 8-iso-PGF(2alpha) in preeclamptic gestational tissue at delivery. Assuming an elevated level of 8-iso-PGF(2alpha) during the invasion period of the pregnancy, we hypothesized that 8-iso-PGF(2alpha) could reduce invasion of JAR cells, a choriocarcinoma cell line. We investigated JAR cell invasion with 2 types of Transwell assays and demonstrated that 8-iso-PGF(2alpha) (10 micromol/L) resulted in reduced cell invasion in both the colorimetric and radioactivity Transwell assays (P<0.01). Zymograms revealed reduced MMP-2 and MMP-9 activity in conditioned media from JAR cells incubated with 8-iso-PGF(2alpha) (10 micromol/L) (P<0.02). 8-Iso-PGF(2alpha) (10 micromol/L) also reduced the collagenase type IV activity in the conditioned media of JAR cells (P=0.04). No effects on MMP-2 and MMP-9 mRNA levels were observed after incubation with 8-iso-PGF(2alpha) (10 micromol/L), whereas protein levels were significantly decreased (P<0.02), suggesting a posttranscriptional regulation. We hypothesize a potential role for 8-iso-PGF(2alpha) in the reduced trophoblast invasion in preeclampsia.

  15. Boar spermatozoa and prostaglandin F2alpha. Quality of boar sperm after the addition of prostaglandin F2alpha to the short-term extender over cooling time.

    PubMed

    Yeste, M; Briz, M; Pinart, E; Sancho, S; Garcia-Gil, N; Badia, E; Bassols, J; Pruneda, A; Bussalleu, E; Casas, I; Bonet, S

    2008-10-01

    Prostaglandin F2alpha (PGF2alpha) has been used to improve reproductive performance in swine. The goal of the present work was to determine how the addition of PGF2alpha affects boar sperm quality. Eleven different treatments were evaluated: eight with only PGF2alpha (0.625, 1.25, 2.50, 5, 10, 12.50, 25 and 50mg PGF2alpha/100ml) and three binary treatments (0.625mg PGF2alpha/100ml+200microg/ml hyaluronic acid (HA), 1.25mg PGF2alpha/100ml+200microg/ml HA, 0.625mg PGF2alpha/100ml+7.5microM caffeine (Caf)). All these substances were added to 16 ejaculates from 16 healthy and sexually mature boars (n=16), and each ejaculate was considered as a replicate. Our study also assessed the effects of these 11 treatments over different periods of preservation. Sperm quality was tested immediately after the addition of treatments (time 0), and after 1, 3, 6 and 10 days of cooling at 15 degrees C. To evaluate sperm quality, five parameters were analysed: (1) sperm viability, acrosome and mitochondrial sheath integrity (using a multiple fluorochrome-staining test), (2) sperm motility, (3) sperm morphology and (4) agglutination (using a computer assisted system) and (5) osmotic resistance (using the ORT). Parametric (analysis of variance for repeated measures) and non-parametric tests (Friedman test) were used as statistical analyses. Treatments with PGF2alpha concentrations higher than 12.5mg/100ml were cytotoxic while the others did not damage boar spermatozoa. Thus, the other treatments may be used to produce profitable effects without adverse effects. Moreover, the addition of PGF2alpha at 5mg/100ml to sperm diluted in BTS may maintain sperm viability and motility better after 6 days of cooling, because significant differences were observed (P<0.05) compared with control at the same time.

  16. 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.

  17. 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.

  18. Effects of prostaglandin-F2alpha on some reproductive parameters of fertile male rats.

    PubMed

    Saksena, S K; Lau, I F; Chang, M C

    1978-08-01

    Silastic-PVP-PGF2alpha tubes significantly reduced the sperm population in the epididymis and vas-deferens of male rats 14 days after their insertion into the scrotal sacs. A reduction in testis and epididymal weights was also evident. The reduction of sperm population was accompanied by a normal sexual drive and circulating testosterone level and partial sterility. The reduction in sperm population and induction of partial sterility was detected at least 7 days after the total release of prostaglandin F2alpha from the Silastic-PVP tubes. The results suggest that the changes in the reproductive parameters might be a consequence of endocrinological and functional disturbances induced by PGF2alpha and that PGs can be used to induce temporary sterility in the male.

  19. Decidual activation: abundance and localization of prostaglandin F2alpha receptor (FP) mRNA and protein and uterine activation proteins in human decidua at preterm birth and term birth.

    PubMed

    Makino, S; Zaragoza, D B; Mitchell, B F; Yonemoto, H; Olson, D M

    2007-01-01

    To study how the decidua contributes to parturition, we examined prostaglandin F(2alpha) concentrations as well as prostaglandin 15-hydroxy dehydrogenase, prostaglandin F(2alpha) receptor, matrix metalloproteinases 2 and 9, oxytocin receptor, prostaglandin-H synthase-2, and the prostaglandin E(2) receptor expression in human decidua. Decidual samples were isolated from placentas collected from patients at preterm not in labor (PTNIL), preterm labor (PTL), term not in labor (TNIL), and term labor (TL). For immunohistochemistry, fresh membranes which included chorion, amnion and decidua from term patients were collected. Prostaglandin F(2alpha) receptor mRNA was low in all preterm patients and then significantly increased towards term (p=0.049). Prostaglandin F(2alpha) receptor protein was identified in the amnion epithelium and mesoderm, chorion trophoblasts and decidua by immunohistochemistry, and levels were highest at TNIL (p=0.007) as measured by western blot. Prostaglandin F(2alpha) levels were higher at PTNIL than TNIL. Matrix metalloproteinases 2 and 9 protein and pro-enzyme activities were higher at TL than TNIL. There were no significant changes among the groups for any of the other factors measured. These results suggest that the induction of Prostaglandin F(2alpha) receptor at term may facilitate the decidua contribution to parturition, and its regulation and role should be examined further.

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

    PubMed Central

    Zannoni, Augusta; Bernardini, Chiara; Rada, Tommaso; Ribeiro, Luciana A; Forni, Monica; Bacci, Maria L

    2007-01-01

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

  1. Pyometra in bitches induces elevated plasma endotoxin and prostaglandin F2alpha metabolite levels.

    PubMed

    Hagman, R; Kindahl, H; Lagerstedt, A S

    2006-01-01

    Endotoxemia in bitches with pyometra can cause severe systemic effects directly or via the release of inflammatory mediators. Plasma endotoxin concentrations were measured in ten bitches suffering from pyometra with moderately to severely deteriorated general condition, and in nine bitches admitted to surgery for non-infectious reasons. Endotoxin samples were taken on five occasions before, during and after surgery. In addition, urine and uterine bacteriology was performed and hematological, blood biochemical parameters, prostaglandin F2alpha metabolite 15-ketodihydro-PGF2alpha (PG-metabolite), progesterone and oestradiol (E2-17beta) levels were analysed. The results confirm significantly increased plasma levels of endotoxin in bitches with pyometra and support previous reports of endotoxin involvement in the pathogenesis of the disease. Plasma concentrations of PG-metabolite were elevated in pyometra bitches and provide a good indicator of endotoxin release since the concentrations were significantly correlated to the endotoxin levels and many other hematological and chemistry parameters. The gamma-globulin serum protein electrophoresis fraction and analysis of PG-metabolite can be valuable in the diagnosis of endotoxin involvement if a reliable, rapid and cost-effective test for PG-metabolite analysis becomes readily available in the future. Treatment inhibiting prostaglandin biosynthesis and related compounds could be beneficial for bitches suffering from pyometra.

  2. Rapid induction of gene expression in the corpus luteum following in vivo treatment with prostaglandin F2 alpha

    USDA-ARS?s Scientific Manuscript database

    The pulsatile uterine secretion of prostaglandin F2 alpha (PGF) triggers the regression of the corpus luteum (CL). Research from many laboratories has identified the early intracellular signaling events initiated by PGF (for example, activation of phospholipases, increased intracellular calcium, an...

  3. 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.

  4. Repeated sauna therapy reduces urinary 8-epi-prostaglandin F(2alpha).

    PubMed

    Masuda, Akinori; Miyata, Masaaki; Kihara, Takashi; Minagoe, Shinichi; Tei, Chuwa

    2004-03-01

    We have reported that repeated sauna therapy improves impaired vascular endothelial function in a patient with coronary risk factors. We hypothesized that sauna therapy decreases urinary 8-epi-prostaglandin F(2alpha) (PGF(2alpha)) levels as a marker of oxidative stress and conducted a randomized, controlled study. Twenty-eight patients with at least one coronary risk factor were divided into a sauna group (n = 14) and non-sauna group (n = 14). Sauna therapy was performed with a 60 degrees C far infrared-ray dry sauna for 15 minutes and then bed rest with a blanket for 30 minutes once a day for two weeks. Systolic blood pressure and increased urinary 8-epi-PGF(2alpha) levels in the sauna group were significantly lower than those in the non-sauna group at two weeks after admission (110 +/- 15 mmHg vs 122 +/- 13 mmHg, P < 0.05, 230 +/- 67 pg/mg x creatinine vs 380 +/- 101 pg/mg x creatinine, P < 0.0001, respectively). These results suggest that repeated sauna therapy may protect against oxidative stress, which leads to the prevention of atherosclerosis.

  5. Transpulmonary prostaglandin F2 alpha metabolism in sheep: an in vivo model.

    PubMed

    Kong, D L; Peterson, M B; Watkins, W D

    1989-12-01

    We investigated transpulmonary enzymatic conversion of prostaglandin F2 alpha (PGF) to the 13,14-dihydro-15-keto metabolite (PGFM) in normal and acutely lung injured sheep. PGF was infused directly into the right ventricle. Sequential, simultaneous blood samples were drawn from the pulmonary artery (PA) and aorta (A). PGF and PGFM plasma concentrations were quantitated by double antibody radioimmunoassay (RIA). The pulmonary conversion rate of PGF in normal lung was established over a wide range of concentrations in intubated, normoxic, and hemodynamically stable sheep. Both zero and first order kinetics were present. PGF had no physiological effects on either pulmonary or systemic hemodynamics at any infusion rate studied. Acute lung injury was produced by intravenous injections of oleic acid into the PA until the resting mean pulmonary artery pressure doubled. Infusions were then repeated and fractional metabolism of PGF across the lung was assessed. PGF, at infusion rates of 2 micrograms/kg/min and 8 micrograms/kg/min, was metabolized greater than 70% respectively. Thus, there was no difference between control or experimental groups in PGF conversion. We conclude that the in vivo sheep lung has an extensive substrate-dependent capacity to metabolize PGF and this mechanism is resistant to severe acute oleic acid lung injury.

  6. Activin A, corticotropin-releasing factor and prostaglandin F2 alpha increase immunoreactive oxytocin release from cultured human placental cells.

    PubMed

    Florio, P; Lombardo, M; Gallo, R; Di Carlo, C; Sutton, S; Genazzani, A R; Petraglia, F

    1996-01-01

    The aim of the present study was to investigate the presence of the immunoreactive oxytocin in human placental extracts and putative factors regulating the release of immunoreactive oxytocin from cultured human placental cells. Fresh placental tissue was collected from pregnant women at term and dissected of membranes (n = 5). Presence of immunoreactive oxytocin in trophoblast tissue was evaluated by a specific radio-immunoassay after acidic extraction and high-pressure liquid chromatography. In a second set of experiments, primary cultures of placental cells were performed and, 48-72 h after dissociation, the effect of arginine vasopressin, corticotropin-releasing factor, neuropeptide Y, activin A, inhibin A, noradrenaline or prostaglandins on immunoreactive oxytocin level in culture medium was investigated. The presence of immunoreactive oxytocin was shown in the acidic extract of trophoblast at term, and in the culture medium of human placental cells, and it was identical to the native peptide. The addition of corticotropin-releasing factor or arginine vasopressin, but not of neuropeptide Y, increased the release of immunoreactive oxytocin three- to fourfold from placental cells, with a dose-dependent effect (P < 0.01). A significantly increased release of immunoreactive oxytocin was shown in presence of noradrenaline (P < 0.01), which was reversed by prazosin, an antagonist of alpha-adrenergic receptors. Recombinant human activin A (P < 0.01), but not inhibin A, stimulated the release of immunoreactive oxytocin three- to fourfold from placental cells. Prostaglandin F2 alpha was a potent secretagogue of immunoreactive oxytocin, whereas a partial or no effect was observed when prostaglandin E2 or prostaglandin I2 was added. Thus, the present findings showed that human placenta contains immunoreactive oxytocin, and that its release from cultured placental cells is regulated by neurohormones, growth factors or prostaglandins.

  7. Prostaglandin F2alpha receptors in bovine corpus luteum cell membranes. Effect of enzymes and protein reagents.

    PubMed

    Rao, C V

    1976-06-04

    Various enzymes and protein reagents inhibited [3H]prostaglandin F2alpha binding to bovine corpus luteum cell membranes. Studies were undertaken (a) to explore further on the dose response relationships with the above agents, (b) to investigate the mechanism of inhibition of binding with respect to receptor affinities and number and (c) to assess whether decreased binding reflected changes in receptors and/or other membrane components. Preincubation of membranes with phospholipase A, trypsin, pronase, lipase, tetranitromethane, dinitrofluorobenzene, acetic anhydride and N-ethylmaleimide resulted in moderate to drastic inhibitions of [3H]prostaglandin F2alpha binding. The dose-dependent inhibition of binding by enzymes, but not by protein reagents (except for N-ethylmaleimide), exhibited a biphasic pattern: at lower concentrations, the loss of binding was low and relatively plateaued, but at higher concentrations, the losses were dramatic. The drastic reduction in binding by trypsin was due to destruction rather than solubilization of receptors from membranes. Phospholipase A was intrinsically more effective than phospholipases C and Ca2+ was not required for its inhibition of [3H]prostaglandin F2alpha binding. Protein reagents inhibition of binding was differently influenced by added Ca2+ i.e., loss of binding increased with some (N-ethylmaleimide), decreased with others (tetranitromethane, dinitrofluorobenzene and azobenzene sulfenylbromide). These results are interpreted to indicate that Ca2+ induced conformational changes in membranes which may result in exposure of new groups and burying of already exposed modifiable groups. Treatment of membranes with trypsin and N-ethylmaleimide selectively abolished high affinity prostaglandin F2alpha receptors. The low affinity receptors were present but their numbers as well as their affinity were decreased. Lipase, phospholipase A, acetic anhydride, dinitrofluorobenzene and tetranitromethane appear to decrease binding by

  8. Bovine somatotropin attenuates phorbol ester-induced prostaglandin F2alpha production in bovine endometrial cells.

    PubMed

    Badinga, L; Guzeloglu, A; Thatcher, W W

    2002-03-01

    The recent observation that bovine somatotropin (bST) treatment at a timed insemination improves pregnancy rates in lactating dairy cows raises the possibility that growth hormone (GH) may modulate the endocrine and biochemical cross talk between the conceptus and maternal uterus at the time of pregnancy establishment in cattle. The objective of this study was to characterize the cellular and molecular mechanisms by which exogenous GH affects phorbol ester-induced prostaglandin F2alpha (PGF2alpha) production in cultured bovine endometrial (BEND) cells. Serum-deprived BEND cells were incubated with or without recombinant bovine GH (rbGH), insulin-like growth factor (IGF)-I, recombinant bovine interferon (rbIFN)-tau or a combination of rbGH + rbIFN-tau for 3 h and then treated with phorbol 12,13-dibutyrate (PDBu) for an additional 6 h. Exogenous PDBu increased PGF2alpha secretion and steady-state levels of COX-2 mRNA within 3 h. Priming of BEND cells with rbGH reduced PGF2alpha response to PDBu, whereas cotreatment with IGF-I amplified PDBu induction of PGF2alpha. Preincubation of cell monolayers with rbIFN-tau suppressed PGF2alpha and COX-2 mRNA responses to PDBu. Inhibitory effects of rbGH and rbIFN-tau on PDBu-induced PGF2alpha production were additive. Results provide the first direct evidence that supplemental bST may interact with conceptus-secreted IFN-tau to modulate PGF2alpha secretion at the critical time of maternal recognition of pregnancy.

  9. A novel angiogenic role for prostaglandin F2alpha-FP receptor interaction in human endometrial adenocarcinomas.

    PubMed

    Sales, Kurt J; List, Tammy; Boddy, Sheila C; Williams, Alistair R W; Anderson, Richard A; Naor, Zvi; Jabbour, Henry N

    2005-09-01

    Prostaglandins have been implicated in several neovascular diseases. In the present study, we found elevated FP receptor and vascular endothelial growth factor (VEGF) expression colocalized in glandular epithelial and vascular cells lining the blood vessels in endometrial adenocarcinomas. We investigated the signaling pathways activated by the FP receptor and their role in modulating VEGF expression in endometrial adenocarcinoma (Ishikawa) cells. Ishikawa cells were stably transfected with FP receptor cDNA in the sense or antisense orientations. Treatment of Ishikawa cells with prostaglandin F2alpha (PGF2alpha) rapidly induced transphosphorylation of the epidermal growth factor receptor (EGFR) and phosphorylation of extracellular signal-regulated kinase (ERK) 1/2 via the FP receptor. Activation of EGFR-Ras-mitogen-activated protein kinase/ERK kinase (MEK) signaling via the FP receptor resulted in an increase in VEGF promoter activity, expression of VEGF mRNA, and secretion of VEGF protein. These effects of PGF2alpha on the FP receptor could be abolished by treatment of cells with a specific FP receptor antagonist, chemical inhibitors of c-Src, matrix metalloproteinase, and EGFR kinase or by inactivation of signaling with dominant-negative mutant isoforms of EGFR, Ras, or MEK or with small inhibitory RNA oligonucleotides targeted against the EGFR. Finally, we confirmed that PGF2alpha could potentiate angiogenesis in endometrial adenocarcinoma explants by transactivation of the EGFR and induction of VEGF mRNA expression.

  10. Cardiorespiratory collapse and pulmonary oedema due to intravascular absorption of prostaglandin F2 alpha administered extraamniotically for midtrimester termination of pregnancy.

    PubMed

    Wein, P; Robertson, B; Ratten, G J

    1989-08-01

    A case of severe reaction to extraamniotically administered prostaglandin F2 alpha, with cardiorespiratory collapse and pulmonary oedema necessitating transfer to an intensive care unit, is presented. Attention is drawn to the profound haemodynamic effects of systemically administered prostaglandin, and the need for caution and ready availability of facilities for resuscitation when this potent substance is administered. Treatment for the effects of intravascular absorption of prostaglandin F2 alpha is discussed.

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

    PubMed Central

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

    1991-01-01

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

  12. Retrospective case study of fetal mummification in cows that did not respond to prostaglandin F2alpha treatment.

    PubMed

    Lefebvre, Réjean C; Saint-Hilaire, Emilie; Morin, Isabelle; Couto, Gabriel B; Francoz, David; Babkine, Marie

    2009-01-01

    Mummification of bovine fetuses is an uncommon condition, and cows do not always respond to treatment with prostaglandin F2alpha. The objective of the present retrospective and descriptive case study was to determine the conception rate and survival time of nonresponsive, prostaglandin F2alpha (PGF2alpha)-treated cows (n = 14), following hysterotomy or medical treatment and manual removal. Animal records from 1990 to 2005 from the Centre Hospitalier Universitaire Vétérinaire (CHUV) of the Université de Montréal were studied. Inclusion criteria were the nonexpulsion of the mummified fetus following PF2alpha treatment and absence of concomitant conditions upon physical examination. Of the animals included in the study, 36% (n = 5) became pregnant after extraction of the mummified fetus by hysterotomy and 0% conceived after medical treatment and manual extraction. In this study, hysterotomy represented an effective approach for extracting mummified fetuses from cows that did not respond to PF2alpha treatment.

  13. Prostaglandins E2 and F2 alpha increase fructose 2,6-bisphosphate levels in isolated hepatocytes.

    PubMed Central

    Gómez-Foix, A M; Rodríguez-Gil, J E; Guinovart, J J; Bosch, F

    1991-01-01

    In hepatocytes isolated from fed rats, prostaglandin E2 (PGE2) and prostaglandin F2 alpha (PGF2 alpha) increased, in a time- and dose-dependent manner, fructose 2,6-bisphosphate [Fru(2,6)P2] levels and stimulated the glycolytic flux. The rise in Fru(2,6)P2 was related to an increase in glucose 6-phosphate levels which resulted from the stimulation of glycogenolysis. In cells obtained from 24 h-starved rats, no effects of either PGE2 or PGF2 alpha could be observed. In addition, when the stimulation of glycogenolysis was abolished by incubation of fed-rat hepatocytes in a Ca2(+)-depleted medium, Fru(2,6)P2 levels did not increase. Furthermore, no effects of PGs on 6-phosphofructo-2-kinase activity could be observed. These results indicate that PGE2 and PGF2 alpha show similar actions to Ca2(+)-dependent hormones on hepatic glucose metabolism. PMID:2001249

  14. The effect of inhibition of prostaglandin F2 alpha synthesis on placental expulsion in the ewe.

    PubMed Central

    Chassagne, M; Barnouin, J

    1993-01-01

    Five ewes were injected with two doses of a nonsteroidal anti-inflammatory drug (NSAI), lysine acetyl salicylate, at birth of their first lamb and one hour later, and five others were injected once only, at birth of their first lamb. A control group of six animals was constituted. The times needed for fetal expulsion and placental release were recorded. The peripheral plasma PgF2 alpha (as PGFM) levels were measured prepartum during the seven last days of gestation, at parturition, then 1 h, 2 h and 12 h after lambing. The results were compared among and within treatment groups. They indicate that the physiological increase in peripheral PGFM levels starts two days before lambing and that the level peaks at lambing. The normal decrease after parturition is emphasized by NSAI injections as detected 1 h and 2 h posttreatment (p < 0.01). The NSAI drug is short-acting as revealed by the lower PGFM levels in twice-treated animals 2 h after birth compared to once treated animals and the similar low levels in all three groups 12 h after birth. The fetal membranes were expelled normally in all treated and nontreated animals, but the time needed for placental expulsion in ewes injected with two doses of NSAI was longer than in controls (p < 0.05). A negative correlation (p < 0.05) was found between plasma PGFM levels measured two hours after lambing and the time needed for fetal membrane expulsion. PgF2 alpha appears to have a role in placental release in the ewe. PMID:8490813

  15. Effect of flunixin meglumine on prostaglandin F2 alpha synthesis and metabolism in the pig.

    PubMed

    Odensvik, K; Cort, N; Basu, S; Kindahl, H

    1989-09-01

    The effect of flunixin meglumine on prostaglandin synthesis and metabolism was evaluated in the pig in vivo. It was found that the prostaglandin metabolite, 15-ketodihydro-PGF2 alpha, was decreased in the peripheral circulation within 20 min of injection of the drug. In therapeutic doses in the pig the drug had no effect on the metabolism of PGF2 alpha. Flunixin was compared with some other non-steroidal anti-inflammatory drugs in an in vitro test system utilizing sheep vesicular gland microsomes. It was concluded that this drug is a potent inhibitor of prostaglandin synthesis.

  16. [Maturation of the cervix uteri using prostaglandin F2 alpha before induction of labor in pathologic pregnancies].

    PubMed

    Maria, B; Fayette, E; Stampf, F; Gandon, C; Gantrel, J; Barrat, J

    1983-01-01

    It is possible to induce labour in pathological pregnancies after artificial ripening of the cervix. The present study concerns 70 patients (45 primipara, 25 multipara). The main pathologies are hypertension of pregnancy and pregnancies past dates. Prostaglandin F2 alpha has been used with a Tylose gel containing 5 mg of PGF2 alpha introduced by the extra-amniotic route. The cervical change was noted using Bishop's score. The mean increase of the cervical score was 0.8 with the first PGF2 alpha gel. The total mean increase was 1.2. Two cases of hyperstimulation of the uterus were observed and they led to Caesarean section. Prostaglandin gel induced labour in 56% of the patients. The mean time between the introduction of the gel and the delivery was 14 h for primipara and 10 h for multipara. Other patients were induced with oxytocin on the following day. Epidural analgesia was widely used in this study (in 64% of cases). The mean duration of labour was 6 h 10 for primipara and 4 h 30 for multipara. 30% of the patients needed Caesarean section but there was a marked difference between primipara (36%) and multipara (4%). After a review of the literature the authors conclude that it is useful to ripen the cervix prostaglandin but, as foreign authors do, they think that PGE2 should be more efficient.

  17. Participation of intraluteal progesterone and prostaglandin F2 alpha in LH-induced luteolysis in pregnant rat.

    PubMed

    Stocco, C O; Deis, R P

    1998-02-01

    We examined the participation of the intraluteal levels of progesterone (P4) and prostaglandin F2 alpha (PGF2 alpha) in the induction of luteolysis by LH and its relationship with the induction of the 20 alpha-hydroxysteroid dehydrogenase activity (20 alpha-HSD). Subcutaneous administration of four doses of 10 microgram ovine LH (oLH) at 0800, 0900, 1000 and 1100 h on day 19 of pregnancy induced a decrease in the activity of the enzyme 3 beta-HSD 24 and 48 h after treatment and an increase in luteal 20 alpha-HSD activity 48 h after oLH treatment when compared with control rats. Intraluteal and serum P4 levels were lower than control values 24 and 48 h after oLH treatment, with a significant increase in luteal PGF2 alpha content and a decrease in corpus luteum (CL) weight 48 h after oLH treatment. Intrabursal ovarian (i.b.) treatment with an inhibitor of PG's biosynthesis (diclofenac) (70 microgram/ovary) or P4 (3 microgram/ovary) on day 20 of pregnancy, prevented the increase in 20 alpha-HSD activity observed 48 h after oLH treatment, without any effect on 3 beta-HSD activity. The i.b. administration of P4 prevented the increase in intraluteal PGF2 alpha content induced by oLH treatment and the increases in 20 alpha-HSD activity and intraluteal PGF2 alpha content observed in control animals on day 21 of pregnancy. The inhibition of PG biosynthesis also prevents the decrease in intraluteal and serum P4 level induced by oLH. These results provide good evidence of the important participation of intraluteal P4 and PGF2 alpha on the oLH-induced luteolysis in pregnant rats. We also found the P4 produced by the CL is involved, in part, in the regulation of luteal PG synthesis. Thus, the early decline in 3 beta-HSD activity and the consequent fall in intraluteal P4 content, may trigger the synthesis of PGs and thereafter the increase in luteal 20 alpha-HSD activity to establish luteolysis.

  18. Loss of prostaglandin F2alpha, but not thromboxane, responsiveness in pregnant human myometrium during labour.

    PubMed

    Fischer, Deborah P; Hutchinson, Jonathon A; Farrar, Diane; O'Donovan, Peter J; Woodward, David F; Marshall, Kay M

    2008-04-01

    Prostaglandins (PG) E2, PGF2alpha and thromboxane (TX) mediate uterine contractility by targeting prostonoid EP, FP and TP receptors respectively. The aim of this study was to elucidate the function of these receptors in isolated human myometrium taken at term gestation prior to and following labour onset. Lower segment myometrial strips were immersed in organ baths in oxygenated Krebs' solution at 37 degrees C and connected to isometric force transducers. After equilibration, spontaneous activity and concentration responses to PGE2, PGF2alpha and U46619 (a stable TX mimetic) were measured as area under the curve and expressed as a percentage of the final contraction induced by hypotonic shock. Results were expressed as arithmetic means+/-s.e.m. and analysed using two-way ANOVA with Bonferroni's post hoc test. Myometrium excised at late gestation displayed the greatest spontaneous activity compared with the tissues taken during labour (P<0.001). Excitation evoked by PGF2alpha (P<0.01) and PGE2 at 10(-5) mol/l were attenuated after labour onset. U46619 consistently stimulated concentration-dependent contractions (P<0.001) and selective antagonists confirmed TP-mediated effects. The maintained responses to TX indicate crucial roles for TP receptors in the muscular tonus of the parturient uterus. This receptor and its secondary messenger system represent effective myometrial targets for tocolytic agents in both pregnancy and labour-associated disorders.

  19. Transcriptomic and bioinformatics analysis of the early time-course of the response to prostaglandin F2 alpha in the bovine corpus luteum

    USDA-ARS?s Scientific Manuscript database

    RNA expression analysis was performed on the corpus luteum tissue at five time points after prostaglandin F2 alpha treatment of midcycle cows using an Affymetrix Bovine Gene v1 Array. The normalized linear microarray data was uploaded to the NCBI GEO repository (GSE94069). Subsequent statistical ana...

  20. [Induced abortion using prostaglandin E2 and F2alpha gel].

    PubMed

    Lippert, T H; Modly, T

    1974-01-01

    In this study of 20 patients in the 13th-17th week of pregnancy abortion was induced with intrauterine, extraamniotic application of prostaglandins (PG) E2 or F2 in gel form. The gel composition was as follows: 4% tylose MH 300, 2% glycerine, 1% chlorhexidine digluconate, 83% sterile distilled water and 10% PG stock solution. Both PGE2 and PGF2 gels were used. Final concentration was 2.5 mg E2 or 2.5 mg F2 per g of gel. Gel was applied via transcervical, extraamniotic polyethylene catheter every 2-3 hours. Results: PGE2-gel was used in 14 cases. After 3-4 applications both fetus and placenta were expelled. Average dose used was 4.6 mg E2/patient. First contractions started in 30 minutes; induction to expulsion time was 11 hours 35 minutes. F2-gel given to 6 patients resulted in expulsion of the fetus in all cases but placenta needed removal by curettage in 4 patients. Average dose per patient was 17.7 mg of F2; first contractions in 30 minutes, average expulsion time 17 hours 38 minutes. With both PGs there were painful contractions which were controlled with a combination of pentazocine and Valium. PGE2 caused vomiting in 5 patients. No increased bleeding or postabortion infection occurred. Follow-up curettage was done in all patients to ensure removal of all tissues. Overall evaluation of the PG-gels was considered good. PG stability in gel form is good; during 8 months of preservation in sterile aluminum tubes at -25 degrees Celsius no decline in clinical effectiveness was noted. The gel application is less expensive than the slow-injection pump method.

  1. Testosterone induction of prostaglandin-endoperoxide synthase 2 expression and prostaglandin F(2alpha) production in hamster Leydig cells.

    PubMed

    Matzkin, María E; Gonzalez-Calvar, Silvia I; Mayerhofer, Artur; Calandra, Ricardo S; Frungieri, Mónica B

    2009-07-01

    We have previously observed expression of prostaglandin-endoperoxide synthase 2 (PTGS2), the key enzyme in the biosynthesis of prostaglandins (PGs), in reproductively active Syrian hamster Leydig cells, and reported an inhibitory role of PGF(2alpha) on hamster testicular steroidogenesis. In this study, we further investigated PTGS2 expression in hamster Leydig cells during sexual development and photoperiodic gonadal regression. Since PTGS2 is mostly expressed in pubertal and reproductively active adult hamsters with high circulating levels of LH and androgens, we studied the role of these hormones in the regulation/maintenance of testicular PTGS2/PGF(2alpha). In active hamster Leydig cells, LH/hCG and testosterone induced PTGS2 and PGF(2alpha) production, and their actions were abolished by the antiandrogen bicalutamide (Bi). These results indicate that LH does not exert a direct effect on PG synthesis. Testosterone also stimulated phosphorylation of the mitogen-activated protein kinase isoforms 3/1 (MAPK3/1) within minutes and hours, but the testosterone metabolite dihydrotestosterone had no effect on PTGS2 and MAPK3/1. Because Bi and U0126, an inhibitor of the MAP kinase kinases 1 and 2 (MAP2K1/2), abolished testosterone actions on MAPK3/1 and PTGS2, our studies suggest that testosterone directly induces PTGS2/PGF(2alpha) in hamster Leydig cells via androgen receptors and a non-classical mechanism that involves MAPK3/1 activation. Since PGF(2alpha) inhibits testosterone production, it might imply the existence of a regulatory loop that is setting a brake on steroidogenesis. Thus, the androgen environment might be crucial for the regulation of testicular PG production at least during sexual development and photoperiodic variations in hamsters.

  2. Improved quantification of 8-epi-prostaglandin F2 alpha and F2-isoprostanes by gas chromatography/triple-stage quadrupole mass spectrometry: partial cyclooxygenase-dependent formation of 8-epi-prostaglandin F2 alpha in humans.

    PubMed

    Schweer, H; Watzer, B; Seyberth, H W; Nüsing, R M

    1997-12-01

    F2-isoprostanes are considered to be novel markers of lipid peroxidation. To study the in vivo formation of F2-isoprostanes, an improved method was developed for isotope dilution assays involving gas chromatography/triple-stage quadrupole mass spectrometry (GC/MS/MS) including thin-layer chromatography (TLC) (sum of all F2-isoprostanes) and high-performance liquid chromatographic (HPLC) purification (prostaglandin F2 alpha (PGF2 alpha) and 8-epi-PGF2 alpha). Following the addition of isotopically labeled prostaglandins to urine, the sample was acidified and applied to a C18 cartridge. After elution, prostaglandins were derivatized to pentafluorobenzyl esters and subjected to TLC. A broad zone was scratched off, isoprostanes were eluted and after formation of their trimethylsilyl ether derivatives the sum of F2-isoprostanes was determined by GC/MS/MS. For the determination of PGE2 alpha and 8-epi-PGF2 alpha prior to trimethylsilylation an additional HPLC step was performed and the fractions containing PGF2 alpha and 8-epi-PGF2 alpha were analyzed by GC/MS/MS. Using this technique, 8-epi-PGF2 alpha concentrations in urine samples as low as 5 pg ml-1 could be determined with high accuracy. The excretion rates of isoprostanes were studied in comparison with the classical prostaglandins in three different groups: healthy adults, healthy children and children with hyper-PGE syndrome (HPS), a pathological situation associated with a stimulated PGE2 synthesis. F2-isoprostanes represented the main arachidonic acid metabolites in these groups and 8-epi-PGF2 alpha excretion was comparable in its amount to the classical prostanoids. To delineate the cyclooxygenase-catalyzed contribution, the influence of indomethacin, an inhibitor of cyclooxygenases, on F2-isoprostane formation in healthy adults and in HPS children was analyzed. Significantly decreased excretion rates were observed 2 days after indomethacin administration for all prostanoids, including F2-isoprostanes and 8

  3. Effects of progesterone and estradiol-17 beta on uterine secretion of prostaglandin F2 alpha in response to oxytocin in ovariectomized ewes.

    PubMed

    Homanics, G E; Silvia, W J

    1988-05-01

    Twenty ovariectomized ewes were used in an experiment designed to examine the interaction of progesterone, estradiol, and oxytocin in the regulation of uterine secretion of prostaglandin F2 alpha (PGF2 alpha). All ewes underwent a steroid pretreatment that mimicked the changes in progesterone and estradiol which occur during the six days immediately prior to estrus. After pretreatment, ewes were randomly assigned to 1 of 4 treatment groups: 1) control (n = 4); 2) estradiol-17 beta (n = 6); 3) progesterone (n = 4); and 4) progesterone and estradiol-17 beta (n = 6). Progesterone was injected twice daily for 15 days. The dose of progesterone varied with day postestrus in a manner designed to simulate endogenous luteal secretion of progesterone. Estradiol-17 beta was administered in s.c. Silastic implants. The implants maintained circulating concentrations of estradiol at 3 pg/ml. On Days 5, 10, and 15 of treatment, ewes were injected with oxytocin (10 IU in 1.0 ml saline, i.v.). Jugular venous blood samples were collected beginning one-half hour prior to and continuing for 2 hours post-oxytocin injection for quantification of 13,14-dihydro-15-keto-prostaglandin F2 alpha (PGFM). No changes in concentration of PGFM following injection of oxytocin were observed on Day 5 or 10 in any treatment group. Concentrations of PGFM increased following injection of oxytocin on Day 15 only in groups receiving progesterone. Both the area under the PGFM response curve (p = 0.08) and peak response (p = 0.06) were greater in ewes treated with progesterone and estradiol-17 beta than in those receiving progesterone alone.(ABSTRACT TRUNCATED AT 250 WORDS)

  4. Arachidonic acid release and prostaglandin F(2alpha) formation induced by anandamide and capsaicin in PC12 cells.

    PubMed

    Someya, Akiyoshi; Horie, Syunji; Murayama, Toshihiko

    2002-08-23

    Anandamide, an endogenous agonist of cannabinoid receptors, activates various signal transduction pathways. Anandamide also activates vanilloid VR(1) receptor, which was a nonselective cation channel with high Ca(2+) permeability and had sensitivity to capsaicin, a pungent principle in hot pepper. The effects of anandamide and capsaicin on arachidonic acid metabolism in neuronal cells have not been well established. We examined the effects of anandamide and capsaicin on arachidonic acid release in rat pheochromocytoma PC12 cells. Both agents stimulated [3H]arachidonic acid release in a concentration-dependent manner from the prelabeled PC12 cells even in the absence of extracellular CaCl(2). The effect of anandamide was neither mimicked by an agonist nor inhibited by an antagonist for cannabinoid receptors. The effects of anandamide and capsaicin were inhibited by phospholipase A(2) inhibitors, but not by an antagonist for vanilloid VR(1) receptor. In PC12 cells preincubated with anandamide or capsaicin, [3H]arachidonic acid release was marked and both agents were no more effective. Co-addition of anandamide or capsaicin synergistically enhanced [3H]arachidonic acid release by mastoparan in the absence of CaCl(2). Anandamide stimulated prostaglandin F(2alpha) formation. These findings suggest that anandamide and capsaicin stimulated arachidonic acid metabolism in cannabinoid receptors- and vanilloid VR(1) receptor-independent manner in PC12 cells. The possible mechanisms are also discussed.

  5. Prostaglandin F2 alpha administered in vivo induces Ca2+-dependent protein phosphorylation in rat luteal tissue

    SciTech Connect

    Baum, M.S.

    1989-01-01

    The present study was performed in order to further elucidate the mechanism of action of PGF2 alpha in luteolysis in the rat ovary. Seven days after priming with superovulatory doses of pregnant mare serum gonadotropin and human chorionic gonadotropin to induce luteal tissue formation, the rats were injected with a luteolytic dose of the prostaglandin F2 alpha analogue cloprostenol. The ovaries were then homogenized, a 30,000 x g supernatant and pellet were prepared, whereafter aliquots of the preparations were incubated in the presence of (gamma-/sup 32/P)ATP with or without Ca2+. The phosphorylated proteins were separated by sodium dodecyl sulfate polyacrylamide gel electrophoresis and localized by autoradiography. The presence of Ca2+ caused an increased phosphorylation of a 45 kDa protein band in the particulate, but not in the cytosol, fraction. Furthermore, PGF2 alpha rapidly increased the /sup 32/P incorporation into the same protein band of 45 kDa. Thus, the PGF2 alpha-stimulated /sup 32/P incorporation was Ca2+-dependent and seen only in the particulate fraction. These results suggest that PGF2 alpha in its role as a luteolytic agent stimulates a Ca2+-dependent phosphorylation of a specific protein in luteal membranes of the rat ovary.

  6. Reproducibility of dorsal hand vein responses to phenylephrine and prostaglandin F2 alpha using the dorsal hand vein compliance method.

    PubMed

    Schindler, C; Grossmann, M; Dobrev, D; Francke, K; Ravens, U; Kirch, W

    2003-03-01

    Assessment of drug-induced venodilation by the dorsal hand vein compliance method requires stable constriction of the vein. This study was designed to investigate intra- and intersubject reproducibility of the venous preconstriction technique in response to phenylephrine and prostaglandin F2 alpha and to determine the influence of basal vein size. Twelve healthy male nonsmokers participated in a prospective cross-over study. Inter- and intrasubject variability was tested in response to phenylephrine and PGF2 alpha on different study days in the same hand vein. The dose of the respective constrictor causing approximately 80% constriction of the vein (ED80) was determined and infused for another 100 minutes. Actual vein size was measured every 5 minutes. Coefficient of variation and regression analyses were performed to analyze influence of vessel size on ED80 of the respective constrictor. Adjusted constriction levels were stable and well reproducible in all subjects. The intersubject coefficient of variation of ED80 ranged from 0.9% to 6.7% for phenylephrine and from 0.9% to 6.9% for PGF2 alpha. Whereas responses to phenylephrine were independent of basal vein diameter, there was a positive correlation between ED80 of PGF2 alpha and basal vein size. Thus, the hand vein compliance method is a suitable method to study dilatory responses in phenylephrine- or PGF2 alpha-constricted veins with considerable interindividual but small intraindividual variability. However, in such studies, phenylephrine appears to be a more reliable tool than PGF2 alpha.

  7. Oxytocin- and aluminium fluoride-induced phospholipase C activity and prostaglandin F2 alpha secretion during the ovine luteolytic period.

    PubMed

    Graf, G A; Burns, P D; Silvia, W J

    1998-03-01

    A series of studies was conducted to characterize changes in components of the cell signalling cascade that mediates oxytocin-induced prostaglandin F2 alpha (PGF2 alpha) synthesis at the onset of luteolysis in sheep. In the first experiment, caruncular tissue was dissected from 20 ewes on days 12-15 of the oestrous cycle, and incubated for the measurement of phospholipase C (PLC) activity or secretion of PGF2 alpha. Activation of GTP-binding proteins with aluminium fluoride stimulated both inositol phosphate accumulation and PGF2 alpha secretion on all days examined. However, oxytocin did not stimulate PLC activity or PGF2 alpha accumulation until day 13. While the ability of oxytocin to stimulate PLC activity increased after day 13, oxytocin-induced PGF2 alpha secretion declined slightly from day 13 to 15, suggesting that cell signalling components downstream from PLC modulate the response to oxytocin after day 13. Oxytocin failed to stimulate PGF2 alpha synthesis on day 14 after oestrus. Secretion of endogenous luteal oxytocin may have rendered uterine tissues collected on day 14 refractory to oxytocin in vitro. Therefore, a second study was conducted in ovariectomized, steroid replaced ewes. Ovarian steroids were administered to mimic endogenous changes in progesterone and oestradiol. The temporal patterns of PGF2 alpha synthesis in response to oxytocin and pharmacological agents were similar to uterine tissues from cyclic ewes in the first experiment; however, the magnitude of the response was less. These data suggest that oxytocin receptors are absent or are not coupled to PLC until day 13 after oestrus.

  8. Cellular mechanisms by which oxytocin mediates uterine prostaglandin F2 alpha synthesis in bovine endometrium: role of calcium.

    PubMed

    Burns, P D; Hayes, S H; Silvia, W J

    1998-11-01

    The objective of these experiments was to determine the role of Ca2+ during oxytocin-stimulated prostaglandin (PG) F2 alpha release from bovine endometrial tissue in vitro. Uteri were collected from dairy cows on the day after spontaneous luteal regression. Caruncular endometrial explants were dissected and incubated in vitro to determine phospholipase C activity or PGF2 alpha release. A23,187 (a calcium ionophore) and maitotoxin (an activator of voltage-gated L-type calcium channels) stimulated release of PGF 2 alpha in a concentration-dependent manner (P < 0.05). Thapsigargin (induces accumulation of Ca2+ in the cytoplasm by inhibiting endoplasmic reticulum Ca2+/ATPase pumps) stimulated release of PGF2 alpha in a concentration-dependent manner as well (P < 0.13). Oxytocin (10(-6) M), AIF4- (a nonspecific activator of G-proteins; 10(-5) M), A23,187 (10(-5) M), and melittin (a stimulator of phospholipase A2; 10(-4) M) stimulated PGF2 alpha release when explants were incubated in Ca(2+)-free medium (P < 0.10); however, oxytocin, A23,187, or melittin were unable to stimulate PGF2 alpha release when explants were incubated in Ca(2+)-free medium containing the calcium chelator EGTA (P < 0.10). This treatment did not prevent oxytocin or AIF4- from stimulating phospholipase C activity (P < 0.08). CoCl2 (a nonspecific Ca2+ channel blocker) and methoxyverapamil (a specific voltage-gated L-type Ca2+ channel blocker) prevented oxytocin from stimulating PGF2 alpha release (P < 0.05). Our results suggest that both extracellular and intracellular Ca2+ may be required for oxytocin to stimulate PGF2 alpha secretion in bovine endometrial tissue.

  9. Effects of progesterone withdrawal on uterine secretion of prostaglandin F2 alpha in response to oxytocin in ewes.

    PubMed

    Kaminski, M A; Hayes, S H; Silvia, W J

    1997-01-01

    Two experiments were conducted to determine if withdrawal of progesterone during the luteal phase of the oestrous cycle affected the ability of the ovine uterus to secrete prostaglandin F2 alpha (PGF2 alpha) in response to oxytocin. In Experiment 1, 18 ewes were ovariectomized on Day 9 and Day 12 after oestrus. Ewes were subdivided into three treatment groups (n = 6 per group): Group-1 ewes underwent sham surgery; Group-2 ewes received oestradiol (OVX + O); and Group-3 ewes received oestradiol + progesterone (OVX + O,P). Oxytocin was administered to each ewe on Days 10, 13 and 15 after oestrus. Concentrations of 13, 14-dihydro-15-keto-PGF2 alpha (PGFM) were determined in samples of jugular venous blood for 2 h after oxytocin challenge. The magnitude of the PGFM response 24 h after ovariectomy was greater (P < 0.1) in ewes from which progesterone had been withdrawn (OVX + O) than in ewes in which progesterone was maintained (intact controls and OVX + O,P). Therefore, progesterone appears to exert an inhibitory effect on uterine secretory responsiveness to oxytocin which is removed by progesterone withdrawal. In Experiment 2, ewes were ovariectomized on Day 11 and assigned to 1 of 4 treatment groups (n = 6 per group): Group 1, no steroid replacement (OVX); Group 2, oestradiol replacement (OVX + O); Group 3, progesterone replacement (OVX + P); or Group 4, progesterone + oestradiol replacement (OVX + O,P). Ewes received oxytocin on Day 12 and Day 15. On Day 12, uterine secretory responsiveness to oxytocin was greatest in ewes in the OVX + O group (P < 0.1). Responsiveness was low in ewes in the OVX group, as it was in ewes in both groups that received progesterone replacement. Therefore, the increase in uterine secretory responsiveness to oxytocin following progesterone withdrawal is dependent on oestradiol replacement.

  10. Activity of phospholipase C and release of prostaglandin F2 alpha by endometrial tissue from ovariectomized ewes receiving progesterone and estradiol.

    PubMed

    Raw, R E; Silvia, W J

    1991-03-01

    Progesterone and estradiol interact to regulate secretion of prostaglandin (PG) F2 alpha from the ovine endometrium in response to oxytocin. Two experiments were conducted to determine if these effects were due to changes in activity of phospholipase C or in the second messenger responsive pathways that regulate production of PGF2 alpha. In both experiments, ovariectomized ewes were assigned to one of four treatment groups (control, estradiol, progesterone, progesterone and estradiol). Steroids were administered, in vivo, to mimic the changes that occur during the estrous cycle. On Day 16 of steroid treatment, endometrial tissue was collected and incubated, in vitro, to measure activity of phospholipase C and release of PGF2 alpha. Treatment with progesterone, in vivo, enhanced basal and oxytocin-induced activity of phospholipase C and release of PGF2 alpha, in vitro. Estradiol suppressed oxytocin-induced activity of phospholipase C, both in the presence and absence of progesterone. In contrast to its effects on phospholipase C, estradiol inhibited basal and oxytocin-induced release of PGF2 alpha when administered alone, but not when administered with progesterone. Steroids had similar effects on the release of PGF2 alpha induced by phorbol 12-myristate 13-acetate and A23187. It was concluded that progesterone and estradiol regulate endometrial release of PGF2 alpha by affecting both the activity of phospholipase C and its associated second messenger responsive pathways that may regulate production of PGF2 alpha.

  11. Biochemical and clinical evaluation of the efficiency of intracervical extraamniotic prostaglandin F2 alpha and intravenous oxytocin infusion to induce labour at term.

    PubMed

    Kaminski, K; Rechberger, T; Oleszczuk, J; Jakowicki, J; Oleszczuk, J

    1994-08-01

    A prospective randomized study of 296 patients was undertaken to evaluate the efficiency of 15 mg prostaglandin F2 alpha (PGF2 alpha) suspended in tylose gel and applied intracervically for labour induction. The control group was treated with standard oxytocin intravenous infusion. Results indicated that local PGF2 alpha was superior to oxytocin therapy in shortening the duration of labour (6.3 +/- 2.3 versus 8.1 +/- 2.6 hours, p < 0.05). Only 19% of the patients treated with PGF2 alpha required oxytocin augmentation during labour. Our data suggest that PGF2 alpha treatment is associated with few maternal side-effects, few failed inductions, a low operative delivery rate and favourable neonatal outcome. To investigate the influence of PGF2 alpha for labour promotion we have measured interstitial collagenase and elastase activity in the lower uterine segment after both methods of labour induction. The total collagenase activity was 22 times higher in tissue samples obtained from patients in active spontaneous and oxytocin-induced labour, compared with women not in labour (at term) (p < 0.001). The total interstitial elastase activity was 2-fold higher in women in active labour than in patients at term (p < 0.03). A significantly higher collagenase and elastase activity was observed in uterine specimens obtained from patients treated with PGF2 alpha compared to oxytocin, and this indicates that cervical collagen may be digested more quickly in the presence of exogenous prostaglandin F2 alpha.

  12. Transcriptomic and bioinformatics analysis of the early time-course of the response to prostaglandin F2 alpha in the bovine corpus luteum.

    PubMed

    Talbott, Heather; Hou, Xiaoying; Qiu, Fang; Zhang, Pan; Guda, Chittibabu; Yu, Fang; Cushman, Robert A; Wood, Jennifer R; Wang, Cheng; Cupp, Andrea S; Davis, John S

    2017-10-01

    RNA expression analysis was performed on the corpus luteum tissue at five time points after prostaglandin F2 alpha treatment of midcycle cows using an Affymetrix Bovine Gene v1 Array. The normalized linear microarray data was uploaded to the NCBI GEO repository (GSE94069). Subsequent statistical analysis determined differentially expressed transcripts ± 1.5-fold change from saline control with P ≤ 0.05. Gene ontology of differentially expressed transcripts was annotated by DAVID and Panther. Physiological characteristics of the study animals are presented in a figure. Bioinformatic analysis by Ingenuity Pathway Analysis was curated, compiled, and presented in tables. A dataset comparison with similar microarray analyses was performed and bioinformatics analysis by Ingenuity Pathway Analysis, DAVID, Panther, and String of differentially expressed genes from each dataset as well as the differentially expressed genes common to all three datasets were curated, compiled, and presented in tables. Finally, a table comparing four bioinformatics tools' predictions of functions associated with genes common to all three datasets is presented. These data have been further analyzed and interpreted in the companion article "Early transcriptome responses of the bovine mid-cycle corpus luteum to prostaglandin F2 alpha includes cytokine signaling" [1].

  13. Receptors for gonadotrophin and prostaglandin F2 alpha in bovine corpora lutea of early, mid and late luteal phase.

    PubMed

    Rao, C V; Estergreen, V L; Carman, F R; Moss, G E

    1979-07-01

    A total of 15 corpora lutea representing early (day 3), mid (day 13) and late luteal phase (day 20 and 21-24) were obtained by ovariectomy on cycling cows. The luteal weights and peripheral plasma progesterone levels just prior to ovariectomy, were consistent with the above luteal phases. The specific binding of [125I]human chorionic gonadotrophin to membranes prepared from corpora lutea was significantly higher (P less than 0.01) for days 13 and 20 than for days 3 and 21-24. The binding in day 21-24 corpora lutea was higher (P less than 0.01) than day 3. Although there was no different either in number or affinity (apparent dissociation constant (Kd) = 0.04 nM) of gonadotrophin receptors in days 13 and 20 corpora lutea, only in the former did the binding correlate well with plasma progesterone levels. The specific binding of [3H]prostaglanding (PG)F2 alpha to the membranes of the same corpora lutea showed a progressive increase (P less than 0.01) from day 3, reached the highest value at a time when corpora lutea were actively regressing (day 20) and the decline (P less than 0.01) by day 21-24. Although a considerable number of PGF2 alpha receptors existed at day 13, the affinity of these same receptors was 203 times lower (Kd = 3458 nM) than the affinity of receptors in day 20 corpora lutea (Kd = 17 nM). In summary, the above results show that gonadotrophin receptors correlate with luteotrophic, whereas PGF2 alpha receptors correlate with luteolytic phases in bovine corpora lutea.

  14. Cellular mechanisms by which oxytocin mediates ovine endometrial prostaglandin F2alpha synthesis: role of G(i) proteins and mitogen-activated protein kinases.

    PubMed

    Burns, P D; Mendes, J O; Yemm, R S; Clay, C M; Nelson, S E; Hayes, S H; Silvia, W J

    2001-10-01

    Oxytocin stimulates a rapid increase in ovine endometrial prostaglandin (PG) F2alpha synthesis. The overall objective of these experiments was to investigate the cellular mechanisms by which oxytocin induces endometrial PGF2alpha synthesis. The objective of experiment 1 was to determine whether G(i) proteins mediate oxytocin-induced PGF2alpha synthesis. Uteri were collected from four ovary-intact ewes on Day 14 postestrus. Caruncular endometrial explants were dissected and subjected to in vitro incubation. Pertussis toxin, an inhibitor of G(i) proteins, had no effect on the ability of oxytocin to induce PGF2alpha synthesis (P > 0.10). The objective of experiment 2 was to determine whether any of the three mitogen-activated protein kinases (MAPKs), extracellular signal regulated protein kinase (ERK1/2), c-Jun N-terminal/stress-activated protein kinase (JNK/SAPK), or p38 MAPK, mediate oxytocin-induced PGF(2alpha) synthesis. Eleven ovary-intact ewes were given an injection of oxytocin (10 IU; i.v.; n = 5) or physiological saline (i.v.; n = 6) on Day 15 postestrus. Uteri were collected 15 min after injection and caruncular endometrium was dissected. Endometrial homogenates were prepared and subjected to Western blotting. Membranes were probed for both total and phosphorylated forms of all three classes of MAPK. All classes of MAPK were detected in ovine endometrium, but oxytocin treatment had no effect on the expression of these proteins (P > 0.10). ERK1/2 was the only phosphorylated MAPK detected and its concentrations were higher in oxytocin-treated ewes (P < 0.01). The objective of experiment 3 was to further investigate the role of ERK1/2 during oxytocin-induced PGF2alpha synthesis. Uteri were collected from four ovary-intact ewes on Day 14 postestrus. Caruncular endometrial explants were dissected and subjected to in vitro incubation. PD98059, a specific inhibitor of ERK1/2 activity, blocked the ability of oxytocin to stimulate PGF(2alpha synthesis in a dose

  15. Effects of progesterone and estradiol on uterine secretion of prostaglandin f(2alpha)in response to oxytocin in ovariectomized sows.

    PubMed

    Edgerton, L A; Kaminski, M A; Silvia, W J

    2000-02-01

    Thirty ovariectomized sows were used in an experiment designed to determine whether the ability of the porcine uterus to release prostaglandin (PG) F(2alpha) in response to oxytocin is regulated by progesterone (P(4)) and estradiol (E(2)). Sows were assigned to one of four treatment groups: 1) no steroids (ovariectomized controls; n = 8), 2) E(2) (n = 8), 3) P(4) (n = 7), or 4) E(2) + P(4) (n = 7). P(4) and E(2) were administered so as to mimic the normal temporal changes that occur in these hormones during the estrous cycle. A group of intact sows (n = 9) was included for comparison. All sows received an injection of oxytocin (30 IU, i.v.) on Days 12, 15, and 18 postestrus. Jugular venous blood samples were collected from 60 min before through 120 min after injection of oxytocin for quantification of 13,14-dihydro-15-keto-PGF(2alpha) (PGFM). Preinjection baseline concentrations of PGFM, the magnitude of the PGFM response above baseline, and area under the PGFM response curve (AUC) were calculated for each sow on each day and compared among treatment groups by ANOVA. Among the ovariectomized sows receiving steroid replacement, baseline concentrations of PGFM were low on Day 12 postestrus in all four groups. On Days 15 and 18, baseline concentrations remained low in the two groups that did not receive P(4) but increased in those that did. Both the magnitude of the response to oxytocin and AUC were small on Day 12 postestrus in all 4 groups. By Day 15, the magnitude of the response and AUC increased in the group that received both P(4) and E(2) but remained low in the other three groups. By Day 18, responses to oxytocin were greater in both groups that received P(4) than in those that did not. Baseline concentrations were similar in intact sows and in those that received both P(4) and E(2) on all three days examined. The magnitude of the response and the AUC were greater in the ovariectomized sows receiving P(4) and E(2) replacement than in the intact control sows on

  16. Relationship between urinary prostaglandin E2 and F2 alpha excretion and plasma arginine vasopressin during renal concentrating and diluting tests in renal transplant recipients.

    PubMed

    Pedersen, E B; Christensen, P; Danielsen, H; Eiskjaer, H; Jespersen, B; Knudsen, F; Kornerup, H J; Leyssac, P P; Nielsen, A H; Sørensen, S S

    1987-10-01

    Urinary excretion of prostaglandin E2 (PGE2 and F2 alpha (PGF2 alpha) and plasma concentration of arginine vasopressin (AVP) were determined during urinary concentrating and diluting tests in renal transplant recipients and control subjects. During the concentrating test PGE2 and PGF2 alpha remained unchanged in the renal transplant recipients, whereas both PGE2 and PGF2 alpha were significantly reduced in the control subjects. During the diluting test PGE2 and PGF2 alpha increased in both groups but, contrary to PGF2 alpha, PGE2 was significantly higher in all periods in the transplant recipients compared to the controls. However, the prostaglandin excretion rates per kidney were significantly higher in the renal transplant recipients than control subjects, for all periods during both the concentrating and the diluting test. Arginine vasopressin was significantly higher in renal transplant recipients than control subjects during basal conditions, increased to a significantly higher level in the transplant recipients after thirst, but was reduced to the same levels in the two groups during the diluting test. It is concluded that the increased excretion of prostaglandins in renal transplant recipients may be a compensatory phenomenon representing an adaptation to a reduced renal mass in order to maintain adequate renal water excretion. Although a direct relationship between the prostaglandin excretions of PGE2 and PGF2 alpha and AVP does not seem to exist, it is possible that the higher prostaglandin excretion in the renal transplant recipients may be a counterbalancing mechanism to the higher AVP level, which most likely is secondary to a decreased responsiveness to vasopressin of the renal collecting ducts in the transplanted kidney.

  17. 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.

  18. Prostaglandin F(2alpha) receptor signaling facilitates bleomycin-induced pulmonary fibrosis independently of transforming growth factor-beta.

    PubMed

    Oga, Toru; Matsuoka, Toshiyuki; Yao, Chengcan; Nonomura, Kimiko; Kitaoka, Shiho; Sakata, Daiji; Kita, Yoshihiro; Tanizawa, Kiminobu; Taguchi, Yoshio; Chin, Kazuo; Mishima, Michiaki; Shimizu, Takao; Narumiya, Shuh

    2009-12-01

    Idiopathic pulmonary fibrosis (IPF) is a progressive disease characterized by fibroblast proliferation and excess deposition of collagen and other extracellular matrix (ECM) proteins, which lead to distorted lung architecture and function. Given that anti-inflammatory or immunosuppressive therapy currently used for IPF does not improve disease progression therapies targeted to blocking the mechanisms of fibrogenesis are needed. Although transforming growth factor-beta (TGF-beta) functions are crucial in fibrosis, antagonizing this pathway in bleomycin-induced pulmonary fibrosis, an animal model of IPF, does not prevent fibrosis completely, indicating an additional pathway also has a key role in fibrogenesis. Given that the loss of cytosolic phospholipase A(2) (cPLA(2)) suppresses bleomycin-induced pulmonary fibrosis, we examined the roles of prostaglandins using mice lacking each prostoaglandin receptor. Here we show that loss of prostaglandin F (PGF) receptor (FP) selectively attenuates pulmonary fibrosis while maintaining similar levels of alveolar inflammation and TGF-beta stimulation as compared to wild-type (WT) mice, and that FP deficiency and inhibition of TGF-beta signaling additively decrease fibrosis. Furthermore, PGF(2alpha) is abundant in bronchoalveolar lavage fluid (BALF) of subjects with IPF and stimulates proliferation and collagen production of lung fibroblasts via FP, independently of TGF-beta. These findings show that PGF(2alpha)-FP signaling facilitates pulmonary fibrosis independently of TGF-beta and suggests this signaling pathway as a therapeutic target for IPF.

  19. Changes in growth and lipid profiles of silk gland, mid-gut biochemical composition of silkworm, Bombyx mori L. on exposure to prostaglandin F2alpha.

    PubMed

    Miao, Yun-gen; Jiang, Li-jun

    2003-01-01

    The growth of the silkworm is influenced by the outside and inside environment. Among them, the category of various endocrine hormone of inside is the main factors that adjust the characters such as growth and propagate. In this experiment, we applied different dosage of prostaglandin to the fourth and fifth instar silkworm to observe the effects of prostaglandin F2alpha (PGF2alpha) on silk gland growth, mid-gut biochemical constituents and the lipid profiles of silkworm larva, Bombyx mori L. The weight of the posterior silk gland increased significantly (P < 0.001) by 20-24% after treatment with PGF2alpha. The increase in the lipid profiles except lipase activity suggests that the silk gland had more synthetic activity that might reflect in active spinning of silkworm larva. The changes of total proteins, free amino acids and alkaline phosphatase in mid-gut of control and PGF2alpha treated silkworm, B. mori L. indicate that PGF2alpha favored stimulatory effect on physiology of digestion, absorption and transportation of nutrients which might influence on the growth and development of larva.

  20. [Therapeutic interruption of pregnancy in the second trimester after preparation of the cervix with prostaglandins F2 alpha].

    PubMed

    Maria, B; Stampf, F; Barrat, J

    1983-01-01

    The use of prostaglandins is one of the best techniques for second trimester abortion. The authors present 40 patients aborted by a new two stage technique: First: ripening of the cervix a tylose gel containing 5 or 10 mg PGF2 alpha every 12 hours during 3 days. Then, if abortion is not obtained, previously published techniques are used: intra-amniotic injection (40 mg PGF2 alpha) or intra-cervical infusion (2 mg/hour). The mean duration of these abortions is 52 hours using 29 mg of PGF2 alpha. 22 patients aborted during ripening (mean = 27 hours), 12 patients needed an intracervical infusion (mean = 88 hours) and 6, an intra-amniotic injection (mean = 72 hours). It seems that abortion is easier when pregnancy is earlier, under 20 weeks of gestation. Few side effects were observed: only three cases of fever with a single case of endometritis. Failure of this technique occurred in five patients (4 aborted outside the time allowed for, and one needed instrumental extraction). With this technique, the mean duration is longer than those previously described in the literature but the efficiency is over 90%.

  1. Temporary sterility induced by intrascrotal deposition of silastic-polyvinylpyrrolidone-prostaglandin F2alpha tubes in the rabbit: effect on fetal survival after regain of fertility.

    PubMed

    Saksena, S K; Lau, I F

    1979-09-01

    In male rabbits of proven fertility, the intrascrotal deposition of two Silastic-polyvinylpyrrolidone tubes containing 3 mg of prostaglandin F2alpha (PGF2alpha)/tube induced within 2 to 4 weeks temporary sterility which lasted for 10 to 14 weeks. Associated with induced sterility were reduction in testicular weight, increase in abnormal spermatozoa (8% to 78% versus 0 to 3.7%), and reduction in sperm motility along the reproductive tract and in the semen for a period of 6 to 7 weeks. During the period of temporary sterility the weight of the epididymis, the sexual drive, and semen volume remained unaltered. Normal fertility was associated with an increase in testicular weight, reduction in the proportion of abnormal sperm, and improved sperm motility. In addition to an altered spermatogenesis, the integrity of mature spermatozoa seemed to be severely affected after PGF2alpha treatment. The reduced number of viable young sired by males that recovered from temporary sterility (pregnancy wastage 35%) as compared with sham-treated controls (pregnancy wastage 3%) suggests that a small percentage of spermatozoa might still be defective at the time of testing. A longer waiting period might be needed to ensure a completely normal reproductive process.

  2. Influence of acupuncture on maternal serum levels of interleukin-8, prostaglandin F2alpha, and beta-endorphin: a matched pair study.

    PubMed

    Tempfer, C; Zeisler, H; Heinzl, H; Hefler, L; Husslein, P; Kainz, C

    1998-08-01

    To measure the serum levels of interleukin (IL)-8, prostaglandin (PG) F2alpha, and beta-endorphin in parturients with acupuncture treatment and in controls to clarify the effect of acupuncture and duration of labor on the serum levels of substances active in cervical ripening and dilatation. A matched pair study was performed involving 80 women with and without prenatal acupuncture treatment, matched for age and parity. Serum levels of IL-8, PGF2alpha, and beta-endorphin were measured in serum samples taken after delivery by use of enzyme-linked immunosorbent assay, enzyme immunoassay, and immunoradiometric assay, respectively. The mean difference in total duration of labor between matched pairs with and without acupuncture was -136.5 minutes (95% confidence interval [CI] 191.1 minutes, -81.9 minutes; paired t test, P < .001). The mean difference of the duration of the first and second stages of labor between matched pairs with and without acupuncture was -138.8 minutes (95% CI 188.6, -89.0 minutes; paired t test, P < .001) and 2.3 minutes (95% CI 15.5, 20.1 minutes; paired t test, P = .8), respectively. The geometric means of ratios of IL-8, PGF2alpha, and beta-endorphin between matched pairs in women with and without acupuncture showed no statistically significant differences. Serum levels of IL-8, PGF2alpha, and beta-endorphin were not significantly correlated with the duration of the first and second stages of labor. Prenatal acupuncture treatment significantly reduces the duration of labor and may be a valuable tool in prenatal preparation. Serum levels of IL-8, PGF2alpha, and beta-endorphin are not significantly influenced by acupuncture and are therefore not likely to mediate acupuncture-related effects during labor.

  3. Patterns of relaxin and steroids in the reproductive cycle of the common marmoset (Callithrix jacchus): effects of prostaglandin F2 alpha on relaxin and progesterone secretion during pregnancy.

    PubMed

    Steinetz, B G; Randolph, C; Mahoney, C J

    1995-10-01

    We measured the concentrations of relaxin (Rlx), progesterone, and estradiol-17 beta in serum samples obtained twice or three times weekly from marmosets during the estrous cycle and pregnancy. The cyclic patterns and concentrations of progesterone and estradiol-17 beta were similar to those reported by previous investigators. Rlx was not detected in individual serum samples ( < 0.62-1.25 ng/ml) obtained from nonpregnant marmosets. However, pooling of luteal serum from all animals permitted assay of much larger volumes of serum (0.4 ml vs. 0.1 ml), and a concentration of about 1 ng/ml was detected. Rlx was first detected in serum in the second or third week of the 21-wk marmoset pregnancy, rose to a peak during Weeks 10-14, and then declined slowly as the time of parturition approached. The pattern of Rlx was unlike that observed during pregnancy in Old World monkeys, chimpanzees, or women, and resembled, instead, that seen in rodents, carnivores, and equids. Progesterone and estradiol-17 beta likewise increased throughout pregnancy, and their patterns were similar to those previously described for marmosets by other investigators. The concentrations of the steroids and Rlx in serum of pregnant marmosets was 10-fold or more higher than those found in Old World monkeys, baboons, chimpanzees, or women. Spontaneous abortions in two of the marmosets were accompanied by precipitous falls in serum levels of progesterone, estradiol-17 beta, and Rlx. Following s.c. injection of the luteolytic agent prostaglandin F2 alpha (PGF2 alpha) into two marmosets at midpregnancy, serum progesterone and Rlx fell to low levels. These animals received a progestin, 17 alpha-ethyl-19-nortesterone, to preclude abortion. Serum progesterone rose again, but serum Rlx remained low for the duration of pregnancy.(ABSTRACT TRUNCATED AT 250 WORDS)

  4. Concentrations of oxytocin in the intercavernous sinus of mares during luteolysis: temporal relationship with concentrations of 13,14-dihydro-15-keto-prostaglandin F2 alpha.

    PubMed

    Vanderwall, D K; Silvia, W J; Fitzgerald, B P

    1998-03-01

    The reproductive tracts of nine thoroughbred mares were examined by ultrasound to determine the day of ovulation (day 0). Mares were fitted with intercavernous sinus cannulae on the day before the start of sample collection of pituitary venous effluent rich in oxytocin. Intercavernous sinus blood samples were collected for at least 36 h at 5 min intervals beginning at noon on day 13 (n = 2), day 15 (n = 5) or day 16 (n = 2) after ovulation. Concentrations of oxytocin and 13,14-dihydro-15-keto prostaglandin F2 alpha (PGFM) in plasma were determined by radioimmunoassay. Three high-magnitude surges of PGFM (> 1 ng ml-1) were found in these samples. Three high magnitude pulses of oxytocin (> 200 pg ml-1) were also observed, one associated with each of the PGFM surges. In each of these cases, the oxytocin pulse appeared to follow or coincide with the onset of the PGFM surge. Lower magnitude pulses of both hormones were detected throughout the bleeding period in every mare. The average interval between these pulses was 122.3 min for oxytocin and 121.0 min for PGFM. The interval between pulses for individual mares varied from 90 to 199 min for oxytocin, and from 87 to 213 min for PGFM. However, there was no correlation between PGFM and oxytocin pulse intervals among mares. Within each mare, there was no discernable association between low magnitude pulses of oxytocin and PGFM. From these data, it was concluded that high-magnitude surges of PGF2 alpha are associated with similar surges of oxytocin from the posterior pituitary gland, and that PGF2 alpha may induce their secretion. The posterior pituitary gland also appears to secrete oxytocin in a pulsatile manner at a frequency of approximately 1 pulse every 2 h but these pulses do not appear to be associated with the low magnitude pulses of PGF2 alpha secreted from the uterus.

  5. Maintenance of the corpus luteum of early pregnancy in the ewe. IV. Changes in luteal sensitivity to prostaglandin F2 alpha throughout early pregnancy.

    PubMed

    Silvia, W J; Niswender, G D

    1986-10-01

    Two experiments were conducted to examine the temporal aspects of luteal resistance to the luteolytic effect of prostaglandin (PG) F2 alpha during early pregnancy. In Exp. 1, 14 pregnant and 12 nonpregnant ewes were treated with PGF2 alpha either on d 10 or 13 post-estrus. Jugular venous blood samples were collected at -30 min, 0, 6, 12, 18, 24, 30 and 36 h post-injection for quantification of progesterone. The difference (delta P) between pre-treatment and post-treatment concentrations of progesterone was calculated for each ewe. There was a significant interaction between pregnancy status and day of treatment on delta P (P less than .05). Pregnant and nonpregnant ewes treated on d 10 showed a large delta P. A large delta P also was observed in nonpregnant ewes treated on d 13 post-estrus. However, delta P in pregnant ewes treated on d 13 was smaller than in the other three groups (P less than .05). The temporal patterns of concentrations of progesterone in serum were different among treatment groups (P less than .05). A suppression in the concentration of progesterone was observed by 24 h post-injection in all four treatment groups. Progesterone returned to pre-treatment levels only in pregnant ewes treated on d 13. In Exp. 2, 47 pregnant ewes were treated with PGF2 alpha on d 10, 13, 16, 19, 22, 26 or 30 postestrus. Blood samples were collected and data were analyzed as described for Exp. 1.(ABSTRACT TRUNCATED AT 250 WORDS)

  6. Cellular mechanisms mediating the stimulation of ovine endometrial secretion of prostaglandin F2 alpha in response to oxytocin: role of phospholipase A2.

    PubMed

    Lee, J S; Silvia, W J

    1994-06-01

    Four experiments were conducted to determine whether phospholipase (PL) A2 mediates the stimulatory effect of oxytocin on the release of prostaglandin (PG) F2 alpha from ovine endometrial tissue. Caruncular endometrial tissue was collected from ovariectomized ewes on the day after a steroid replacement protocol had been completed. The replacement protocol consisted of progesterone for 10 days (12 mg/day) followed by oestradiol on days 10 and 11 (100 micrograms/day) and had been shown previously to provide endometrial tissue that would release PGF2 alpha in response to oxytocin in vitro. In experiment 1, oxytocin (10(-7) M) and melittin (1.76 x 10(-6) M; a stimulator of PLA2) stimulated release of PGF2 alpha from tissue explants (P < 0.05). Aristolochic acid (10(-4) M; an inhibitor of PLA2) decreased oxytocin- and melittin-induced release of PGF2 alpha by 77% and 71% respectively (P < 0.05). Experiment 2 was conducted to establish the minimum inhibitory dose of aristolochic acid. Basal release of PGF2 alpha was inhibited at 10(-5) M aristolochic acid, but 10(-4) M was required to block the stimulatory effect of oxytocin. Experiment 3 was carried out to identify the precise intracellular locus at which aristolochic acid was exerting its effect. Oxytocin (10(-7) M), AlF4- (5 x 10(-2) M NaF, 10(-5) M AlCl3), melittin (1.76 x 10(-6) M) and arachidonic acid (AA; 20 micrograms/ml) stimulated release of PGF2 alpha (P < 0.05). Aristolochic acid (10(-4) M) blocked the release of PGF2 alpha stimulated by oxytocin, AlF4- or melittin by > 80% (P < 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

  7. Uterine secretion of prostaglandin F2 alpha in response to oxytocin in ewes: changes during the estrous cycle and early pregnancy.

    PubMed

    Silvia, W J; Raw, R E; Aldrich, S L; Hayes, S H

    1992-06-01

    Experiment 1 was conducted to determine when the ovine uterus develops the ability to secrete prostaglandin F2 alpha (PGF2 alpha) in response to oxytocin and how development is affected by pregnancy. Pregnant and nonpregnant ewes received an injection of oxytocin (10 IU, i.v.) on Day 10, 13, or 16 postestrus. Jugular venous blood samples were collected for 2 h after injection for quantification of 13,14-dihydro-15-keto-PGF2 alpha (PGFM). In nonpregnant ewes, concentrations of PGFM increased following oxytocin on Day 16 but not on Day 10 or 13. Concentrations of PGFM did not increase following treatment on Day 10, 13, or 16 in pregnant ewes. Therefore, the ability of oxytocin to induce uterine secretion of PGF2 alpha develops after Day 13 in nonpregnant but not in pregnant ewes. Experiment 2 was conducted to precisely define when uterine secretory responsiveness to oxytocin develops. Pregnant and nonpregnant ewes received oxytocin on Day 12, 13, 14, or 15. In nonpregnant ewes, concentrations of PGFM increased following treatment on Days 14 and 15, but not earlier. Peripheral concentrations of progesterone showed that uterine secretory responsiveness to oxytocin developed prior to the onset of luteal regression. As in experiment 1, the increase in concentrations of PGFM following administration of oxytocin was much lower in pregnant than in nonpregnant ewes; however, some pregnant ewes did respond to oxytocin with an increase in PGFM. In experiment 3, pregnant ewes received an injection of oxytocin on Day 18, 24, or 30 postmating. Concentrations of PGFM increased following oxytocin on Days 18 and 24. The conceptus appears to delay and attenuate the development of uterine secretory responsiveness to oxytocin.

  8. Effect of Mailuoning injection on 8-iso-prostaglandin F2 alpha and superoxide dismutase in rabbits with extremity ischemia-reperfusion injury.

    PubMed

    Wang, Dai-Jun; Tian, Hua

    2014-12-01

    To date, there are no effective treatments for extremity ischemia-reperfusion (IR) injury. The objective of the present study was to explore the protective effect of Mailuoning on IR injury by investigating the plasma levels of 8-iso-prostaglandin F2 alpha (8-iso-PGF2α) and the activity of superoxide dismutase (SOD) in rabbits. The experimental models of posterior limb IR injury were established in thirty rabbits that were divided into three groups: the sham, IR, and IR + Mailuoning groups. At the end of ischemia, Mailuoning was injected intravenously into the rabbits in the IR + Mailuoning group, and normal saline solution was administered to the rabbits in the sham and IR groups. Venous blood samples were collected to measure the levels of 8-iso-PGF2α and the activity of SOD in the plasma at the following time points: at the onset of ischemia, the end of ischemia, and 2, 4, 8, 12, and 24 h after reperfusion. The skeletal muscles were harvested to examine the ultrastructure. The levels of 8-iso-PGF2α increased significantly and SOD activity decreased in the IR group at every time point after reperfusion (P <0.01 or P <0.05). In contrast, the levels of 8-iso-PGF2α and SOD activity were not significantly different after reperfusion in the IR + Mailuoning group (P >0.05) but were significantly different compared with the IR group (P <0.01). Using electron microscopy, the skeletal muscle injury was shown to be milder in the IR+ Mailuoning group after reperfusion compared with the IR group. The Mailuoning is capable of decreasing the excessive production of 8-iso-PGF2α and protecting SOD activity, thereby exhibiting a protective effect on extremity IR injury. Copyright © 2014 Elsevier Inc. All rights reserved.

  9. Changes in uterine secretion of prostaglandin F2 alpha in response to oxytocin during the estrous cycle, early pregnancy, and estrogen-induced pseudopregnancy in swine.

    PubMed

    Edgerton, L A; Kaminski, M A; Silvia, W J

    1996-09-01

    Thirty-one sows were used in an experiment designed to determine whether the ability of the porcine uterus to release prostaglandin (PG) F2 alpha in response to oxytocin was suppressed in pregnancy and pseudopregnancy. Sows were assigned to one of three treatment groups: nonbred (nonpregnant) controls (n = 8), pseudopregnant (5 mg estradiol benzoate, i.m., daily on Days 11-15 postestrus; n = 8), or bred (bred once daily throughout the estrous period; n = 15). Jugular venous blood samples were collected daily for quantification of progesterone. Pregnancy was determined by uterine examination at slaughter 51-72 days postmating. On the basis of progesterone and embryo recovery, bred sows were classified into three subgroups: confirmed pregnant (n = 4), suspected pregnant based on delayed luteal regression (n = 5), or bred/not pregnant (n = 6). All sows received an injection of oxytocin (30 IU, i.v.) on Days 12, 15, and 18 postestrus. Jugular venous blood samples were collected from 60 min prior to through 120 min after injection of oxytocin for quantification of 13, 14-dihydro-15-keto-PGF2 alpha (PGFM). Magnitude of response above baseline and area under the PGFM response curve (AUC) were calculated for each sow on each day and compared among treatment groups by analysis of variance. Responses in pregnant and suspected-pregnant sows were not different on any day examined; therefore the two groups were combined (n = 9) and considered pregnant for all subsequent analyses. Responses in the nonpregnant and bred/not pregnant sows were pooled and compared to the responses in the pregnant and pseudopregnant sows. Magnitudes of response were similar between these pooled groups on Day 12 (p > 0.5), but were less in pregnant and pseudopregnant sows on Days 15 and 18 (p < 0.01). When nonpregnant and bred/not pregnant sows were compared to each other, the magnitudes of the response were similar on Days 12, 15, and 18 (p > 0.3 on each day). In contrast, when pregnant and

  10. Cellular mechanisms mediating the stimulation of ovine endometrial secretion of prostaglandin F2 alpha in response to oxytocin: role of phospholipase C and diacylglycerol.

    PubMed

    Silvia, W J; Lee, J S; Trammell, D S; Hayes, S H; Lowberger, L L; Brockman, J A

    1994-06-01

    The first objective was to describe and evaluate the relationship between the ability of oxytocin to stimulate the activity of phospholipase (PL) C and its ability to stimulate the release of prostaglandin (PG) F2 alpha in ovine endometrial tissue. Caruncular endometrial tissue was collected from ovariectomized ewes after completion of an 11-day steroid replacement protocol. In experiment 1, explants were incubated either in the presence (10(-6) M) or absence of oxytocin for 0, 1, 3, 10, 30 or 100 min to examine the time-course for activation of PLC and release of PGF2 alpha in response to oxytocin. An increase in the activity of PLC was detected at 3 min while an increase in the release of PGF2 alpha was not detected until 10 min (P < 0.05). In experiment 2, explants were incubated in the presence of various oxytocin analogues (10(-6) M) to compare their abilities to activate PLC and release PGF2 alpha. Oxytocin and three receptor agonists stimulated the activity of PLC and the release of PGF2 alpha (P < 0.05) while two oxytocin receptor antagonists had no effect on either response. In experiment 3, explants were incubated in the presence of oxytocin or arginine vasopressin at 10(-9) to 10(-6) M to establish dose-response curves for the activation of PLC and release of PGF2 alpha. For both hormones, significant increases (P < 0.05) in the release of PGF2 alpha were observed at 10(-8) M while increases in PLC activity were not detected until 10(-7) M was used. In experiment 4, explants were pretreated with either U-73122 (an inhibitor of PLC activity) or U-73343 (an inactive analogue of U-73122). Explants were then treated with control medium, oxytocin or AlF4-. Both oxytocin and AlF4-stimulated the activity of PLC and the release of PGF2 alpha (P < 0.05). U-73122 blocked the ability of oxytocin to stimulate the release of PGF2 alpha (P < 0.05) but had no effect on its ability to stimulate the activity of PLC (P > 0.1). Based on the results from these experiments

  11. Effects of prostaglandin F2 alpha and a gonadotropin-releasing hormone agonist on inositol phospholipid metabolism in isolated rat corpora lutea of various ages

    SciTech Connect

    Lahav, M.; West, L.A.; Davis, J.S.

    1988-08-01

    The sensitivity of rat corpora lutea to luteolytic agents increases with luteal age. We examined the effect of prostaglandin F2 alpha (PGF2 alpha) and (D-Ala6,Des-Gly10)GnRH ethylamide (GnRHa) on inositol phospholipid metabolism in day 2 and day 7 corpora lutea from PMSG-treated rats. Isolated corpora lutea were incubated with 32PO4 or (3H)inositol and were treated with LH, PGF2 alpha, or GnRHa. Phospholipids were purified by TLC, and the water-soluble products of phospholipase-C activity (inositol phosphates) were isolated by ion exchange chromatography. In day 2 corpora lutea, PGF2 alpha, (10 microM) and GnRHa (100 ng/ml) significantly increased 32PO4 incorporation into phosphatidic acid (PA) and phosphatidylinositol (PI), but not into other fractions. LH provoked slight increases in PA. Results were similar with 30 min of prelabeling or simultaneous addition of 32PO4 and stimulants. In other experiments, PGF2 alpha and GnRHa provoked rapid increases (1-5 min) in the accumulation of inositol mono-, bis-, and trisphosphates. LH did not significantly increase inositol phosphate accumulation, but stimulated cAMP accumulation in 2-day-old corpora lutea. Inositol phospholipid metabolism was increased in day 7 corpora lutea compared to that in day 2 corpora lutea. This increase was associated with increased incorporation of 32PO4 into PA and PI and increased accumulation of (3H)inositol phosphates. In day 7 corpora lutea, which are very sensitive to the luteolytic effect of PGF2 alpha, the PG-induced increase in PA labeling was small and inconsistent, whereas PI labeling was unaffected in 30-min incubations. GnRHa was without effect in such corpora lutea. LH, PGF2 alpha, or GnRHa did not increase inositol phosphate accumulation in 7-day-old corpora lutea. These studies demonstrate that the transformation of young (day 2) to mature (day 7) corpora lutea is associated with an increase in luteal inositol phospholipid metabolism.

  12. Local changes in blood flow within the early and midcycle corpus luteum after prostaglandin F(2 alpha) injection in the cow.

    PubMed

    Acosta, Tomas J; Yoshizawa, Nobuyuki; Ohtani, Masayuki; Miyamoto, Akio

    2002-03-01

    One of the postulated main luteolytic actions of prostaglandin (PG) F(2 alpha) is to decrease ovarian blood flow. However, before Day 5 of the normal cycle, the corpus luteum (CL) is refractory to the luteolytic action of PGF(2 alpha). Therefore, we aimed to determine in detail the real-time changes in intraluteal blood flow after PGF(2 alpha) injection at the early and middle stages of the estrous cycle in the cow. Normally cycling cows at Day 4 (early CL, n = 5) or Days 10--12 (mid CL, n = 5) of the estrous cycle (estrus = Day 0) were examined by transrectal color and pulsed Doppler ultrasonography to determine the blood flow area, the time-averaged maximum velocity (TAMXV), and the volume of the CL after an i.m. injection of a PGF(2 alpha) analogue. Ultrasonographic examinations were carried out just before PG injection (0 h) and then at 0.5, 1, 2, 4, 8, 12, 24, and 48 h after the injection. Blood samples were collected at each of these times for progesterone (P) determination. The ratio of the colored area to a sectional plane at the maximum diameter of the CL was used as a quantitative index of the changes in blood flow within the luteal tissue. Blood flow within the midcycle CL initially increased (P < 0.05) at 0.5-2 h, decreased at 4 h to the same levels observed at 0 h, and then further decreased to a lower level from 8 h (P < 0.05) to 48 h (P < 0.001). Plasma P concentrations decreased (P < 0.05) from 4.7 +/- 0.5 ng/ml (0 h) to 0.6 +/- 0.2 ng/ml (24 h). The TAMXV and CL volume decreased at 8 h (P < 0.05) and further decreased (P < 0.001) from 12 to 24 h after PG injection, indicating structural luteolysis. These changes were not detected in the early CL, in which luteolysis did not occur. In the early CL, the blood flow gradually increased in parallel with the CL volume, plasma P concentration, and TAMXV from Day 4 to Day 6. The present results indicate that PGF(2 alpha) induces an acute blood flow increase followed by a decrease in the midcycle CL but not

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

    SciTech Connect

    Raisz, L.G.; Alander, C.B.; Fall, P.M.; Simmons, H.A. )

    1990-02-01

    Although most studies show that prostaglandin E2 (PGE2) is the most potent and effective of the prostanoids in bone, recent data in cell culture suggest that PGF2 alpha may have unique effects, particularly on cell replication. The present study was undertaken to compare the effects of PGF2 alpha and PGE2 in cultured neonatal mouse parietal bones by simultaneous measurement of bone resorption as release of previously incorporated 45Ca, bone formation as incorporation of (3H)proline into collagenase-digestible (CDP) and noncollagen protein, and DNA synthesis as incorporation of (3H)thymidine. PGF2 alpha was less effective than PGE2 as a stimulator of bone resorption, and its effects were partially inhibited by indomethacin and markedly inhibited by glucocorticoids. In contrast, the resorptive response to PGE2 was unaffected by indomethacin and only partially inhibited by cortisol. PGF2 alpha had little effect on bone formation, in contrast to the biphasic effect of PGE2, which inhibited labeling of CDP in the absence of cortisol and stimulated CDP labeling in the presence of cortisol. PGF2 alpha increased thymidine incorporation into DNA, but the effect was smaller than that of PGE2 and was inhibited by indomethacin. These observations suggested that PGF2 alpha might act in part by stimulating PGE2 production. By RIA, PGE2 concentrations were increased in the medium of bones treated with PGF2 alpha, and this increase was blocked by indomethacin. By HPLC, bones prelabeled with (3H)arachidonic acid showed an increase in labeled PGE2 release, and RIA showed an increase in PGE2 after PGF2 alpha treatment. These results indicate that PGF2 alpha is a relatively weak agonist in bone compared to PGE2 and that some of the effects of PGF2 alpha on bone resorption, formation, and cell replication may be mediated by an increase in endogenous PGE2 production.

  14. Concentrations of prostaglandins E2, F2 alpha and 6-keto-prostaglandin F1 alpha in the utero-ovarian venous plasma of nonpregnant and early pregnant ewes.

    PubMed

    Silvia, W J; Ottobre, J S; Inskeep, E K

    1984-05-01

    The effect of pregnancy on concentrations of prostaglandins E2, F2 alpha and 6-keto-prostaglandin F1 alpha (PGE2, PGF2 alpha and 6-keto-PGF1 alpha) in utero-ovarian venous plasma was examined in ewes on Days 10 through 14 after estrus, an interval which includes the critical period for maternal recognition of pregnancy. The utero-ovarian vein ipsilateral to a corpus luteum was catheterized on Day 9 or 10 in 6 pregnant and 8 nonpregnant ewes. Five blood samples were collected at 30-min intervals for 2 h beginning at 0500 and 1700 h daily. Sampling began at 0500 h on the day after catheterization. The mean and variance within each 2-h collection period were calculated for each ewe. The natural logarithm of the variance in each collection period (ln variance) was used as an estimate of the fluctuations in secretory activity by the endometrial-conceptus complex. Patterns of the mean concentrations of PGE2 were different between pregnant and nonpregnant ewes (P less than 0.01); PGE2 being higher in the pregnant ewes beginning on Day 13. There was a trend for the patterns of ln variance in PGE2 to differ (P less than 0.1) with pregnancy status over the entire period; ln variance was greater in pregnant ewes beginning on Day 13. The patterns of the mean concentrations and ln variances for PGF2 alpha and 6-keto-PGF1 alpha did not differ between pregnant and nonpregnant ewes. There were significant increases in both of these prostaglandins over time, independent of pregnancy status (P less than 0.01). The association of higher concentrations of PGE2 in utero-ovarian venous plasma with early pregnancy is consistent with the hypothesis that PGE2, originating from the uterus and/or conceptus, is one factor involved in maintenance of the corpus luteum of pregnancy.

  15. A study on the effects of inhibition of prostaglandin biosynthesis with flunixin meglumine and later administration of prostaglandin F2 alpha on the intraluminal pressure variations in the isthmus of the oviduct in unrestrained gilts.

    PubMed

    Pettersson, A; Einarsson, S; Kindahl, H

    1993-01-01

    Three gilts were each equipped with 2 ultra-miniature pressure sensors, placed at 2 different points along the same isthmus of the oviduct. Following base recordings of isthmic intraluminal pressure, the gilts were treated with 2.2 mg flunixin meglumine (FM) per kg body weight. After FM treatment, the peripheral plasma levels of 15-ketodihydro-PGF2 alpha, the major metabolite of prostaglandin F2 alpha (PGF2 alpha), decreased within 30 min. The frequency of the phasic pressure fluctuations in the isthmus of the oviduct decreased after FM treatment. Exogenous administration of PGF2 alpha increased the peripheral plasma levels of 15-ketodihydro-PGF2 alpha. When administered at a dose of 0.1 mg, PGF2 alpha produced an increase in the frequency of the phasic pressure fluctuations in the oviductal isthmus. When the PGF2 alpha dose was increased to 0.5 mg, a marked increase in the base and total pressures was seen in addition to the increase in the frequency of the phasic pressure fluctuations.

  16. Cervical ripening with intracervical prostaglandin-E2 gel. I. Clinical results and effect on plasma levels of oxytocin and 13,14-dihydro,15-ketoprostaglandin-F2 alpha.

    PubMed

    Fuchs, A R; Goeschen, K; Rasmussen, A B; Rehnström, J V; Saling, E; Fuchs, F

    1983-10-01

    Tylose gel containing 400 micrograms prostaglandin E2 in 3 ml gel was injected into the cervical canal of 20 patients with high-risk pregnancy and indication for induction of labor, but with unfavorable cervix. Ten were studied after the first gel application, five during repeat injection, and five after application of gel without PGE2. Blood samples were drawn serially during the first 8 hours for determination of oxytocin and 13,14-dihydro,15-ketoprostaglandin-F2 alpha (PGFM). The PGE2 gel increased the Bishop score within 8 hours in all patients; in half of them, artificial rupture of the membranes could be performed and labor induced without further gel application; in the others, it was repeated every 8 hours until a Bishop score of greater than or equal to 8 was achieved. Fourteen of the 15 PGE2-induced patients delivered vaginally. Mean PGFM levels did not increase significantly during the 8 hours of observation, but in patients who responded with rapid progression, an increase was seen after cervical dilation was 6 cm or more. The mean oxytocin levels increased within 60 minutes after PGE2 application and were increased for the remaining observation period. Application of inactive gel had no effect on cervical ripening nor on oxytocin or PGFM levels.

  17. Surfactant protein-A (SP-A) selectively inhibits prostaglandin F2alpha (PGF2alpha) production in term decidua: implications for the onset of labor.

    PubMed

    Snegovskikh, Victoria V; Bhandari, Vineet; Wright, Jo Rae; Tadesse, Serkalem; Morgan, Thomas; Macneill, Colin; Foyouzi, Nastaran; Park, Joong Shin; Wang, Yuguang; Norwitz, Errol R

    2011-04-01

    Labor is characterized by "decidual activation" with production of inflammatory mediators. Recent data suggest that surfactant protein-A (SP-A) may be critical to the onset of labor in mice. Whether this is also true in humans is unclear. The aim was to investigate: 1) the expression of SP-A at the maternal-fetal interface; 2) the effect of SP-A on the production of inflammatory mediators by human decidua; and 3) the association between single nucleotide polymorphisms in maternal SP-A genes and spontaneous preterm birth. In situ expression of SP-A was investigated by immunohistochemistry and quantitative RT-PCR. Term decidual stromal cells were isolated, purified, and treated with/without SP-A (1-100 μg/ml), IL-1β, and/or thrombin. Levels of inflammatory mediators [IL-6, IL-8, TNFα, matrix metalloproteinase-3, monocyte chemotactic protein-1, IL-1β, PGE(2), prostaglandin F(2α) (PGF(2α))] and angiogenic factors (soluble fms-like tyrosine kinase-1, vascular endothelial growth factor) were measured in conditioned supernatant by ELISA and corrected for protein content. The effect of SP-A on eicosanoid gene expression was measured by quantitative RT-PCR. SP-A localized to endometrium/decidua. High-dose SP-A (100 μg/ml) inhibited PGF(2α) by term decidual stromal cells without affecting the production of other inflammatory mediators, and this effect occurred at a posttranscriptional level. Decidual SP-A expression decreased significantly with labor. Single nucleotide polymorphisms in the SP-A genes do not appear to be associated with preterm birth. SP-A is produced by human endometrium/decidua, where it significantly and selectively inhibits PGF(2α) production. Its expression decreases with labor. These novel observations suggest that decidual SP-A likely plays a critical role in regulating prostaglandin production within the uterus, culminating at term in decidual activation and the onset of labor.

  18. The effects of prostaglandins E2, F2 alpha, prostacyclin, flurbiprofen and aspirin on arrhythmias resulting from coronary artery ligation in anaesthetized rats.

    PubMed Central

    Coker, S. J.; Parratt, J. R.

    1981-01-01

    1 Various prostaglandins and inhibitors of prostaglandin synthesis were administered prior to acute coronary artery ligation in anaesthetized rats and their effects were assessed on the number and severity of the resulting early arrhythmias (ventricular ectopic activity; incidence and duration of ventricular tachycardia and of ventricular fibrillation). 2 Prostaglandin E2 (PGE2), PGF2 alpha and prostacyclin all showed antiarrhythmic activity; in contrast flurbiprofen increased the incidence of ventricular fibrillation and mortality. 3 Both the number of ventricular ectopic beats and the incidence of ventricular fibrillation were reduced by aspirin. 4 The results suggest that the release of endogenous PGE2, PGF2 alpha and prostacyclin could reduce early post-infarction ventricular arrhythmias whilst the protective effect of aspirin in this model adds further support for the hypothesis that thromboxane release is involved in the genesis of these arrhythmias. PMID:7023587

  19. Fimbrial capture of the ovum and tubal transport of the ovum in the rabbit, with emphasis on the effects of beta 2-adrenoreceptor stimulant and prostaglandin F2 alpha on the intraluminal pressures of the tubal ampullae.

    PubMed

    Osada, H; Fujii, T K; Tsunoda, I; Takagi, K; Satoh, K; Kanayama, K; Endo, T

    1999-08-01

    Our purpose was to elucidate the roles of the ampullar and isthmic portions of the oviduct and the effects of drugs on oviductal contractility. Prostaglandin F2 alpha (PGF2 alpha; Ono Pharmaceuticals, Osaka) and oxytocin (Atonin-O; Teikoku Hormone Manufacturing Co. Ltd., Tokyo) were used to stimulate oviductal contractility, and ritodrine hydrochloride (Utemerin; Solvay-Duphar Corp., Denmark) to inhibit the contractility. Both PGF2 alpha and Atonin-O were involved in ovum capture by the ampullar oviduct by stimulating contractility, thus altering the intraductal pressures. Utemerin is effective in inhibiting the enhanced contractility induced by PGF2 alpha and Atonin-O. Variations in pressure of the ampullar portion of the oviduct seem necessary for the capture of ova expelled from the ovary. Once in the isthmic portion of the oviduct, transport appears to be under the influence of ciliary activity rather than variations in contractility.

  20. Regional expression of prostaglandin E2 and F2alpha receptors in human myometrium, amnion, and choriodecidua with advancing gestation and labor.

    PubMed

    Grigsby, Peta L; Sooranna, Suren R; Adu-Amankwa, Bernice; Pitzer, Brad; Brockman, Diane E; Johnson, Mark R; Myatt, Leslie

    2006-08-01

    The change from uterine quiescence to enhanced contractile activity may be due to the differential expression of prostaglandin receptors within the myometrium and fetal membranes, in a temporal and topographically distinct manner. To address this question, we determined the localization and expression of the PGE2 receptor subtypes (PTGER1-4) and the PGF2alpha receptor (PTGFR) in paired upper and lower segment myometrium, amnion, and choriodecidual samples throughout human pregnancy, with and without labor. All receptor subtypes were found throughout the muscle layers in both the upper and lower uterine segments, colocalizing with alpha smooth muscle actin. A change in intracellular localization was observed at term labor, where PTGER1 and PTGER4 were predominately associated with the nucleus. Minimal changes in the expression of the PGE2 and PGF2alpha receptor subtypes were observed with gestational age, labor, or between the upper and lower myometrial segments. Receptor expression in maternal and fetal tissues differed between the receptor subtypes; PTGER1 and PTGER4 were predominately expressed in the fetal membranes, PTGER2 was greatest in the myometrium, whereas PTGER3 and PTGFR were similarly expressed in the myometrium and fetal membranes. Myometrial activation through the prostaglandin receptors is perhaps more subtle and may be mediated by a balance between one or several of the prostaglandin receptor subtypes together with other known contraction associated proteins. Lack of coordination in receptor expression between the myometrium and fetal membranes may indicate different regulatory mechanisms between these tissues, or it may suggest a function for these receptors in the amnion and choriodecidua that is independent of that seen in the myometrium.

  1. Synchronization of estrus in suckled beef cows for detected estrus and artificial insemination and timed artificial insemination using gonadotropin-releasing hormone, prostaglandin F2alpha, and progesterone.

    PubMed

    Larson, J E; Lamb, G C; Stevenson, J S; Johnson, S K; Day, M L; Geary, T W; Kesler, D J; DeJarnette, J M; Schrick, F N; DiCostanzo, A; Arseneau, J D

    2006-02-01

    We determined whether a fixed-time AI (TAI) protocol could yield pregnancy rates similar to a protocol requiring detection of estrus, or estrous detection plus TAI, and whether adding a controlled internal device release (CIDR) to GnRH-based protocols would enhance fertility. Estrus was synchronized in 2,598 suckled beef cows at 14 locations, and AI was preceded by 1 of 5 treatments: 1) a CIDR for 7 d with 25 mg of PG F(2alpha) (PGF) at CIDR removal, followed by detection of estrus and AI during the 84 h after PGF; cows not detected in estrus by 84 h received 100 mug of GnRH and TAI at 84 h (control; n = 506); 2) GnRH administration, followed in 7 d with PGF, followed in 60 h by a second injection of GnRH and TAI (CO-Synch; n = 548); 3) CO-Synch plus a CIDR during the 7 d between the first injection of GnRH and PGF (CO-Synch + CIDR; n = 539); 4) GnRH administration, followed in 7 d with PGF, followed by detection of estrus and AI during the 84 h after PGF; cows not detected in estrus by 84 h received GnRH and TAI at 84 h (Select Synch & TAI; n = 507); and 5) Select Synch & TAI plus a CIDR during the 7 d between the first injection of GnRH and PGF (Select Synch + CIDR & TAI; n = 498). Blood samples were collected (d -17 and -7, relative to PGF) to determine estrous cycle status. For the control, Select Synch & TAI, and Select Synch + CIDR & TAI treatments, a minimum of twice daily observations for estrus began on d 0 and continued for at least 72 h. Inseminations were performed using the AM/PM rule. Pregnancy was diagnosed by transrectal ultrasonography. Percentage of cows cycling at the initiation of treatments was 66%. Pregnancy rates (proportion of cows pregnant to AI of all cows synchronized during the synchronization period) among locations across treatments ranged from 37% to 67%. Pregnancy rates were greater (P < 0.05) for the Select Synch + CIDR & TAI (58%), CO-Synch + CIDR (54%), Select Synch & TAI (53%), or control (53%) treatments than the CO-Synch (44

  2. Prostaglandin F2alpha potentiates cortisol production by stimulating 11beta-hydroxysteroid dehydrogenase 1: a novel feedback loop that may contribute to human labor.

    PubMed

    Alfaidy, N; Xiong, Z G; Myatt, L; Lye, S J; MacDonald, J F; Challis, J R

    2001-11-01

    In human pregnancy, cortisol and PGs are involved in the onset of labor and play an important role in the mechanisms leading to parturition. Recent studies have shown that at term, cortisol increases PG synthesis and decreases PG metabolism in chorion trophoblast (CT) cells. In CT, 11 beta-hydroxysteroid oxidase type 1 (11 beta-HSD1) converts biologically inactive cortisone to cortisol to regulate cortisol availability. In the present study, we have investigated whether 11 beta-HSD1 activity could be influenced by PGs. We have shown that in CT, PGF2alpha rapidly increased 11 beta-HSD1 reductase activity in a dose-dependent manner via the PGF2alpha receptor, localized in the fetal membranes. PGF2alpha stimulated 11 beta-HSD1 activity through increased intracellular calcium mobilization, activation of PKC, and the phosphorylation of the 11 beta-HSD enzyme. We propose that within CT there is a novel feed forward loop by which PGF2alpha acts to promote cortisol production from cortisone through increases in 11beta-HSD1, and this in turn leads to further net PG output for the onset of labor and birth.

  3. Variation in plasma concentrations of oestradiol-17 beta and their relationship to those of progesterone, 13,14-dihydro-15-keto-prostaglandin F-2 alpha and oxytocin across pregnancy and at parturition in pony mares.

    PubMed

    Haluska, G J; Currie, W B

    1988-11-01

    Concentrations of plasma progesterone were similar to values reported in the literature except that a significant decrease in progesterone during the last day, but before parturition, was detected by systematic, high-intensity blood sampling. Mean concentrations of oestradiol-17 beta increased sharply and significantly, plateaued for 132.8 +/- 1.5 days (mean +/- s.e.m., N = 9), then declined sharply in each mare. There was obvious variation between the mares in when these increases and decreases in oestradiol-17 beta occurred, with the events being related closely to ambient photoperiod conditions rather than to the stage of pregnancy. Concentration of 13,14-dihydro-15-keto-prostaglandin F-2 alpha (PGFM) remained at low levels (less than 400 pg/ml) until Day 200 then increased to peak pregnancy levels (greater than 2000 pg/ml) by Day 300 and remained at this value until parturition. The concentrations of oxytocin remained basal (less than 15 microU/ml) throughout pregnancy and increased only at the beginning of the expulsive stage of labour. There was an increase, although not statistically significant, in the relative concentrations of oestradiol-17 beta to progesterone beginning 3 days before parturition, with the highest value of the ratio occurring at fetal delivery. Far more striking were acute changes in PGFM and oxytocin during parturition. Maximal concentrations of PGFM (approximately 30 ng/ml) and oxytocin (greater than 200 microU/ml) were measured between rupture of the chorioallantois and the completion of delivery. Closely timed samples from one animal showed that oxytocin increased (more than 10 standard deviations of the mean levels during late pregnancy for this animal) before any change in PGFM. In another dystocic mare, both oxytocin and PGFM peaked in the initial stages of delivery but only oxytocin remained elevated until the dystocia was remedied. The results suggest that an abrupt increase in oxytocin secretion precipitates the expulsive phase

  4. The relationship between the production and the anti-gonadotrophic action of prostaglandin F 2 alpha in luteal cells from the marmoset monkey (Callithrix jacchus) in the early and mid-luteal phase.

    PubMed

    Webley, G E; Michael, A E; Abayasekara, D R E

    2010-04-01

    To address the potential luteolytic role for prostaglandin F(2 alpha) (PGF(2 alpha)) in the corpus luteum of the common marmoset monkey (Callithrix jacchus), the ability of marmoset luteal cells, maintained in monolayer culture, to produce PGF(2 alpha) was determined in vitro in the presence and absence of human chorionic gonadotrophin (hCG) and other established pharmacological modulators of PGF(2 alpha) synthesis. We also assessed the effects of the PGF(2 alpha) analogue, cloprostenol, on progesterone output from luteal cells isolated in the early luteal phase versus the mid-luteal phase (days 3 and 14 post ovulation, respectively). Cloprostenol had no effect on progesterone output from luteal cells isolated on day 3 of the luteal phase, whereas it significantly inhibited both basal and hCG-stimulated progesterone synthesis by day 14 luteal cells during the culture period 48-72 h (P<0.001). Intra-luteal PGF(2 alpha) concentrations were 5-fold higher in luteal cells isolated in the early luteal phase than in mid-luteal phase cells (16.5+/-3.5 versus 3.5+/-0.6 pmol/10(5) cells). While PGF(2 alpha) production was unaffected by hCG in vitro, it was decreased by indomethacin (1000 ng/ml) (P<0.05) and stimulated by the calcium ionophore A23187 (10 micromol/l) (P<0.05) in luteal cells from both stages of the luteal phase. Phospholipase A(2) did not influence PGF(2 alpha) production by day 3 luteal cells whereas at 10 IU/ml, it significantly stimulated PGF(2 alpha) production by day 14 luteal cells (P<0.05). Hence, the timing of luteolysis in the common marmoset monkey appears to involve changes in both the luteal cell response to and production of PGF(2 alpha).

  5. Role of intestinal epithelial cells in the host secretory response to infection by invasive bacteria. Bacterial entry induces epithelial prostaglandin h synthase-2 expression and prostaglandin E2 and F2alpha production.

    PubMed Central

    Eckmann, L; Stenson, W F; Savidge, T C; Lowe, D C; Barrett, K E; Fierer, J; Smith, J R; Kagnoff, M F

    1997-01-01

    Increased intestinal fluid secretion is a protective host response after enteric infection with invasive bacteria that is initiated within hours after infection, and is mediated by prostaglandin H synthase (PGHS) products in animal models of infection. Intestinal epithelial cells are the first host cells to become infected with invasive bacteria, which enter and pass through these cells to initiate mucosal, and ultimately systemic, infection. The present studies characterized the role of intestinal epithelial cells in the host secretory response after infection with invasive bacteria. Infection of cultured human intestinal epithelial cell lines with invasive bacteria, but not noninvasive bacteria, is shown to induce the expression of one of the rate-limiting enzymes for prostaglandin formation, PGHS-2, and the production of PGE2 and PGF2alpha. Furthermore, increased PGHS-2 expression was observed in intestinal epithelial cells in vivo after infection with invasive bacteria, using a human intestinal xenograft model in SCID mice. In support of the physiologic importance of epithelial PGHS-2 expression, supernatants from bacteria-infected intestinal epithelial cells were shown to increase chloride secretion in an in vitro model using polarized epithelial cells, and this activity was accounted for by PGE2. These studies define a novel autocrine/paracrine function of mediators produced by intestinal epithelial cells in the rapid induction of increased fluid secretion in response to intestinal infection with invasive bacteria. PMID:9218506

  6. A study of prostaglandin F2alpha as the luteolysin in swine: III effects of estradiol valerate on prostaglandin F, progestins, estrone and estradiol concentrations in the utero-ovarian vein of nonpregnant gilts.

    PubMed

    Frank, M; Bazer, F W; Thatcher, W W; Wilcox, C J

    1977-01-01

    Polyvinyl catheters were placed into the right and left utero-ovarian veins and saphenous vein and artery of three control (C) and four estradiol valerate (EV) treated gilts on Day 9 after onset of estrus. The EV treated gilts received 5mg EV/day on Days 11 through 15 after onset of estrus. On Days 12 through 17 utero-ovarian vein blood samples were collected at 15 min intervals from 0700 to 1000 hr and 1900 to 2200 hr and single samples were taken at 1100 and 2300 hr. Peripheral blood samples (saphenous vein or artery) were taken at 0700, 1100, 1900 and 2300 hr from Day 12 until the control gilts returned to estrus or until Day 25 for EV treated gilts and used to measure plasma steroid hormone concentrations. Utero-ovarian vein prostaglandin F (gf) concentrations (ng/ml, n-1,177) were measured by RIA. Status (control vs EV treated gilts) by day interactions were detected (P=.10). Curvilinear day trends were detected for plasma PGF concentrations in control (P less than .01) but not EV treated gilts. PGF concentrations (X +/- S.D.) for control and EV treated gilts were 1.20 +/- 2.08 and .26 +/- .84 ng/ml, respectively. PGF peaks (concentrations greater than X + 2 S.D.) occurred with greater frequency in control gilts (X2 =4.87; P less than .05). The interestrus interval (X +/- S.E.) for control and treated gilts was 19.0 +/- .6 and 146.5 +/- 74.8 days, respectively. Data indicate tht t estradiol valerate may exert its luteotrophic effect by preventing PGF release from the uterus.

  7. Liquid chromatography-high resolution mass spectrometry with immunoaffinity clean-up for the determination of the oxidative stress biomarker 8-iso-prostaglandin F2alpha in wastewater.

    PubMed

    Ryu, Yeonsuk; Reid, Malcolm J; Thomas, Kevin V

    2015-08-28

    A reliable oxidative stress biomarker, 8-iso-prostaglandin F2α (8-iso-PGF2α), was for the first time quantitatively analysed in wastewater using an analytical method consisting of liquid chromatography-high resolution mass spectrometry coupled to immunoaffinity clean-up (IAC-LC-HRMS). Factors influencing the method's robustness were investigated, including analyte stability in sewage and enzymatic deconjugation with β-glucuronidase. The IAC-LC-HRMS method was linear over the range of 0.1-100ng/mL with correlation coefficient (R(2)) of 0.999. The quantification limits were sufficiently low to detect 8-iso-PGF2α in sewage (method quantification limit of 0.3ng/L) and precision, expressed as relative standard deviation was less than 7% and the accuracy expressed as relative recovery was in the 103-113% range. As a result, the application of the method to 24-h composite wastewater samples from Oslo showed 8-iso-PGF2α concentrations of 18.9-23.3ng/L for 8 days in March 2015. This study demonstrates a standard method to analyse 8-iso-PGF2α in sewage that will contribute to the further investigation of the potential use of 8-iso-PGF2α as a sewage biomarker for assessing the status of community health. Copyright © 2015 Elsevier B.V. All rights reserved.

  8. Effect of the aromatase inhibitor CGS-16949A on pregnancy and secretion of progesterone, estradiol-17beta, prostaglandins E and F2alpha (PGE; PGF2alpha) and pregnancy specific protein B (PSPB) in 90-day ovariectomized pregnant ewes.

    PubMed

    Weems, Y S; Bridges, P J; LeaMaster, B R; Sasser, R G; Ching, L; Weems, C W

    2001-09-01

    The aromatase inhibitor CGS-16949A was used to determine whether CGS-16949A altered secretion of progesterone, estradiol-17beta, PGE (PGE1 + PGE2), PGF2alpha and PSPB. Ninety day pregnant ewes were ovariectomized and received vehicle, PGF2alpha, CGS-16949A or PGF2alpha+CGS-16949A. None of the ewes treated with PGF2alpha, CGS-16949A or PGF2alpha+CGS-16949A aborted (P > or = 0.05) during the 108-h experimental period. Treatment with CGS-16949A lowered (P < or = 0.05) progesterone in jugular venous plasma but concentrations of progesterone were not affected (P > or = 0.05) by treatment with PGF2alpha. Concentrations of estradiol-17beta and PSPB in jugular venous plasma and PGE in inferior vena cava plasma were decreased (P < or = 0.05) by treatment with CGS-16949A. Concentrations of PGF2alpha in inferior vena cava plasma were not affected (P > or = 0.05) by treatment with CGS-16949A. Decreases in estradiol-17beta occurred before decreases in PSPB, which was then followed by decreases in PGE (P < or = 0.05). It is concluded that these data support the hypothesis that estradiol-17beta regulates placental secretion of PSPB; PSPB regulates placental secretion of PGE; and PGE regulates placental secretion of progesterone during mid-pregnancy in ewes.

  9. The influence of prostaglandins on sperm motility.

    PubMed

    Schlegel, W; Rotermund, S; Färber, G; Nieschlag, E

    1981-01-01

    Prostaglandin E2 and F2 alpha were measured in ejaculates from 10 fertile and 55 infertile men. Prostaglandin F2 alpha was negatively correlated with motility (r = 0.77; p less than 0.01) in normal men. In patients with disturbed fertility, prostaglandin F2 alpha was always higher than in the controls, while prostaglandin E2 was elevated only in patients with persisting varicocele and in those with very low sperm counts and severely impaired motility. There was neither de novo synthesis of prostaglandins in spermatozoa nor were binding sites for prostaglandin E2 and F2 alpha detectable. Inactivation of seminal prostaglandins by incubation with prostaglandin 15-hydroxydehydrogenase resulted in a dramatic fall in motility. The results suggest that prostaglandin F2 alpha act on motility, but the action is not mediated by receptors.

  10. Canine prostaglandin F2alpha receptor (FP) and prostaglandin F2alpha synthase (PGFS): molecular cloning and expression in the corpus luteum.

    PubMed

    Kowalewski, Mariusz Pawel; Mutembei, Henry M'ikiugu; Hoffmann, Bernd

    2008-08-01

    In the dog luteolysis is not affected by hysterectomy. This observation led to the hypothesis that paracrine/autocrine rather than endocrine mechanisms of PGF2alpha are responsible for luteal regression in the dioestric bitch. The present experiments tested for the capacity of canine CL to produce and respond to PGF2alpha by qualitatively and quantitatively determining the expressions of PGFS, the enzyme converting PGH2 into PGF2alpha, and the PGF2alpha-receptor (FP) in CL of non-pregnant dogs during dioestrus. Canine PGFS and FP were isolated and cloned; both genes show a high homology (82-94%) when compared to those of other species. Relatively weak FP mRNA expression was detected on day 5 of dioestrus. It had increased by day 25 and remained constant thereafter. In situ hybridization (ISH) localized FP solely to the cytoplasm of the luteal cells, suggesting that these cells are the only luteal targets of PGF2alpha in this species. Only negative results were obtained for the expression of PGFS in canine CL by routine qualitative RT-PCR. When Real Time (TaqMan) PCR was applied, repetitively more negative than positive results were obtained at all timepoints. Any positive measurements observed at any point were neither repeatable nor related to the stage of dioestrus. This led us to conclude that expression of PGFS is either absent or present at very low level only. These data suggest that luteal regression in non-pregnant bitches is not modulated by PGF2alpha. However, the FP seems to be constitutionally expressed, explaining the receptivity of canine CL to exogenous PGF2alpha.

  11. Effect of prostaglandin F2alpha on subclinical endometritis and fertility in dairy cows.

    PubMed

    Galvão, K N; Frajblat, M; Brittin, S B; Butler, W R; Guard, C L; Gilbert, R O

    2009-10-01

    The objectives were to determine the effects of PGF(2alpha) treatment on the prevalence of subclinical endometritis (SCE) and fertility of dairy cows. A total of 406 Holstein cows (167 primiparous and 239 multiparous) from 5 herds were used. Uterine lavage for diagnosis of SCE, PGF(2alpha) treatment, evaluation of body condition scores (BCS), and collection of blood samples for estrous cyclicity determination were performed at 21, 35, and 49 d in milk (DIM). Polymorphonuclear cells (PMN) were quantified and thresholds for diagnosing SCE were selected by receiver operating characteristics analysis. Cows classified as having SCE at 35 DIM (>or=6.5% PMN) and 49 DIM (>or=4.0% PMN) had increased time to pregnancy; however, cows classified as having SCE at 21 DIM (>or=8.5% PMN) did not. Median days to pregnancy were delayed by 30 (151 vs. 121 d) and 40 (169 vs. 129) d for cows classified as having SCE at 35 and 49 DIM, respectively. Treatment with PGF(2alpha) did not affect the prevalence of SCE either at 35 (37.9 vs. 38.4%) or at 49 DIM (34.0 vs. 40.4%). Treatment with PGF(2alpha) did not affect time to first insemination (AI; median 76 DIM for cows treated with PGF(2alpha); 79 DIM for control. Nonetheless, PGF(2alpha) treatment increased pregnancy to first AI in all the cows (35.5 vs. 24.1%) and hazard ratio (HR) of pregnancy in cows with BCS

  12. Midtrimester abortion with intravenous administration of 15 methyl prostaglandin F2 alpha.

    PubMed

    Mapa, M K; Kochhar, U; Raghavan, K S; Devi, P K

    1982-04-01

    In a trial of 71 women, 15(S) 15 methyl PGF2 alpha was administered intravenously at the dose level of 1 microgram/min for termination of pregnancy of between 11 weeks and 20 weeks of gestation. Sixty-one subjects (85.9%) aborted within 30 h of administration of the drug. The mean induction abortion interval was 15.65 h. The mean number of episodes of vomiting and diarrhea was 0.9 and 0.6, respectively. The effectiveness of the method is comparable to that of intramuscular method of administration, but the side effects are much less in comparison.

  13. Extra-amniotic prostaglandin F2alpha in gel for prelabor cervical ripening.

    PubMed

    Thiery, M; Parewyck, W; de Gezelle, H; van Kets, H; Derom, R; Martens, G

    1978-08-01

    In 22 normal term gravidas with unfavorable cervix, 5 mg PGF2alpha in Tylose gel was instilled into the extra-amniotic space. The treatment improved the cervical state so much that the women could be successfully induced by conventional methods. The procedure was well tolerated by the mother and it appeared to be perinatally safe.

  14. Steroidal regulation of uterine resistance to bacterial infection in livestock

    PubMed Central

    Lewis, Gregory S

    2003-01-01

    Postpartum uterine infections reduce reproductive efficiency and have significant animal welfare and economic consequences. Postpartum uterine infections are classified as nonspecific, but Arcanobacterium pyogenes and Escherichia coli are usually associated with them in cattle and sheep. Pyometra is the most common type of uterine infection in dairy cattle, and it is detected almost exclusively in cows with active corpora lutea. Luteal progesterone typically down-regulates uterine immune functions and prevents the uterus from resisting infections. Progesterone also can down-regulate uterine eicosanoid synthesis. This seems to be a critical event in the onset of uterine infections, because eicosanoids can up-regulate immune cell functions in vitro. In addition, exogenous prostaglandin F2 alpha stimulates uterine secretion of prostaglandin F2 alpha and enhances immune functions in vivo. Thus, one may hypothesize that eicosanoids can override the negative effects of progesterone and that the up-regulatory effects of exogenous prostaglandin F2 alpha allow the uterus to resolve an infection, regardless of progesterone concentrations. Based on the results of studies to test that hypothesis, cows, sheep, and pigs in various physiological statuses are resistant to intrauterine infusions of Arcanobacterium pyogenes and Escherichia coli, unless progesterone concentrations are increased. In sheep and pigs, exogenous prostaglandin F2 alpha stimulates uterine production of prostaglandin F2 alpha and allows the uterus to resolve Arcanobacterium pyogenes-Escherichia coli-induced infections, even when progesterone is maintained at luteal phase concentrations before and after treatment. Prostaglandin F2 alpha is a proinflammatory molecule that stimulates the production of various proinflammatory cytokines, and it may enhance uterine production of leukotriene B4. Proinflammatory cytokines and leukotriene B4 enhance phagocytosis and lymphocyte functions. Even though there are clear

  15. Insulin/FOXO Signaling Regulates Ovarian Prostaglandins Critical for Reproduction

    PubMed Central

    Edmonds, Johnathan W.; Prasain, Jeevan K.; Dorand, Dixon; Yang, Youfeng; Hoang, Hieu D.; Vibbert, Jack; Kubagawa, Homare M.; Miller, Michael A.

    2010-01-01

    SUMMARY Abnormalities in insulin/IGF-1 signaling are associated with infertility, but the molecular mechanisms are not well understood. Here we use liquid chromatography with electrospray ionization tandem mass spectrometry to show that the C. elegans insulin/FOXO pathway regulates the metabolism of locally acting lipid hormones called prostaglandins. C. elegans prostaglandins are synthesized without prostaglandin G/H synthase homologs, the targets of non-steroidal anti-inflammatory drugs. Our results support the model that insulin signaling promotes the conversion of oocyte polyunsaturated fatty acids (PUFAs) into F-series prostaglandins that guide sperm to the fertilization site. Reduction in insulin signaling activates DAF-16/FOXO, which represses the transcription of germline and intestinal genes required to deliver PUFAs to oocytes in lipoprotein complexes. Nutritional and neuroendocrine cues target this mechanism to control prostaglandin metabolism and reproductive output. Prostaglandins may be conserved sperm guidance factors and widespread downstream effectors of insulin actions that influence both reproductive and nonreproductive processes. PMID:21145501

  16. A comparison of intraamniotic prostaglandin and extraamniotic prostaglandin gel for midtrimester termination of pregnancy.

    PubMed

    Smith, D H; Dalrymple, J C

    1983-02-01

    A comparison between midtrimester abortion induced by the intraamniotic injection of prostaglandin F2 alpha and abortion induced by prostaglandin F2 alpha in Tylose gel administered extraamniotically was made in a group of 40 patients. The induction-abortion interval in the extraamniotic group was 12.1 hours which was significantly shorter (P less than 0.001) than the intraamniotic group (27.6 hours). The placenta was expelled completely more often and there were no cervical lacerations using the extraamniotic method whereas 2 patients required repair of cervical lacerations after intraamniotic prostaglandin. Extraamniotic administration of prostaglandin F2 alpha in Tylose gel is recommended as a safe and more effective method for inducing midtrimester abortion than intraamniotic prostaglandin.

  17. Intravesical prostaglandin F2 for promoting bladder emptying after surgery for female stress incontinence.

    PubMed

    Tammela, T; Kontturi, M; Käär, K; Lukkarinen, O

    1987-07-01

    Prostaglandin F2 alpha 10 mg was administered intravesically in a double-blind placebo-controlled study to promote micturition in cases of urinary retention after operative treatment of urinary stress incontinence in women. Fifteen of 18 patients (83%) succeeded in voiding after treatment with prostaglandin F2 alpha, but the placebo was ineffective in all 18 patients (P less than 0.001). Although the effect of prostaglandin F2 alpha on bladder muscle contraction was short-lived, it seemed to enhance the restoration of bladder motor function with no serious side effects, and thus to be clinically useful in the treatment of post-operative urinary retention.

  18. [Prostaglandins].

    PubMed

    1973-01-01

    The mode of action of prostaglandins (PGs) is today well known; PGs behave as tissular hormones, and exercise their action near the place of their biosynthesis. Such action is exercised through the adenosine cyclic 3',5' monophosphate system. They play an extremely important role in endocrine physiology and pathology, but their pharmaceutical action is mostly evident in inducing delivery at term and in inducing abortion. Several ways of administration, vaginal, intraamniotic, and intrauterine, as well as several modes of dosage have been tried to eliminate the side effects of PGs. PG induced abortion is recommended only between the 15th and the 22nd week of pregnancy; before that time the other classical techniques of abortion are better suited. PGs may induce abortion either by direct action on the myometrium, or by luteolytic destruction of the corpus luteum, thus inhibiting progesterone secretion. PGs may also be used for postcoital contraception since they intervene in induction of menstruation; side effects, however, are very important. If it is true, as it has been reported, that PGE1 and PGE2 can inhibit spermatogenesis and sperm transport, they may eventually be used in male contraception. Aspirin has been proven to inhibit PGs liberation.

  19. Prostaglandin E2 regulates vertebrate haematopoietic stem cell homeostasis

    PubMed Central

    North, Trista E.; Goessling, Wolfram; Walkley, Carl R.; Lengerke, Claudia; Kopani, Kamden R.; Lord, Allegra M.; Weber, Gerhard J.; Bowman, Teresa V.; Jang, Il-Ho; Grosser, Tilo; FitzGerald, Garret A.; Daley, George Q.; Orkin, Stuart H.; Zon, Leonard I.

    2009-01-01

    Haematopoietic stem cell (HSC) homeostasis is tightly controlled by growth factors, signalling molecules and transcription factors. Definitive HSCs derived during embryogenesis in the aorta-gonad-mesonephros region subsequently colonize fetal and adult haematopoietic organs1,2. To identify new modulators of HSC formation and homeostasis, a panel of biologically active compounds was screened for effects on stem cell induction in the zebrafish aorta-gonad-mesonephros region. Here, we show that chemicals that enhance prostaglandin (PG) E2 synthesis increased HSC numbers, and those that block prostaglandin synthesis decreased stem cell numbers. The cyclooxygenases responsible for PGE2 synthesis were required for HSC formation. A stable derivative of PGE2 improved kidney marrow recovery following irradiation injury in the adult zebrafish. In murine embryonic stem cell differentiation assays, PGE2 caused amplification of multipotent progenitors. Furthermore, ex vivo exposure to stabilized PGE2 enhanced spleen colony forming units at day 12 post transplant and increased the frequency of long-term repopulating HSCs present in murine bone marrow after limiting dilution competitive transplantation. The conserved role for PGE2 in the regulation of vertebrate HSC homeostasis indicates that modulation of the prostaglandin pathway may facilitate expansion of HSC number for therapeutic purposes. PMID:17581586

  20. Tandem mass spectrometric quantification of 8-iso-prostaglandin F2alpha and its metabolite 2,3-dinor-5,6-dihydro-8-iso-prostaglandin F2alpha in human urine.

    PubMed

    Schwedhelm, E; Tsikas, D; Durand, T; Gutzki, F M; Guy, A; Rossi, J C; Frölich, J C

    2000-07-07

    Whole body synthesis of F2-isoprostanes, a family of cyclooxygenase-independent eicosanoids formed by free-radical catalysed peroxidation, should be best assessed by quantifying their urinary metabolites. Two methods for the quantitative determination of F2-isoprostane metabolites in human urine performing either thin-layer chromatography (TLC) (method A) or high-performance liquid chromatography (HPLC) (method B) prior to GC-tandem MS are described. Method A allows for simultaneous quantification of 8-iso-PGF2alpha, one prominent member of the F2-isoprostane family, and its major urinary metabolite, 2,3-dinor-5,6-dihydro-8-iso-PGF2alpha. Mean excretion was found to be 223 and 506 pg/mg creatinine of 8-iso-PGF2alpha and 2,3-dinor-5,6-dihydro-8-iso-PGF2alpha, respectively (n=14). A tight correlation existed between the urinary excretion of these two isoprostanes (r=0.86). Method B enables quantification of dinor-dihydro metabolites of various F2-isoprostanes including 8-iso-PGF2alpha. 2,3-Dinor-5,6-dihydro-8-iso-PGF2alpha was found to be an abundant dinor-dihydro F2-isoprostane metabolite. Validity of method A was proven by a combination of HPLC with TLC prior to GC-tandem MS analysis. A correlation was observed between the urinary concentrations of 2,3-dinor-5,6-dihydro-8-iso-PGF2alpha measured by GC-MS and GC-tandem MS (r=0.84).

  1. Prostaglandin signaling regulates ciliogenesis by modulating intraflagellar transport

    PubMed Central

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

    2014-01-01

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

  2. Prostaglandin signalling regulates ciliogenesis by modulating intraflagellar transport.

    PubMed

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

    2014-09-01

    Cilia are microtubule-based organelles that mediate signal transduction in a variety of tissues. Despite their importance, the signalling cascades that regulate cilium formation remain incompletely understood. Here we report that prostaglandin signalling affects ciliogenesis by regulating anterograde intraflagellar transport (IFT). Zebrafish leakytail (lkt) mutants show ciliogenesis defects, and the lkt locus encodes an ATP-binding cassette transporter (ABCC4). We show that Lkt/ABCC4 localizes to the cell membrane and exports prostaglandin E2 (PGE2), a function that is abrogated by the Lkt/ABCC4(T804M) mutant. PGE2 synthesis enzyme cyclooxygenase-1 and its receptor, EP4, which localizes to the cilium and activates the cyclic-AMP-mediated signalling cascade, are required for cilium formation and elongation. Importantly, PGE2 signalling increases anterograde but not retrograde velocity of IFT and promotes ciliogenesis in mammalian cells. These findings lead us to propose that Lkt/ABCC4-mediated PGE2 signalling acts through a ciliary G-protein-coupled receptor, EP4, to upregulate cAMP synthesis and increase anterograde IFT, thereby promoting ciliogenesis.

  3. Prostaglandin F2 alpha stimulates progesterone secretion by porcine luteal cells in vitro throughout the estrous cycle.

    PubMed

    Gadsby, J E; Earnest, K L

    1994-08-01

    In this study we examined the stimulatory effects of PGF2 alpha on progesterone secretion by porcine luteal cells on different days of the estrous cycle, and the effects of PGF2 alpha, A23187 and PMA on progesterone secretion by isolated large and small luteal cells, in vitro. Corpora lutea were obtained from cycling pigs (days 6-16), collagenase dispersed and luteal cells incubated in medium 199 in the absence or presence of increasing doses of PGF2 alpha, A23187, and PMA. Progesterone concentrations in spent media were measured by RIA. PGF2 alpha stimulation of progesterone secretion by mixed luteal cells did not vary significantly throughout the estrous cycle. Progesterone secretion by large, but not small, luteal cells was increased (p < 0.05) in a dose-dependent fashion by PGF2 alpha. A23187 also caused a dose-dependent increase in progesterone secretion by large luteal cells but inhibited small luteal cells. Progesterone secretion by both large and small luteal cells was significantly increased by increasing doses of PMA. We conclude that the stimulatory response of luteal cells to PGF2 alpha in vitro did not correlate with PGF2 alpha receptor concentrations (not measured in this study), and we speculate that calcium/protein kinase C may be involved in mediating the stimulatory action of PGF2 alpha on luteal cell progesterone secretion.

  4. [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.

  5. A comparative study of intra-amniotic saline and two prostaglandin F2alpha dose schedules for midtrimester abortion.

    PubMed

    Edelman, D A; Brenner, W E; Mehta, A C; Philips, F S; Bhatt, R V; Bhiwandiwala, P

    1976-05-15

    The efficacy, side effects, and complications of two intra-amniotic PGF2alpha dose schedules and the unaugmented intra-amniotic instillation of saline are compared. All three methods resulted in satisfactory rates of abortion within a relatively short period of time and within clinically acceptable rates of complications. Each method has its advantages and disadvantages. Further large comparative studies were needed.

  6. 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.

  7. Temperature regulation and prostaglandin E1 fever in scorpions.

    PubMed Central

    Cabanac, M; Le Guelte, L

    1980-01-01

    1. Scorpions Buthus occitanus and Androctonus australis were placed in a temperature gradient where they could select their thermopreferendum. Intrathoracic temperature was recorded continuously. 2. Both species selected 24.8 +/- 1.0 degrees C as their preferred body temperature. No nycthemeral cycle of preference was observed in the experimental conditions. Saline injection did not modify this thermopreferendum. 3. Prostaglandin E1 (PGE1) produced a fever. Duration and magnitude of fevers were related to PGE1 doses in a bell-shaped curve. The longest and highest fevers were obtained with 4 microgram . g-1 PGE1. 4. These results show that there is an ability to produce fever and, thus, indirectly, that there is a set point in body temperature regulation in arthropods, among the oldest known terrestrial animals. PMID:7431238

  8. Prostaglandin E2 Regulation of Chondrocyte Proliferation and Differentiation

    DTIC Science & Technology

    1994-05-01

    increases bone prostaglandin E. Effect of acetylsalicylic acid on disuse osteoporosis studied in dogs. Acta Orthopaedica Scandinavica, 62:238-243. 121...bovine serum, 1% antibiotics, and 50 pg/ml ascorbic acid in 100% humidity at 37oC. Prostaglandin E2 was added to confluent, fourth passage cultures... acid from membrane phospholipids. This, in turn, may lead to the formation of prostaglandins, thromboxanes and prostacyclins through the metabolism of

  9. 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.

  10. Prostaglandins and adenosine in the regulation of sleep and wakefulness.

    PubMed

    Huang, Zhi-Li; Urade, Yoshihiro; Hayaishi, Osamu

    2007-02-01

    Prostaglandin (PG) D2 and adenosine are potent humoral sleep-inducing factors that accumulate in the brain during prolonged wakefulness. PGD2 is produced in the brain by lipocalin-type PGD synthase, which is localized mainly in the leptomeninges, choroid plexus and oligodendrocytes, and circulates in the cerebrospinal fluid as a sleep hormone. It stimulates DP1 receptors on leptomeningeal cells of the basal forebrain to release adenosine as a paracrine signaling molecule to promote sleep. Adenosine activates adenosine A2A receptor-expressing sleep-active neurons in the basal forebrain and the ventrolateral preoptic area. Sleep-promoting neurons in the ventrolateral preoptic area send inhibitory signals to suppress the histaminergic neurons in the tuberomammillary nucleus, which contribute to arousal through histamine H1 receptors. Increased knowledge of the molecular mechanisms by which PGD2 induces sleep through activation of adenosine A2A receptors and inhibition of the histaminergic arousal system will be useful both for a better understanding of sleep/wake regulation and for the development of novel types of sleeping pills or anti-doze drugs.

  11. Histamine and prostaglandin interaction in regulation of oxytocin and vasopressin secretion.

    PubMed

    Knigge, U; Kjaer, A; Kristoffersen, U; Madsen, K; Toftegaard, C; Jørgensen, H; Warberg, J

    2003-10-01

    Prostaglandins and histamine in the hypothalamus are involved in the regulation of oxytocin and vasopressin secretion, and appear to be involved in the mediation of pituitary hormone responses to immunochallenges. Therefore, we investigated in conscious male rats: (i) whether blockade of H1 or H2 receptors affected the oxytocin and vasopressin responses to prostaglandins and (ii) whether blockade of prostaglandin synthesis affected the oxytocin and vasopressin responses to histamine or to Escherichia coli lipopolysaccharide (LPS), in order to determine any interaction between prostaglandins and histamine in the hypothalamus. Oxytocin secretion was dose-dependently stimulated by intracerebroventricular infusion of 1 or 5 microg of PGE1, PGE2 or PGF2alpha, with PGE2 being the most potent of the compounds used. Prior central infusion of the H1 receptor antagonist mepyramine or the H2 receptor antagonist cimetidine significantly inhibited the oxytocin response to all three prostaglandins by approximately 50%. Vasopressin secretion was increased by PGE1 but not by PGE2 or PGF2alpha. The stimulatory effect of PGE1 was almost annihilated by prior administration of mepyramine or cimetidine. Central infusion of histamine or immunochallenge with LPS administered intraperitoneally increased oxytocin and vasopressin secretion four- and two-fold, respectively. Pretreatment with systemic injection of the prostaglandin synthesis inhibitor indomethacin dose-dependently reduced the oxytocin response and prevented the vasopressin response to histamine or LPS. We conclude that histamine and PGE1, PGE2 or PGF2alpha interact in the regulation of oxytocin secretion, whereas histamine and only PGE1 interact in the regulation of vasopressin secretion. Furthermore, histamine as well as LPS may affect oxytocin and vasopressin neurones via activation of prostaglandins, probably in the hypothalamic supraoptic nucleus.

  12. Reduction in urinary prostaglandin excretion in the premenstrual syndrome.

    PubMed

    Piccoli, A; Modena, F; Calò, L; Cantaro, S; Avogadro, A; Nardo, G; Cerutti, R

    1993-12-01

    The purpose of the present work was to study some factors involved in renal handling of salt and water in the premenstrual syndrome (PMS), in which salt and water retention is frequently observed. In 18 women with PMS and in 18 healthy women we studied the levels of cyclic adenosine monophosphate, aldosterone, prostaglandin E2, prostaglandin F2 alpha and kallikrein in urinary samples collected during the luteal phase. There was no difference between the two groups regarding sodium, aldosterone and kallikrein urinary excretion. In the PMS group there was a significant reduction in urinary excretion of cyclic adenosine monophosphate, prostaglandin E2 and prostaglandin F2 alpha with respect to the control group. At multivariate analysis sodium urinary excretion proved not to be the same as the model validated in healthy women. There may be different renal handling of water and electrolytes during the luteal phase of the menstrual cycle in women with PMS.

  13. [COX-2 regulation of prostaglandins in synaptic signaling].

    PubMed

    Yang, Hong-Wei

    2009-10-01

    Cyclooxygenase-2 (COX-2) is a rate-limiting enzyme converting arachidonic acid to prostaglandins (PGs), which is a key messenger in traumatic brain injury- and ischemia-induced neuronal damage and in neuroinflammation. COX-2 is implicated in the pathogeneses of neurodegenerative diseases. Growing evidence implies that the contribution of COX-2 to neuropathology is associated with its involvement in synaptic alteration. Elevation or inhibition of COX-2 has been shown to enhance or suppress excitatory glutamatergic neurotransmission and long-term potentiation (LTP). These events are mainly mediated via PGE2, the predominant reaction product of COX-2, and the PGE2 subtype 2 receptor (EP2). Thus, elucidation of COX-2 in synaptic signaling may provide a mechanistic basis for designing new drugs aimed at preventing, treating or alleviating neuroinflammation-associated neurological disorders.

  14. Prostaglandin signaling regulates nephron segment patterning of renal progenitors during zebrafish kidney development

    PubMed Central

    Poureetezadi, Shahram Jevin; Cheng, Christina N; Chambers, Joseph M; Drummond, Bridgette E; Wingert, Rebecca A

    2016-01-01

    Kidney formation involves patterning events that induce renal progenitors to form nephrons with an intricate composition of multiple segments. Here, we performed a chemical genetic screen using zebrafish and discovered that prostaglandins, lipid mediators involved in many physiological functions, influenced pronephros segmentation. Modulating levels of prostaglandin E2 (PGE2) or PGB2 restricted distal segment formation and expanded a proximal segment lineage. Perturbation of prostaglandin synthesis by manipulating Cox1 or Cox2 activity altered distal segment formation and was rescued by exogenous PGE2. Disruption of the PGE2 receptors Ptger2a and Ptger4a similarly affected the distal segments. Further, changes in Cox activity or PGE2 levels affected expression of the transcription factors irx3b and sim1a that mitigate pronephros segment patterning. These findings show for the first time that PGE2 is a regulator of nephron formation in the zebrafish embryonic kidney, thus revealing that prostaglandin signaling may have implications for renal birth defects and other diseases. DOI: http://dx.doi.org/10.7554/eLife.17551.001 PMID:27996936

  15. MicroRNA and AU-rich element regulation of prostaglandin synthesis

    PubMed Central

    Moore, Ashleigh E.; Young, Lisa E.

    2012-01-01

    Many liness of evidence demonstrate that prostaglandins play an important role in cancer, and enhanced synthesis of prostaglandin E2 (PGE2) is often observed in various human malignancies often associated with poor prognosis. PGE2 synthesis is initiated with the release of arachidonic acid by phospholipase enzymes, where it is then converted into the intermediate prostaglandin prostaglandin H2 (PGH2) by members of the cyclooxygenase family. The synthesis of PGE2 from PGH2 is facilitated by three different PGE synthases, and functional PGE2 can promote tumor growth by binding to four EP receptors to activate signaling pathways that control cell proliferation, migration, apoptosis, and angiogenesis. An integral method of controlling gene expression is by posttranscriptional mechanisms that regulate mRNA stability and protein translation. Messenger RNA regulatory elements typically reside within the 3′ untranslated region (3′UTR) of the transcript and play a critical role in targeting specific mRNAs for posttranscriptional regulation through micro-RNA (miRNA) binding and adenylate- and uridylate-rich element RNA-binding proteins. In this review, we highlight the current advances in our understanding of the impact these RNA sequence elements have upon regulating PGE2 levels. We also identify various RNA sequence elements consistently observed within the 3′UTRs of the genes involved in the PGE2 pathway, indicating these binding sites for miRNAs and RNA-binding proteins to be central regulators of PGE2 synthesis and function. These findings may provide a rationale for the development of new therapeutic approaches to control tumor growth and metastasis promoted by elevated PGE2 levels. PMID:22005950

  16. 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

  17. Effect of timing of second prostaglandin F 2 alpha administration in a 5-day, progesterone-based CO-Synch protocol on AI pregnancy rates in beef cows.

    PubMed

    Whittier, W D; Kasimanickam, R K; Currin, J F; Schramm, H H; Vlcek, M

    2010-10-01

    The objective was to compare the timed AI pregnancy rate of Angus-cross beef cows synchronized with a 5-d CO-Synch + CIDR (a progesterone-releasing intravaginal insert) protocol and given two doses of PGF(2 alpha) (PGF), with the first dose in conjunction with CIDR withdrawal on Day 5, and the second dose given either early or late relative to the first dose. All cows (N = 1782) at 16 locations received 100 microg of GnRH + CIDR on Day 0. Cows received 25 mg of PGF concurrent with removal of the CIDR on Day 5, and were randomly allocated within locations to receive a second PGF either early (N = 881; from 0.5 to 3.9 h) or late (N = 901; from 4.5 to 8.15 h) relative to the first PGF treatment. On Day 8 (72 h after CIDR removal), all cows were inseminated and concurrently given 100 microg of GnRH. Cows were fitted with a pressure-sensitive mount detection device (Kamar) at CIDR removal. Cows were observed twice daily through Day 7 and at the time of AI on Day 8 for estrus and Kamar status (estrus - red, partial and lost Kamar versus no estrus - white Kamar) was recorded. Accounting for location, season, AI sire, cow observed in estrus or not at or before timed AI, and treatment by cows observed in estrus interaction, timed AI pregnancy rates were greater for the late (6.45 +/- 0.03 h) than the early (2.25 +/- 0.05 h) interval, 57.2 vs. 52.7%, respectively (P < 0.05). In conclusion, cows that received the second PGF late after the first PGF on the day of CIDR removal in a 5 d CO-Synch + CIDR synchronization protocol had significantly higher timed AI pregnancy rates than those receiving the second PGF early after the first PGF.

  18. Involvement of prostaglandin F2alpha in the adverse effect of PCB 77 on the force of contractions of bovine myometrium.

    PubMed

    Wrobel, Michal H; Rekawiecki, Robert; Kotwica, Jan

    2009-08-21

    Polychlorinated biphenyls (PCBs) stimulate in vitro both the force of myometrial contractions and endometrial secretion of PGF2alpha in cattle. Therefore, the goal of this study was to investigate the participation of PGF2alpha in the effect of PCBs on uterine contractility. For this aim, the myometrial strips were incubated (48h) with PCB 77 at the dose of 1, 10 and 100ng/ml (i.e., 0.0034, 0.034 and 0.34nmol/ml) separately or jointly with indomethacin (INDO, 10(-4)M), which blocks the PGF2alpha synthesis. Next, the force of myometrial strips contractions was measured. Further, the influence of PCB 77 (0.1, 1 and 10ng/ml) on the PGF2alpha secretion from myometrial cells after 6, 24, and 48h and PCB 77 (1 and 10ng/ml) on the mRNA expression of cyclooxygenase 2 (COX-2) and PGF2alpha synthase (PGFS) in myometrial cells after 6 and 24h, was investigated. The increase (P<0.05-0.001) of the contractions force of myometrial strips evoked by each dose of PCB 77, was markedly reduced (P<0.05-001) by INDO. There was an increase (P<0.05-0.001) of both PGF2alpha secretion after all studied periods of cell incubation and mRNA expression for COX-2 and PGFS after 6h treatment of myometrial cells with PCB 77. It can be concluded that myometrial synthesis of PGF2alpha and its further secretion is a part of the mechanism by means of which PCB 77 may affect the force of myometrial contractions in cattle.

  19. Effects of prostaglandins E2, I2 and F2 alpha on the tone of isolated coronary arteries from alloxan-diabetic dogs.

    PubMed

    Palik, I; Koltai, M Z; Hadházy, P; Malomvölgyi, B; Wagner, M; Pogátsa, G

    1982-06-01

    Contractile responses to PGF2 alpha of isolated coronary arteries from 7 healthy and 12 alloxan-diabetic dogs without ketosis were considerably increased by indomethacin and decreased by PGI2. The increasing effect of indomethacin was more prominent on diabetic vessels than on those of normal animals while PGI2 had the same relaxant potency in both groups. The contractions induced by PGF2 alpha were inhibited more effectively by PGI2 than those evoked by PGE2 both in healthy and alloxan-diabetic groups.

  20. Prostaglandin F2alpha added to extended boar semen at processing elicits in vitro myometrial contractility after 72 hours of storage.

    PubMed

    Cheng, H; Althouse, G C; Hsu, W H

    2001-06-01

    Improved fertility will maximize productivity of the swine industry. Myometrial contractility is an essential component in the fertilization process because it is the mechanism by which spermatozoa are transported to the site of fertilization. In the present study, we evaluated the potential use of PGF2alpha supplementation to the extended pig semen in regard to inducing myometrial contractility of sows. Extended boar semen (80 mL) was supplemented with PGF2alpha (5 mg) for 72 h at 17 +/- 1 degrees C. Cumulative doses of 0.1, 1, 10 and 100 microL of the mixture were tested on uterine strips obtained from diestrus sows. An increase in myometrial contractility was recorded with PGF2alpha supplementation when compared to extended semen or extender treatment alone after 72 h of incubation. Addition of PGF2alpha to the extended boar semen at the time of the experiment did not differ from the 72 h treated group. The results from this study support that PGF2alpha preparations can be added to extended doses of boar semen at processing to enhance myometrial contractility at the time of insemination for up to 72 h.

  1. [The effect of Oestrophan Spofa (synthetic analog of prostaglandin F2 alpha) added to the insemination dose on pregnancy and fertility in sows].

    PubMed

    Kozumplík, J; Martinek, J

    1986-04-01

    Laboratory trials were conducted to study the effect of various concentrations of cloprostenol on the motility and morphological changes of the acrosomes of boar spermatozoa. As found, a cloprostenol concentration of 250 ng per ml of semen to 2500 ng per ml of diluted semen has no adverse effect on the motility of spermatozoa and on the morphological changes of their acrosomes. The concentration of 5000 ng of cloprostenol (in the Oestrophan Spofa product) per 1 ml of diluted semen negatively influences the motility of spermatozoa. An insemination dose of 100 ml of diluted sperm treated with 500 ng of cloprostenol was used for the artificial insemination of 152 sows; 166 sows of the same farm inseminated with untreated semen were used as controls. No gilts were included in the trial. Out of the 152 test sows, 113 conceived after the first insemination, i.e. 74.35%, and the average litter size was 10.04 piglets. In the control group, 125 sows delivered their litters, i.e. 75.30% of the total number, the average litter size being 9.96 piglets. Comparing the reproduction parameters of the experimental and control groups it can be said that the treatment of an insemination dose with 500 ng of cloprostenol immediately before insemination had no influence on the pregnancy rate and on the size of litters.

  2. Effect of administration of prostaglandin F2alpha or presence of an estrous teaser bitch on characteristics of the canine ejaculate.

    PubMed

    Kustritz, Margaret V Root; Hess, Milan

    2007-01-15

    Semen was collected from eight dogs after SC administration of 0.1mg/kg PGF2alpha or 0.6 mL 0.9% NaCl solution 15 min prior to collection in the presence or absence of an estrous teaser bitch (switchback design; all dogs given all four treatments in random sequence). There were more spermatozoa (P=0.02) in ejaculates collected after administration of PGF2alpha in the presence of an estrous teaser bitch ((852+/-736)x10(6), mean+/-S.D.) than in ejaculates collected in saline-treated dogs in the absence of a teaser bitch ((371+/-620)x10(6)). However, the number of spermatozoa in the ejaculate of dogs given PGF2alpha in the absence of a teaser bitch and in dogs given saline in the presence of a teaser bitch ((556+/-494 and 600+/-622)x10(6), respectively) were not significantly different from each other or from the other two groups. The percentage of morphologically normal spermatozoa did not vary by treatment (P=0.51). In conclusion, treatment with PGF2alpha and presence of a teaser bitch had an additive effect on the number of spermatozoa. This, coupled with relatively minor side-effects, suggests this is a useful technique to increase number of spermatozoa in a single canine ejaculate.

  3. [Estrus and ovulation synchronization in Merino meat sheep. 1. Effect of Gonavet "Berlin Chemie" after estrus synchronization with prostaglandin F2 alpha in Merino meat sheep].

    PubMed

    Wolf, R; Rommel, W; Richter, A; Bier, H; Tschauschev, P

    1991-01-01

    Oestrus synchronisation by means of PGF2 alpha analogues was followed by injection of Gonavet "Berlin-Chemie" which triggered off an LH peak, 2 to 3 hours from injection. Injection of Gonavet "Berlin-Chemie", 44 hours after PGF2 alpha application, caused synchronisation of all LH peaks. The interval between injection of Gonavet "Berlin-Chemie" and onset of ovulation amounted to 22 hours. The length of ovulation was not accurately determinable. Ovulation was successfully induced to all sheep by application of Gonavet "Berlin-Chemie", 44 or 48 hours after PGF2 alpha injection. Ovulation rates were 1.75 or 1.54. Luteolytic action on sheep of Cloprostenol "Jenapharm", a PGF2 alpha analogue, proved to be just as good as that of Oestrophan (SPOFA).

  4. 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

  5. Prostaglandin reductase-3 negatively modulates adipogenesis through regulation of PPARγ activity[S

    PubMed Central

    Yu, Yu-Hsiang; Chang, Yi-Cheng; Su, Tseng-Hsiung; Nong, Jiun-Yi; Li, Chao-Chin; Chuang, Lee-Ming

    2013-01-01

    Adipocyte differentiation is a multistep program under regulation by several factors. Peroxisome proliferator-activated receptor γ (PPARγ) serves as a master regulator of adipogenesis. However, the endogenous ligand for PPARγ remained elusive until 15-keto-PGE2 was identified recently as an endogenous PPARγ ligand. In this study, we demonstrate that zinc-containing alcohol dehydrogenase 2 (ZADH2; here termed prostaglandin reductase-3, PTGR-3) is a new member of prostaglandin reductase family that converts 15-keto-PGE2 to 13,14-dihydro-15-keto-PGE2. Adipogenesis is accelerated when endogenous PTGR-3 is silenced in 3T3-L1 preadipocytes, whereas forced expression of PTGR-3 significantly decreases adipogenesis. PTGR-3 expression decreased during adipocyte differentiation, accompanied by an increased level of 15-keto-PGE2. 15-keto-PGE2 exerts a potent proadipogenic effect by enhancing PPARγ activity, whereas overexpression of PTGR-3 in 3T3-L1 preadipocytes markedly suppressed the proadipogenic effect of 15-keto-PGE2 by repressing PPARγ activity. Taken together, these findings demonstrate for the first time that PTGR-3 is a novel 15-oxoprostaglandin-Δ13-reductase and plays a critical role in modulation of normal adipocyte differentiation via regulation of PPARγ activity. Thus, modulation of PTGR-3 might provide a novel avenue for treating obesity and related metabolic disorders. PMID:23821743

  6. The regulation of prostaglandin output from term intact fetal membranes by anti‐inflammatory cytokines

    PubMed Central

    Brown, N L; Alvi, S A; Elder, M G; Bennett, P R; Sullivan, M H F

    2000-01-01

    Prostaglandins are some of the main mediators which control parturition, and their production by intrauterine tissues can be up‐regulated by pro‐inflammatory cytokines. Anti‐inflammatory cytokines may oppose these effects, and in this study we have investigated how two such cytokines affected fetal membrane function. Interleukin‐10 (IL‐10) inhibited the output of prostaglandin E2 (PGE2) from intact fetal membranes under basal and lipopolysaccharide (LPS)‐stimulated conditions, and there was a parallel decrease in the expression of mRNA for COX‐2. IL‐10 also inhibited the production of interleukin‐1β (IL‐1β) and the expression of mRNA for IL‐1β, indicating that this cytokine has a broad anti‐inflammatory effect. Transforming growth factor‐β1 (TGF‐β1), which is generally considered to be anti‐inflammatory had opposite effects on PGE2 production, in that it increased the output of PGE2 for up to 8 hr. TGF‐β1 increased levels of type‐2 cyclo‐oxygenase (COX‐2) and cytosolic phospholipase A2 (cPLA2) protein, and also activated the cPLA2 enzyme present; the profile of effects is similar to that of the pro‐inflammatory cytokine IL‐1β, and was not expected. Combinations of TGF‐β1 with IL‐1β also increased PGE2 output and caused appropriate changes in prostaglandin pathway enzymes, whereas TGF‐β1 and IL‐1α had more limited effects. Further studies are needed to establish the physiological significance of these findings, but TGF‐β1 does not seem to act as an inhibitory cytokine in intact fetal membranes at term. PMID:10651950

  7. Regulation of prostaglandin production in intact fetal membranes by interleukin-1 and its receptor antagonist.

    PubMed

    Brown, N L; Alvi, S A; Elder, M G; Bennett, P R; Sullivan, M H

    1998-12-01

    There is strong evidence for the involvement of inflammatory mediators such as interleukin (IL)-1 in the biochemical mechanisms of parturition. Therefore the effects of the IL-1 family (IL-1alpha (1 ng/ml), IL-1beta (1 ng/ml) and the IL-1 receptor antagonist (IL-1ra) (10 ng/ml)) on the regulation of prostaglandin synthesis in term human fetal membranes were investigated. It was found that, after 4 h of culture, IL-1beta increased prostaglandin E2 (PGE2) output approximately twofold. This was associated with both a significant increase in cyclo-oxygenase-2 (COX-2) mRNA levels (approximately fourfold compared with control) and translocation of cytoplasmic phospholipase A2 (cPLA2) from the cytosol to the membrane fraction. IL-1alpha was less effective than IL-1beta at stimulating PGE2 production through similar mechanisms. IL-1ra had no effect on PGE2 output. However, in combination treatments, IL-1ra did not inhibit IL-1alpha- or IL-1beta-stimulated PGE2 output, and increased PGE2 production further compared with IL-1beta alone. IL-1ra decreased IL-1beta-induced COX-2 mRNA expression by about half and significantly increased cPLA2 protein levels, as detected by immunoblotting, when used alone and together with IL-1beta. These results suggest that IL-1ra has partial agonist properties when used together with IL-1alpha and IL-1beta in fetal membranes by increasing cPLA2 protein levels, which leads to an increase in the production of prostaglandins.

  8. Urea-prostaglandin versus hypertonic saline for instillation abortion.

    PubMed

    Binkin, N J; Schulz, K F; Grimes, D A; Cates, W

    1983-08-15

    Authorities have suggested use of a combination of hyperosmolar urea and low-dose prostaglandin F2 alpha as a second-trimester intra-amniotic abortifacient to avoid the disadvantages of hypertonic saline solution. To examine the safety and efficacy of urea-prostaglandin compared with the instillation of saline solution, we analyzed data from a prospective multicenter study conducted in the United States between 1975 and 1978. Both agents were highly effective in producing an abortion. However, urea-prostaglandin had a significantly lower rate of serious complications when compared with saline solution (1.03 versus 2.18 per 100 abortions; p less than 0.001). Urea-prostaglandin also had a significantly shorter induction-to-abortion time (14.2 versus 25.6 hours; p less than 0.001). Urea-prostaglandin, therefore, appears to be superior to hypertonic saline solution as an abortifacient.

  9. 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.

  10. Early transcriptome responses of the bovine midcycle corpus luteum to prostaglandin F2a includes cytokine signaling

    USDA-ARS?s Scientific Manuscript database

    In ruminants, prostaglandin F2alpha (PGF2a)-mediated luteolysis is essential prior to estrous cycle resumption, and is a target for improving fertility. To deduce early PGF2a-provoked changes in the corpus luteum a short time-course (0.5–4 h) was performed on cows at midcycle. A microarray-determin...

  11. Prostaglandin E2 regulates pancreatic stellate cell activity via the EP4 receptor.

    PubMed

    Charo, Chantale; Holla, Vijaykumar; Arumugam, Thiruvengadam; Hwang, Rosa; Yang, Peiying; Dubois, Raymond N; Menter, David G; Logsdon, Craig D; Ramachandran, Vijaya

    2013-04-01

    Pancreatic stellate cells are source of dense fibrotic stroma, a constant pathological feature of chronic pancreatitis and pancreatic adenocarcinoma. We observed correlation between levels of cyclooxygenase 2 (COX-2) and its product prostaglandin E2 (PGE2) and the extent of pancreatic fibrosis. The aims of this study were to delineate the effects of PGE2 on immortalized human pancreatic stellate cells (HPSCs) and to identify the receptor involved. Immunohistochemistry, reverse transcription-polymerase chain reaction and quantitative reverse transcription-polymerase chain reaction were used to assess COX-2, extracellular matrix, and matrix metalloproteinase gene expression. Eicosanoid profile was determined by liquid chromatography-tandem mass spectrometry. Human pancreatic stellate cell proliferation was assessed by MTS assay, migration by Boyden chamber assay, and invasion using an invasion chamber. Transient silencing was obtained by small interfering RNA. Human pancreatic stellate cells express COX-2 and synthesize PGE2. Prostaglandin E2 stimulated HPSC proliferation, migration, and invasion and stimulated expression of both extracellular matrix and matrix metalloproteinase genes. Human pancreatic stellate cells expressed all 4 EP receptors. Only blocking the EP4 receptor resulted in abrogation of PGE2-mediated HPSC activation. Specificity of EP4 for the effects of PGE2 on stellate cells was confirmed using specific antagonists. Our data indicate that PGE2 regulates pancreatic stellate cell profibrotic activities via EP4 receptor, thus suggesting EP4 receptor as useful therapeutic target for pancreatic cancer to reduce desmoplasia.

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

    PubMed

    Genetos, Damian C; Yellowley, Clare E; Loots, Gabriela G

    2011-03-16

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

  13. Tryptophan-2,3-dioxygenase is regulated by prostaglandin E2 in malignant glioma via a positive signaling loop involving prostaglandin E receptor-4.

    PubMed

    Ochs, Katharina; Ott, Martina; Rauschenbach, Katharina J; Deumelandt, Katrin; Sahm, Felix; Opitz, Christiane A; von Deimling, Andreas; Wick, Wolfgang; Platten, Michael

    2015-12-27

    Malignant gliomas and other types of tumors generate a local immunosuppressive microenvironment, which prohibits an effective anti-tumor immune response and promotes tumor growth. Along with others, we have recently demonstrated that catabolism of the essential amino acid tryptophan via tryptophan-2,3-dioxygenase (TDO) is an important mechanism mediating tumor-associated immunosuppression particularly in gliomas. The pathways regulating TDO in tumors, however, are poorly understood. Here we show that prostaglandins enhance TDO expression and enzymatic activity in malignant gliomas via activation of prostaglandin E receptor-4 (EP4). Stimulation with prostaglandin E2 (PGE2 ) up-regulated TDO-mediated kynurenine release in human glioma cell lines while knockdown of the PGE2 receptor EP4 inhibited TDO expression and activity. In human malignant glioma tissue expression of the PGE2 -producing enzyme cyclooxygenase-2 (COX2) and its receptor EP4 were associated with TDO expression both on transcript and protein level. High expression of EP4 correlated with poor survival in malignant glioma patients WHO III-IV. Importantly, treatment of glioma cells with an EP4 inhibitor decreased TDO expression and activity. Moreover, TDO-over-expressing murine gliomas showed increased COX2 and EP4 expression suggesting a positive feedback mechanism in vivo. In summary, targeting EP4 may inhibit - in addition to immunosuppressive COX2 signaling - tryptophan degradation as another important immunosuppressive pathway and thus, could provide a dual clinically relevant immunotherapeutic avenue for the treatment of malignant gliomas. This article is protected by copyright. All rights reserved.

  14. Understanding the role of prostaglandin E2 in regulating human platelet activity in health and disease

    PubMed Central

    Friedman, Eitan A.; Ogletree, Martin L.; Haddad, Elias V.; Boutaud, Olivier

    2015-01-01

    The platelet thrombus is the major pathologic entity in acute coronary syndromes, and antiplatelet agents are a mainstay of therapy. However, individual patient responsiveness to current antiplatelet drugs is variable, and all drugs carry a risk of bleeding. An understanding of the complex role of Prostaglandin E2 (PGE2) in regulating thrombosis offers opportunities for the development of novel individualized antiplatelet treatment. However, deciphering the platelet regulatory function of PGE2 has long been confounded by non-standardized experimental conditions, extrapolation of murine data to humans, and phenotypic differences in PGE2 response. This review synthesizes past and current knowledge about PGE2 effects on platelet biology, presents a rationale for standardization of experimental protocols, and provides insight into a molecular mechanism by which PGE2-activated pathways could be targeted for new personalized antiplatelet therapy to inhibit pathologic thrombosis without affecting hemostasis. PMID:26077962

  15. Prostaglandin E2 regulates melanocyte dendrite formation through activation of PKCζ

    PubMed Central

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

    2007-01-01

    Prostaglandins are lipid signaling intermediates released by keratinocytes in response to ultraviolet irradiation (UVR) in the skin. The main prostaglandin released following UVR is PGE2, a ligand for 4 related G-protein coupled receptors (EP1, EP2, EP3 and EP4). Our previous work established that PGE2 stimulates melanocyte dendrite formation through activation of the EP1 and EP3 receptors. The purpose of the present report is to define the signaling intermediates involved in EP1 and EP3-dependent dendrite formation in human melanocytes. We recently showed that activation of the atypical PKCζ isoform stimulates melanocyte dendricity in response to treatment with lysophosphatidylcholine. We therefore examined the potential contribution of PKCζ activation on EP1 and EP3-dependent dendrite formation in melanocytes. Stimulation of the EP1 and EP3 receptors by selective agonists activated PKCζ, and inhibition of PKCζ activation abrogated EP1 and EP3-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 EP1 and EP3 receptor activation on Rac and Rho activity. Neither Rac nor Rho was activated upon treatment with EP1,3-receptor agonists. We show that melanocytes express only the EP3A1 isoform, but not the EP3B receptor isoform, previously associated with Rho activation, consistent with a lack of Rho stimulation by EP3 agonists. Our data suggest that PKCζ activation plays a predominant role in regulation of PGE2-dependent melanocyte dendricity. PMID:17850789

  16. 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.

  17. 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.

  18. Stimulation of 86Rb+ and 32Pi movements in 3T3 cells by prostaglandins and phorbol esters.

    PubMed

    Moroney, J; Smith, A; Tomei, L D; Wenner, C E

    1978-06-01

    The potent tumor promoter tetradecanoyl phorbol acetate (TPA) induces early changes in ion movements analogous to those induced by prostaglandins E1 and F 2alpha. Among the earliest changes induced by TPA is a significant increase in 32Pi incorporation within 15 minutes incubation of TPA (10(-8)-10(-6) M) with post-confluent Swiss 3T3 mouse embryonic fibroblasts. Similarly, the active phorbol ester homolog 4-beta-OH phorbol didecanoate but not the inactive stereoisomeric 4-alpha-OH phorbol didecanoate stimulated 32Pi incorporation. Also, TPA at the above concentrations stimulated 86Rb+ influx shortly after administration. Both fluxes were ouabain-sensitive in accord with the idea that an early effect of TPA is to alter (Na+ + K+)-ATPase activity. Further, prostaglandin E1 (10(-7)-10(-6) M) and prostaglandin F 2alpha (3 X 10(-9)-10(-7) M) caused a similar stimulation of 86Rb+ and 32Pi uptake. The finding that water-soluble prostaglandin F 2alpha also exhibited stimulatory effects indicated that those hormone-induced responses are not mediated by solvent interactions. The similar responses of phorbol esters and prostaglandin derivatives suggests that phorbol esters and prostaglandin derivatives may act at common membrane sites. The finding that stimulatory effects were observed at discrete times in the logarithmic phase of growth suggests that the activation of membrane receptors may be cell-cycle dependent.

  19. Regulation of prostaglandin EP1 and EP4 receptor signaling by carrier-mediated ligand reuptake

    PubMed Central

    Chi, Yuling; Suadicani, Sylvia O; Schuster, Victor L

    2014-01-01

    After synthesis and release from cells, prostaglandin E2 (PGE2) undergoes reuptake by the prostaglandin transporter (PGT), followed by cytoplasmic oxidation. Although genetic inactivation of PGT in mice and humans results in distinctive phenotypes, and although experiments in localized environments show that manipulating PGT alters downstream cellular events, a direct mechanistic link between PGT activity and PGE2 (EP) receptor activation has not been made. Toward this end, we created two reconstituted systems to examine the effect of PGT expression on PGE2 signaling via two of its receptors (EP1 and EP4). In human embryonic kidney cells engineered to express the EP1 receptor, exogenous PGE2 induced a dose-dependent increase in cytoplasmic Ca2+. When PGT was expressed at the plasma membrane, the PGE2 dose–response curve was right-shifted, consistent with reduction in cell surface PGE2 availability; a potent PGT inhibitor acutely reversed this shift. When bradykinin was used to induce endogenous PGE2 release, PGT expression similarly induced a reduction in Ca2+ responses. In separate experiments using Madin–Darby Canine Kidney cells engineered to express the PGE2 receptor EP4, bradykinin again induced autocrine PGE2 signaling, as judged by an abrupt increase in intracellular cAMP. As in the EP1 experiments, expression of PGT at the plasma membrane caused a reduction in bradykinin-induced cAMP accumulation. Pharmacological concentrations of exogenous PGE2 induced EP4 receptor desensitization, an effect that was mitigated by PGT. Thus, at an autocrine/paracrine level, plasma membrane PGT regulates PGE2 signaling by decreasing ligand availability at cell surface receptors. PMID:25505603

  20. Epidermal growth factor receptor transactivation by intracellular prostaglandin E2-activated prostaglandin E2 receptors. Role in retinoic acid receptor-β up-regulation.

    PubMed

    Fernández-Martínez, Ana B; Lucio Cazaña, Francisco J

    2013-09-01

    The pharmacological modulation of renoprotective factor vascular endothelial growth factor-A (VEGF-A) in the proximal tubule has therapeutic interest. In human proximal tubular HK-2 cells, treatment with all-trans retinoic acid or prostaglandin E2 (PGE2) triggers the production of VEGF-A. The pathway involves an initial increase in intracellular PGE2, followed by activation of EP receptors (PGE2 receptors, most likely an intracellular subset) and increase in retinoic acid receptor-β (RARβ) expression. RARβ then up-regulates transcription factor hypoxia-inducible factor-1α (HIF-1α), which increases the transcription and production of VEGF-A. Here we studied the role in this pathway of epidermal growth factor receptor (EGFR) transactivation by EP receptors. We found that EGFR inhibitor AG1478 prevented the increase in VEGF-A production induced by PGE2- and all-trans retinoic acid. This effect was due to the inhibition of the transcriptional up-regulation of RARβ, which resulted in loss of the RARβ-dependent transcriptional up-regulation of HIF-1α. PGE2 and all-trans retinoic acid also increased EGFR phosphorylation and this effect was sensitive to antagonists of EP receptors. The role of intracellular PGE2 was indicated by two facts; i) PGE2-induced EGFR phosphorylation was substantially prevented by inhibitor of prostaglandin uptake transporter bromocresol green and ii) all-trans retinoic acid treatment, which enhanced intracellular but not extracellular PGE2, had lower effect on EGFR phosphorylation upon pre-treatment with cyclooxygenase inhibitor diclofenac. Thus, EGFR transactivation by intracellular PGE2-activated EP receptors results in the sequential activation of RARβ and HIF-1α leading to increased production of VEGF-A and it may be a target for the therapeutic modulation of HIF-1α/VEGF-A. Copyright © 2013 Elsevier B.V. All rights reserved.

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

    PubMed Central

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

    2014-01-01

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

  2. Prostaglandin E2 regulates macrophage colony stimulating factor secretion by human bone marrow stromal cells.

    PubMed

    Besse, A; Trimoreau, F; Faucher, J L; Praloran, V; Denizot, Y

    1999-07-08

    Bone marrow stromal cells regulate marrow haematopoiesis by secreting growth factors such as macrophage colony stimulating factor (M-CSF) that regulates the proliferation, differentiation and several functions of cells of the mononuclear-phagocytic lineage. By using a specific ELISA we found that their constitutive secretion of M-CSF is enhanced by tumour necrosis factor-alpha (TNF-alpha). The lipid mediator prostaglandin E2 (PGE2) markedly reduces in a time- and dose-dependent manner the constitutive and TNF-alpha-induced M-CSF synthesis by bone marrow stromal cells. In contrast, other lipid mediators such as 12-HETE, 15-HETE, leukotriene B4, leukotriene C4 and lipoxin A4 have no effect. EP2/EP4 selective agonists (11-deoxy PGE1 and 1-OH PGE1) and EP2 agonist (19-OH PGE2) inhibit M-CSF synthesis by bone marrow stromal cells while an EP1/EP3 agonist (sulprostone) has no effect. Stimulation with PGE2 induces an increase of intracellular cAMP levels in bone marrow stromal cells. cAMP elevating agents (forskolin and cholera toxin) mimic the PGE2-induced inhibition of M-CSF production. In conclusion, PGE2 is a potent regulator of M-CSF production by human bone marrow stromal cells, its effects being mediated via cAMP and PGE receptor EP2/EP4 subtypes.

  3. Use of vaginal prostaglandin gel before induction of labour.

    PubMed

    Murphy, A J; Jalland, M; Pepperell, R J; Quinn, M A

    1980-05-01

    Tylose gel containing either 1.5 mg, 3.0 mg or 10.0 mg of prostaglandin F2 alpha was inserted into the posterior vaginal fornix of 165 patients on the evening before induction of labour. A control group of 100 patients received the gel alone. There was a significant reduction in the induction-delivery interval in nulliparae receiving at least 3.0 mg of prostaglandin, whereas, in multiparae all doses achieved this effect. There was also a significant reduction in the incidence of forceps delivery in nulliparae who received 3.0 mg or more of the prostaglandin gel; however, there was no difference in the incidence of spontneous labour, epidural anaesthesia or Caesarean section between the patients who received prostaglandin or those receiving gel alone.

  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. Prostaglandin E2 negatively regulates AMP-activated protein kinase via protein kinase A signaling pathway.

    PubMed

    Funahashi, Koji; Cao, Xia; Yamauchi, Masako; Kozaki, Yasuko; Ishiguro, Naoki; Kambe, Fukushi

    2009-01-01

    We investigated possible involvement of prostaglandin (PG) E2 in regulation of AMP-activated protein kinase (AMPK). When osteoblastic MG63 cells were cultured in serum-deprived media, Thr-172 phosphorylation of AMPK alpha-subunit was markedly increased. Treatment of the cells with PGE2 significantly reduced the phosphorylation. Ser-79 phosphorylation of acetyl-CoA carboxylase, a direct target for AMPK, was also reduced by PGE2. On the other hand, PGE2 reciprocally increased Ser-485 phosphorylation of the alpha-subunit that could be associated with inhibition of AMPK activity. These effects of PGE2 were mimicked by PGE2 receptor EP2 and EP4 agonists and forskolin, but not by EP1 and EP3 agonists, and the effects were suppressed by an adenylate cyclase inhibitor SQ22536 and a protein kinase A inhibitor H89. Additionally, the PGE2 effects were duplicated in primary calvarial osteoblasts. Together, the present study demonstrates that PGE2 negatively regulates AMPK activity via activation of protein kinase A signaling pathway.

  6. Coordinated regulation of fetal and maternal prostaglandins directs successful birth and postnatal adaptation in the mouse

    PubMed Central

    Reese, Jeff; Paria, Bibhash C.; Brown, Naoko; Zhao, Xuemei; Morrow, Jason D.; Dey, Sudhansu K.

    2000-01-01

    Cyclooxygenase (COX)-derived prostaglandins (PGs) regulate numerous maternal–fetal interactions during pregnancy. PGs stimulate uterine contractions and prepare the cervix for parturition, whereas in the fetus, PGs maintain patency of the ductus arteriosus (DA), a vascular shunt that transmits oxygenated placental blood to the fetal systemic circulation. However, the origin and site of action of these PGs remain undefined. To address this, we analyzed mice lacking COX-1 (null mutation) or COX-2 (pharmacologic inhibition) or pups with a double null mutation. Our results show that COX-1 in the uterine epithelium is the major source of PGs during labor and that COX-1−/− females experience parturition failure that is reversible by exogenous PGs. Using embryo transfer experiments, we also show that successful delivery occurs in COX-1−/− recipient mothers carrying wild-type pups, establishing the sufficiency of fetal PGs for parturition. Although patency of the DA is PG dependent, neither COX-1 nor COX-2 expression was detected in the fetal or postnatal DA, and offspring with a double null mutation died shortly after birth with open DAs. These results suggest that DA patency depends on circulating PGs acting on specific PG receptors within the DA. Collectively, these findings demonstrate the coordinated regulation of fetal and maternal PGs at the time of birth but raise concern regarding the use of selective COX inhibitors for the management of preterm labor. PMID:10944235

  7. Prostaglandin F2a activates stress response signaling and induces expression of activating transcription factor 3 (ATF3) in bovine large luteal cells

    USDA-ARS?s Scientific Manuscript database

    The pulsatile uterine secretion of prostaglandin F2 alpha (PGF) triggers the regression of the corpus luteum (CL). Recent studies have explored global changes in gene expression in response to PGF that may contribute to structural and functional regression of the CL. Activating transcription facto...

  8. Modification of cysteine residues by cyclopentenone prostaglandins: interplay with redox regulation of protein function.

    PubMed

    Oeste, Clara L; Pérez-Sala, Dolores

    2014-01-01

    Cyclopentenone prostaglandins (cyPG) are endogenous lipid mediators involved in the resolution of inflammation and the regulation of cell proliferation and cellular redox status. Upon exogenous administration they have shown beneficial effects in models of inflammation and tissue injury, as well as potential antitumoral actions, which have raised a considerable interest in their study for the development of therapeutic tools. Due to their electrophilic nature, the best-known mechanism of action of these mediators is the covalent modification of proteins at cysteine residues through Michael addition. Identification of cyPG targets through proteomic approaches, including MS/MS analysis to pinpoint the modified residues, is proving critical to characterize their mechanisms of action. Among the targets of cyPG are proinflammatory transcription factors, proteins involved in cell defense, such as the regulator of the antioxidant response Keap1 and detoxifying enzymes like GST, and key signaling proteins like Ras proteins. Moreover, cyPG may interact with redox-active small molecules, such as glutathione and hydrogen sulfide. Much has been learned about cyPG in the past few years and this knowledge has also contributed to clarify both pharmacological actions and signaling mechanisms of these and other electrophilic lipids. Given the fact that many cyPG targets are involved in or are targets for redox regulation, there is a complex interplay with redox-induced modifications. Here we address the modification of protein cysteine residues by cyPG elucidated by proteomic studies, paying special attention to the interplay with redox signaling.

  9. Localization and steroid regulation of prostaglandin E2 receptor protein expression in ovine cervix.

    PubMed

    Schmitz, Thomas; Levine, Brian A; Nathanielsz, Peter W

    2006-04-01

    Although prostaglandin E2 (PGE2) has been identified as a central mediator of the cervical ripening process, the mechanisms responsible for PGE2 ripening are still poorly understood, partly because of the lack of information concerning the precise cellular localization and regulation of PGE2 (EP) receptors in the cervix. To provide new insights into the mechanisms of cervical ripening, we used indirect immunofluorescence to localize cervical EP receptor protein expression in ovariectomized ewes and examined the effect of administration of progesterone or estradiol. EP receptors were widely distributed in cervical blood vessels, epithelium of the cervical canal, circular and longitudinal muscles, and stroma. Estradiol replacement decreased EP1 and EP3 receptor protein in blood vessel media (by 23 and 31% respectively, P < 0.05) and decreased EP1 receptor protein expression in the longitudinal muscle layer (by 27%, P < 0.05). Stromal EP1 and EP3 receptor protein expression was also reduced by estradiol (by 29 and 20% respectively, P < 0.05). Progesterone replacement had no significant effect on EP receptor protein expression. The arterial changes would favor PGE2-induced vasodilatation, subsequent edema and leukocyte infiltration during the cervical ripening process whereas the muscular alterations would facilitate smooth muscle relaxation and cervical dilatation. Furthermore, estradiol provoked perinuclear localization of EP3 receptor protein in the longitudinal muscle layer. This latter result suggests that cellular EP receptor localization is regulated by estradiol and that PGE2 may also control smooth muscle contraction and regulate ovine cervical dilatation in an intracrine manner via EP3 receptors.

  10. Connexin 43 hemichannel opening associated with Prostaglandin E(2) release is adaptively regulated by mechanical stimulation.

    PubMed

    Burra, Sirisha; Jiang, Jean X

    2009-05-01

    Osteocytes present in the bone are known to be the major mechanosensory cells. Their involvement in mechanoregulation of bone remodeling is not yet clear. Osteocytes are connected with each other through gap junctions formed by Connexin 43 (Cx43). Apart from forming gap junctions, Cx43 in osteocytes is also present in the form of hemichannels. Recently, we have developed a unique antibody that specifically blocks hemichannels and does not have any effect on gap junctions. Cx43 hemichannels present in osteocytes of the bone are mechanosensory in nature as they open when subjected to mechanical stimulation in the form of fluid flow shear stress (FFSS). Opening of Cx43 hemichannels results in the release of molecules like Prostaglandin E(2) (PGE(2)) that are involved in bone remodeling. Our recent report shows that the opening of Cx43 hemichannels depends on the magnitude and duration of shear stress. When osteocytes are subjected to FFSS followed by a brief rest and reapplication of FFSS, it led to further increase in opening of Cx43 hemichannels. Application of continuous FFSS for longer periods of time (24 hrs) results in decreased opening of hemichannels. These results show that Cx43 hemichannels are adaptive in response to mechanical stimulation, possibly to regulate the release PGE(2) during bone remodeling.

  11. Prostaglandins regulate nuclear localization of Fascin and its function in nucleolar architecture

    PubMed Central

    Groen, Christopher M.; Jayo, Asier; Parsons, Maddy; Tootle, Tina L.

    2015-01-01

    Fascin, a highly conserved actin-bundling protein, localizes and functions at new cellular sites in both Drosophila and multiple mammalian cell types. During Drosophila follicle development, in addition to being cytoplasmic, Fascin is in the nuclei of the germline-derived nurse cells during stages 10B–12 (S10B–12) and at the nuclear periphery during stage 13 (S13). This localization is specific to Fascin, as other actin-binding proteins, Villin and Profilin, do not exhibit the same subcellular distribution. In addition, localization of fascin1 to the nucleus and nuclear periphery is observed in multiple mammalian cell types. Thus the regulation and function of Fascin at these new cellular locations is likely to be highly conserved. In Drosophila, loss of prostaglandin signaling causes a global reduction in nuclear Fascin and a failure to relocalize to the nuclear periphery. Alterations in nuclear Fascin levels result in defects in nucleolar morphology in both Drosophila follicles and cultured mammalian cells, suggesting that nuclear Fascin plays an important role in nucleolar architecture. Given the numerous roles of Fascin in development and disease, including cancer, our novel finding that Fascin has functions within the nucleus sheds new light on the potential roles of Fascin in these contexts. PMID:25808493

  12. 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.

  13. Prostaglandin D2 regulates human colonic ion transport via the DP1 receptor.

    PubMed

    Medani, M; Collins, D; Mohan, H M; Walsh, E; Winter, D C; Baird, A W

    2015-02-01

    Prostaglandin D2 is released by mast cells and is important in allergies. Its role in gastrointestinal function is not clearly defined. This study aimed to determine the effect of exogenous PGD2 on ion transport in ex vivo normal human colonic mucosa. Mucosal sheets were mounted in Ussing chambers and voltage clamped to zero electric potential. Ion transport was quantified as changes in short-circuit current. In separate experiments epithelial monolayers or colonic crypts, isolated by calcium chelation, were treated with PGD2 and cAMP levels determined by ELISA or calcium levels were determined by fluorimetry. PGD2 caused a sustained, concentration-dependent rise in short-circuit current by increasing chloride secretion (EC50=376nM). This effect of PGD2 is mediated by the DP1 receptor, as the selective DP1 receptor antagonist BW A686C inhibited PGD2-induced but not PGE2-induced rise in short-circuit current. PGD2 also increased intracellular cAMP in isolated colonic crypts with no measurable influence on cytosolic calcium. PGD2 induces chloride secretion in isolated human colonic mucosa in a concentration-dependent manner with concomitant elevation of cytoplasmic cAMP in epithelial cells. The involvement of DP2 receptor subtypes has not previously been considered in regulation of ion transport in human intestine. Since inflammatory stimuli may induce production of eicosanoids, selective regulation of these pathways may be pivotal in determining therapeutic strategies and in understanding disease. Copyright © 2014. Published by Elsevier Inc.

  14. Regulation of Rat Intrapulmonary Arterial Tone by Arachidonic Acid and Prostaglandin E2 during Hypoxia

    PubMed Central

    Shi, Hui; Han, Yeshan; Ma, Genshan; Tang, Chengchun; Gu, Yuchun

    2013-01-01

    Aims Arachidonic acid (AA) and its metabolites, prostaglandins (PG) are known to be involved in regulation of vascular homeostasis including vascular tone and vessel wall tension, but their potential role in Hypoxic pulmonary vasoconstriction (HPV) remains unclear. In this study, we examined the effects of AA and PGE2 on the hypoxic response in isolated rat intrapulmonary arteries (IPAs). Methods and Results We carried out the investigation on IPAs by vessel tension measurement. Isotetrandrine (20 µM) significantly inhibited phase I, phase IIb and phase IIc of hypoxic vasoconstriction. Both indomethacin (100 µM) and NS398 attenuated KPSS-induced vessel contraction and phase I, phase IIb and phase IIc of HPV, implying that COX-2 plays a primary role in the hypoxic response of rat IPAs. PGE2 alone caused a significant vasoconstriction in isolated rat IPAs. This constriction is mediated by EP4. Blockage of EP4 by L-161982 (1 µM) significantly inhibited phase I, phase IIb and phase IIc of hypoxic vasoconstriction. However, AH6809 (3 µM), an antagonist of EP1, EP2, EP3 and DP1 receptors, exerted no effect on KPSS or hypoxia induced vessel contraction. Increase of cellular cAMP by forskolin could significantly reduce KPSS-induced vessel contraction and abolish phase I, phase II b and phase II c of HPV. Conclusion Our results demonstrated a vasoconstrictive effect of PGE2 on rat IPAs and this effect is via activation of EP4. Furthermore, our results suggest that intracellular cAMP plays dual roles in regulation of vascular tone, depending on the spatial distribution of cAMP and its coupling with EP receptor and Ca2+ channels. PMID:24013220

  15. Coordinated Regulation Among Progesterone, Prostaglandins, and EGF-Like Factors in Human Ovulatory Follicles.

    PubMed

    Choi, Yohan; Wilson, Kalin; Hannon, Patrick R; Rosewell, Katherine L; Brännström, Mats; Akin, James W; Curry, Thomas E; Jo, Misung

    2017-06-01

    In animal models, the luteinizing hormone surge increases progesterone (P4) and progesterone receptor (PGR), prostaglandins (PTGs), and epidermal growth factor (EGF)-like factors that play essential roles in ovulation. However, little is known about the expression, regulation, and function of these key ovulatory mediators in humans. To determine when and how these key ovulatory mediators are induced after the luteinizing hormone surge in human ovaries. Timed periovulatory follicles were obtained from cycling women. Granulosa/lutein cells were collected from in vitro fertilization patients. The in vivo and in vitro expression of PGR, PTG synthases and transporters, and EGF-like factors were examined at the level of messenger RNA and protein. PGR binding to specific genes was assessed. P4 and PTGs in conditioned media were measured. PGR, PTGS2, and AREG expressions dramatically increased in ovulatory follicles at 12 to 18 hours after human chorionic gonadotropin (hCG). In human granulosa/lutein cell cultures, hCG increased P4 and PTG production and the expression of PGR, specific PTG synthases and transporters, and EGF-like factors, mimicking in vivo expression patterns. Inhibitors for P4/PGR and EGF-signaling pathways reduced hCG-induced increases in PTG production and the expression of EGF-like factors. PGR bound to the PTGS2, PTGES, and SLCO2A1 genes. This report demonstrated the time-dependent induction of PGR, AREG, and PTGS2 in human periovulatory follicles. In vitro studies indicated that collaborative actions of P4/PGR and EGF signaling are required for hCG-induced increases in PTG production and potentiation of EGF signaling in human periovulatory granulosa cells.

  16. 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.

  17. [A brief review of recent achievements concerning biochemistry and physiology of prostaglandins in the eye].

    PubMed

    Kahán, L I; Dekov, A M; Pálfalvi, M; Imre, G

    1999-11-28

    Two prostaglandin molecules have important physiological and pathophysiological role in the tissues of the eye. Prostaglandin F2 alpha takes part in mediating intraocular pressure, prostaglandin E2 is the mediator of inflammation. In case of increased intraocular pressure, latanoprost a derivative of prostaglandin F2 alpha can be applied. Numerous data are available on the favourable intraocular pressure lowering effect of latanoprost. It can be applied as a single hypotensive or it can be combined with eye-drops currently used in glaucoma. It exerts its therapeutic effect by increasing uveoscleral outflow. Inflammation in the eye can be diminished by nonsteroidal anti-inflammatory drugs similarly to inflammations in other tissues of the organism. Literature on nonsteroidal anti-inflammatory drugs is enormous. Molecules of different structures inhibit the synthesis of prostaglandins. Primarily they are useful anti-inflammatory agents, reduce intraocular pressure in secundary glaucoma, inhibit intraocular miosis and prevent development of cystoid macula oedema. Nonsteroidal anti-inflammatory drugs do not exert their effects on prostaglandins themselves, but inhibit their synthesis. Hence the use of both, latanoprost and nonsteroidal anti-inflammatory drugs simultaneously, improves safety of therapy in case of patients prone to uveitis.

  18. Prevention of oxytosis-induced c-Raf down-regulation by (arylthio)cyclopentenone prostaglandins is neuroprotective.

    PubMed

    Shibata, Shoko; Furuta, Kyoji; Oh-Hashi, Kentaro; Ueda, Hiroshi; Kiuchi, Kazutoshi; Hirata, Yoko

    2017-09-06

    Prolonged exposure to high concentrations of glutamate leads to cell type specific glutathione depletion and resulting oxidative stress, known as oxytosis. As a result of glutathione depletion, accumulation of reactive oxygen species and Ca(2+) influx are increased; however, the specific target of oxytosis has yet to be identified. In the present study, we focused on the effect of glutamate-induced oxidative stress on the extracellular-regulated protein kinase (ERK) pathway using the murine hippocampal HT22 cell line. Although the contribution of the ERK pathway to glutamate-induced oxytosis in HT22 cells is controversial, Western blot analysis revealed that glutamate caused down-regulation of mitogen-activated protein kinase kinase kinase (c-Raf) and a resulting decrease in the phosphorylation of c-Raf, as well as of mitogen-activated protein kinase kinase1/2 (MEK1/2) and ERK1/2, downstream components of the c-Raf/MEK/ERK pathway. Furthermore, neuroprotective (arylthio)cyclopentenone prostaglandins prevented glutamate-induced c-Raf down-regulation and consequently maintained the basal activity of c-Raf and its downstream signaling components. A pull-down assay using biotin-labeled cyclopentenone prostaglandins revealed that they preferentially bound to c-Raf relative to other signaling molecules of the ERK pathway, including Ras, MEK1/2, and ERK. These results suggest that neuroprotective (arylthio)cyclopentenone prostaglandins directly bind to c-Raf protein and protect cells from down-regulation of the c-Raf protein itself, resulting in neuroprotection against oxidative stress. Copyright © 2017 Elsevier B.V. All rights reserved.

  19. 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

  20. Tumor necrosis factor-alpha inversely regulates prostaglandin D2 and prostaglandin E2 production in murine macrophages. Synergistic action of cyclic AMP on cyclooxygenase-2 expression and prostaglandin E2 synthesis.

    PubMed

    Fournier, T; Fadok, V; Henson, P M

    1997-12-05

    Increased synthesis of insulin-like growth factor-1 is induced in murine macrophages by prostaglandin E2 (PGE2) and tumor necrosis factor-alpha (TNFalpha). Accordingly, we have investigated mechanisms regulating synthesis of PGE2 that might contribute to autocrine/paracrine effects on insulin-like growth factor-1 production. In response to zymosan, TNFalpha specifically induced a 5-fold increase in PGE2 synthesis, at the same time decreasing PGD2 production in a reciprocal fashion. Activators of cyclic AMP-dependent protein kinase (PKA), such as PGE2 itself or dibutyryl cyclic AMP, did not modify PGE2 production by themselves but potentiated the TNFalpha-induced increase in PGE2; this effect required both RNA and protein synthesis. No significant change in arachidonate release or production of other eicosanoids was observed. The inducible form of cyclooxygenase-2 (COX2) but not of the constitutive form COX1 was implicated in the generation of both PGE2 and PGD2 in these cells by use of specific inhibitors and effects of dexamethasone. Neither COX1 nor COX2 protein levels were affected by TNFalpha or PKA activators used alone, whereas in association, marked up-regulation of COX2 mRNA and protein was observed. Incubations of cells carried out with PGH2 demonstrated that PGE2 synthase activity was increased after a TNFalpha pretreatment. Taken together, our results suggest that TNFalpha induced a switch from the PGD2 to PGE2 synthesis pathway by regulating PGE2 synthase expression and/or activity and that activators of PKA markedly potentiated the TNFalpha-induced increase in PGE2 through up-regulation of COX2 gene expression.

  1. O6.09PROSTAGLANDIN E RECEPTOR-4 ACTIVATION REGULATES TRYPTOPHAN METABOLISM IN HUMAN MALIGNANT GLIOMAS

    PubMed Central

    Ochs, K.; Ott, M.; Rauschenbach, K.J.; Sahm, F.; Opitz, C.A.; von Deimling, A.; Wick, W.; Platten, M.

    2014-01-01

    Malignant gliomas generate a local immunosuppressive microenvironment as well as systemic immunosuppression. Tryptophan-2,3-dioxygenase (TDO)-mediated tryptophan metabolism and the production of immunosuppressive prostaglandins relevantly contribute to this inhibition of anti-glioma immune responses. We now connect these two critical immunosuppressive pathways by demonstrating that prostaglandins enhance TDO expression and enzymatic activity in malignant gliomas via activation of prostaglandin E receptor-4 (EP4). Stimulation with prostaglandin E2 (PGE2) concentration-dependently upregulates TDO-mediated kynurenine release in human glioma cell lines, while knockdown of the PGE2 receptor EP4 inhibits TDO expression and activity. In tissue of human malignant gliomas expression of the PGE2-producing enzyme cyclooxygenase-2 (COX-2) and its receptor EP4 are associated with TDO expression both on transcript and protein level. Of clinical relevance, high expression of EP4 correlates with poor survival in patients with gliomas of the WHO grades III and IV. Importantly, treatment of glioma cells with an EP4 inhibitor decreased TDO expression and activity. In summary targeting EP4 may inhibit both immunosuppressive COX-2 signaling as well as tryptophan degradation and thus could provide a novel immunotherapeutic avenue for the treatment of malignant gliomas.

  2. Prostaglandin-induced iridial pigmentation in primates.

    PubMed

    Selén, G; Stjernschantz, J; Resul, B

    1997-02-01

    Latanoprost, a new ocular hypotensive prostaglandin F2 alpha analogue prodrug, was found to induce increased pigmentation of monkey irides in chronic toxicity studies. This prompted us to investigate the effect of naturally occurring prostaglandins on the monkey iris to determine whether this pigmentary effect is unique for latanoprost or whether it is a class effect of prostaglandins. PGF2 alpha-isopropyl ester (IE), PGE2-IE and latanoprost were applied topically to cynomolgus monkey eyes for 18-44 weeks. One eye of each animal was treated, while the other served as control. In addition, latanoprost was applied to sympathectomized monkey eyes. PGF2 alpha-IE, PGE2-IE, as well as latanoprost, induced increased pigmentation in the monkey eye. The first signs of this effect were seen after about two months of treatment. Latanoprost also induced increased pigmentation in sympathectomized eyes. It is concluded that both naturally occurring prostaglandins and their synthetic analogues can induce increased iridial pigmentation in cynomolgus monkeys, and that the effect does not require the presence of sympathetic nerves.

  3. The effects of sulfasalazine on human male fertility potential and seminal prostaglandins.

    PubMed

    Cosentino, M J; Chey, W Y; Takihara, H; Cockett, A T

    1984-10-01

    Fertility parameters of 10 men with chronic inflammatory bowel disease under treatment with sulfasalazine for at least 5 years were compared to those of 19 control subjects. Seminal parameters examined included ejaculate volume, sperm number and concentration, sperm motility index, sperm viability, pH, zinc concentration, prostaglandins E and F2-alpha, prolactin and 7 classes of sperm morphology. In addition, plasma concentrations of follicle-stimulating hormone, luteinizing hormone, testosterone and prolactin were noted. The data indicate that sulfasalazine therapy reduces semen quality and that this effect can be reversed upon removal from therapy. This reversal is independent of seminal prostaglandin concentrations.

  4. Epigenetic mechanisms regulate the prostaglandin E receptor 2 in breast cancer.

    PubMed

    To, Sarah Q; Takagi, Kiyoshi; Miki, Yasuhiro; Suzuki, Koyu; Abe, Eriko; Yang, Yang; Sasano, Hironobu; Simpson, Evan R; Knower, Kevin C; Clyne, Colin D

    2012-11-01

    The increase in local oestrogen production seen in oestrogen receptor positive (ER+) breast cancers is driven by increased activity of the aromatase enzyme. CYP19A1, the encoding gene for aromatase, is often overexpressed in the oestrogen-producing cells of the breast adipose fibroblasts (BAFs) surrounding an ER+ tumour, and the molecular processes underlying this upregulation is important in the development of breast-specific aromatase inhibitors for breast cancer therapy. Prostaglandin E2 (PGE2), a factor secreted by tumours, is known to stimulate CYP19A1 expression in human BAFs. The hormonal regulation of this process has been examined; however, what is less well understood is the emerging role of epigenetic mechanisms and how they modulate PGE2 signalling. This present study characterises the epigenetic processes underlying expression of the prostanoid receptor EP2 in the context of ER+ breast cancer. Sodium bisulphite sequencing of CpG methylation within the promoter region of EP2 revealed that an inverse correlation existed between methylation levels and relative EP2 expression in breast cancer cell lines MDA-MB-231, MCF7 and MCF10A but not in HS578t and T47D. Inhibition of DNA methylation with 5-aza-2'-deoxycytidine (5aza) and histone deacetylation with Trichostatin A (TSA) resulted in upregulation of EP2 mRNA in all cell lines with varying influences of each epigenetic process observed. Expression of EP2 was detected in human BAFs despite a natively methylated promoter, and this expression was further increased upon 5aza treatment. An examination of 3 triple negative, 3 ductal carcinoma in situ and 3 invasive ductal carcinoma samples revealed that there was no change in EP2 promoter methylation status between normal and cancer associated stroma, despite observed differences in relative mRNA levels. Although EP2 methylation status is inversely correlated to expression levels in established breast cancer cell lines, we could not identify that such a

  5. Prostaglandin E receptor subtype 4 regulates lipid droplet size and mitochondrial activity in murine subcutaneous white adipose tissue.

    PubMed

    Ying, Fan; Cai, Yin; Cai, Yu; Wang, Yu; Tang, Eva Hoi Ching

    2017-09-01

    The purpose of this study was to investigate whether genetic ablation of prostaglandin E receptor subtype 4 (EP4) affects white adipose tissue (WAT) remodeling mediated by β3-adrenergic stimulation. The selective β3-adrenergic agonist, CL316243 (1 mg/kg/d, i.p.) caused a greater increase in metabolic rate in EP4-knockout mice. CL316243 fragmented the unilocular lipid droplet into multilocular lipid vacuoles and increased mitochondrial biogenesis and its activity. These changes were amplified in mice with EP4 deficiency and were selectively seen in subcutaneous WAT. The expression of fat-specific protein (FSP)-27, a protein that promotes fusion of triglycerides and formation of unilocular lipid droplets were diminished, whereas the expression of phosphorylated AMPK, the upstream regulator of FSP27, was enhanced in EP4-deficient mice. The present study showed that EP4 acts as a negative regulator of WAT remodeling, it tightly coordinates rates of triglyceride storage in lipid droplets and mitochondrial respiratory function in subcutaneous white adipocytes through the phosphorylated AMPK-FSP27 signaling axis. Thus, deletion of EP4 increases mitochondrial biogenesis and oxidative capacity in WAT, and fat mass loss ensues in mice.-Ying, F., Cai, Y., Cai, Y., Wang, Y., Tang, E. H. C. Prostaglandin E receptor subtype 4 regulates lipid droplet size and mitochondrial activity in murine subcutaneous white adipose tissue. © FASEB.

  6. Close teamwork between Nrf2 and peroxiredoxins 1 and 6 for the regulation of prostaglandin D2 and E2 production in macrophages in acute inflammation.

    PubMed

    Ishii, Tetsuro

    2015-11-01

    Inflammation is a complex biological self-defense reaction triggered by tissue damage or infection by pathogens. Acute inflammation is regulated by the time- and cell type-dependent production of cytokines and small signaling molecules including reactive oxygen species and prostaglandins. Recent studies have unveiled the important role of the transcription factor Nrf2 in the regulation of prostaglandin production through transcriptional regulation of peroxiredoxins 1 and 6 (Prx1 and Prx6) and lipocalin-type prostaglandin D synthase (L-PGDS). Prx1 and Prx6 are multifunctional proteins important for cell protection against oxidative stress, but also work together to facilitate production of prostaglandins E2 and D2 (PGE2 and PGD2). Prx1 secreted from cells under mild oxidative stress binds Toll-like receptor 4 and induces NF-κB activation, important for the expression of cyclooxygenase-2 and microsomal PGE synthase-1 (mPGES-1) expression. The activated MAPKs p38 and ERK phosphorylate Prx6, leading to NADPH oxidase-2 activation, which contributes to production of PGD2 by hematopoietic prostaglandin D synthase (H-PGDS). PGD2 and its end product 15-deoxy-∆(12,14)-prostaglandin J2 (15d-PGJ2) activate Nrf2 thereby forming a positive feedback loop for further production of PGD2 by L-PGDS. Maintenance of cellular glutathione levels is an important role of Nrf2 not only for cell protection but also for the synthesis of prostaglandins, as mPGES-1 and H-PGDS require glutathione for their activities. This review is aimed at describing the functions of Prx1 and Prx6 in the regulation of PGD2 and PGE2 production in acute inflammation in macrophages and the importance of 15d-PGJ2 as an intrinsic Nrf2 activator. Copyright © 2015 Elsevier Inc. All rights reserved.

  7. Role of Prostaglandin Receptor EP2 in the Regulations of Cancer Cell Proliferation, Invasion, and Inflammation

    PubMed Central

    Dingledine, Ray

    2013-01-01

    Population studies, preclinical, and clinical trials suggest a role for cyclooxygenase-2 (COX-2, PTGS2) in tumor formation and progression. The downstream prostanoid receptor signaling pathways involved in tumorigenesis are poorly understood, although prostaglandin E2 (PGE2), a major COX-2 metabolite which is usually upregulated in the involved tissues, presumably plays important roles in tumor biology. Taking advantage of our recently identified novel selective antagonist for the EP2 (PTGER2) subtype of PGE2 receptor, we demonstrated that EP2 receptor activation could promote prostate cancer cell growth and invasion in vitro, accompanied by upregulation of the tumor-promoting inflammatory cytokines, such as IL-1β and IL-6. Our results suggest the involvement of prostaglandin receptor EP2 in cancer cell proliferation and invasion possibly via its inflammatory actions, and indicate that selective blockade of the PGE2-EP2 signaling pathway via small molecule antagonists might represent a novel therapy for tumorigenesis. PMID:23192657

  8. Role of prostaglandin receptor EP2 in the regulations of cancer cell proliferation, invasion, and inflammation.

    PubMed

    Jiang, Jianxiong; Dingledine, Ray

    2013-02-01

    Population studies, preclinical, and clinical trials suggest a role for cyclooxygenase-2 (COX-2, PTGS2) in tumor formation and progression. The downstream prostanoid receptor signaling pathways involved in tumorigenesis are poorly understood, although prostaglandin E2 (PGE(2)), a major COX-2 metabolite which is usually upregulated in the involved tissues, presumably plays important roles in tumor biology. Taking advantage of our recently identified novel selective antagonist for the EP2 (PTGER2) subtype of PGE(2) receptor, we demonstrated that EP2 receptor activation could promote prostate cancer cell growth and invasion in vitro, accompanied by upregulation of the tumor-promoting inflammatory cytokines, such as IL-1β and IL-6. Our results suggest the involvement of prostaglandin receptor EP2 in cancer cell proliferation and invasion possibly via its inflammatory actions, and indicate that selective blockade of the PGE(2)-EP2 signaling pathway via small molecule antagonists might represent a novel therapy for tumorigenesis.

  9. Cytokines, prostaglandins and nitric oxide in the regulation of stress-response systems.

    PubMed

    Gądek-Michalska, Anna; Tadeusz, Joanna; Rachwalska, Paulina; Bugajski, Jan

    2013-01-01

    pituitary. NO also participates in signal transduction pathways that result in the release of corticosterone from the adrenal gland. NO participates in multiple interactions between neuroendocrine and neuroimmune systems in physiological and pathological processes. Neuronal NO synthase (nNOS) modulates learning and memory and is involved in development of neuropsychiatric diseases, including depression. Nitric oxide generated in response to stress exposure is associated with depression-like and anxiety-like behaviors. In the central nervous system (CNS), prostaglandins (PG) generated by the cyclooxygenase (COX) enzyme are involved in the regulation of HPA axis activity. Prior exposure to chronic stress alters constitutive (COX-1) and inducible (COX-2) cyclooxygenase responses to homotypic stress differently in the PFC, hippocampus and hypothalamus. Both PG and NO generated within the PVN participate in this modulation. Acute stress affects the functionality of COX/PG and NOS/NO systems in brain structures. The complex responses of central and peripheral pathways to acute and chronic stress involve cytokines, NO and PG systems that regulate and turn off responses that would be potentially harmful for cellular homeostasis and overall health.

  10. Up-regulation of prostaglandin E receptor EP2 and EP4 subtypes in rat synovial tissues with adjuvant arthritis

    PubMed Central

    Kurihara, Y; Endo, H; Akahoshi, T; Kondo, H

    2001-01-01

    To evaluate the role of the prostaglandin E receptor (EP) subtypes in the development of inflammatory synovitis, we examined EP subtype mRNA distribution in the synovial tissue of rats with adjuvant arthritis and the effect of selective EP agonists on cytokine production by cultured rat synovial cells. We used reverse transcriptase-polymerase chain reaction (RT-PCR) and in situ hybridization to measure the level of EP subtype (EP1, EP2, EP3, and EP4) mRNA expression in synovial tissues and cultured synovial cells from the arthritic joints of rats. RT-PCR and ELISA were used to analyse the effects of two selective EP agonists on IL-6 production by cultured rat synovial cells. EP2 and EP4 mRNA expression in inflamed synovial tissues was up-regulated. EP2 and EP4 mRNA were co-expressed in synovial macrophages and fibroblasts in inflamed tissues. EP4 and EP2 agonists both inhibited IL-1-induced IL-6 production. Our results suggest that prostaglandin E2 regulates the functions of synovial macrophages and fibroblasts through EP2 and EP4, which are induced by inflammatory stimuli in rats with adjuvant arthritis. PMID:11207665

  11. Up-regulation of prostaglandin E receptor EP2 and EP4 subtypes in rat synovial tissues with adjuvant arthritis.

    PubMed

    Kurihara, Y; Endo, H; Akahoshi, T; Kondo, H

    2001-02-01

    To evaluate the role of the prostaglandin E receptor (EP) subtypes in the development of inflammatory synovitis, we examined EP subtype mRNA distribution in the synovial tissue of rats with adjuvant arthritis and the effect of selective EP agonists on cytokine production by cultured rat synovial cells. We used reverse transcriptase-polymerase chain reaction (RT-PCR) and in situ hybridization to measure the level of EP subtype (EP1, EP2, EP3, and EP4) mRNA expression in synovial tissues and cultured synovial cells from the arthritic joints of rats. RT-PCR and ELISA were used to analyse the effects of two selective EP agonists on IL-6 production by cultured rat synovial cells. EP2 and EP4 mRNA expression in inflamed synovial tissues was up-regulated. EP2 and EP4 mRNA were co-expressed in synovial macrophages and fibroblasts in inflamed tissues. EP4 and EP2 agonists both inhibited IL-1-induced IL-6 production. Our results suggest that prostaglandin E2 regulates the functions of synovial macrophages and fibroblasts through EP2 and EP4, which are induced by inflammatory stimuli in rats with adjuvant arthritis.

  12. Endogenous E-type prostaglandins in regulation of basal alkaline secretion by amphibian duodenum in vitro.

    PubMed

    Heylings, J R; Hampson, S E; Garner, A

    1985-01-01

    Segments of proximal duodenum from Rana catesbeiana, stripped of external muscle and mounted as a tube in a glass chamber, alkalinized the luminal-side bathing solution at a rate of 1.70 +/- 0.16 microEq/cm . h (n = 18, gross surface area approximately 1.5 cm2/cm). A single change of the serosal-side bathing solution for fresh solution reduced the rate of titratable alkaline secretion, which achieved a new steady state after 45 min amounting to 66% +/- 2% of the initial rate; transmucosal potential difference (lumen negative) fell from 10.6 +/- 1.2 to 8.8 +/- 1.1 mV. Concentrations of E-type prostaglandins in the serosal-side solution measured by radioimmunoassay were 8.5 nM (3 ng/ml) before, 0.17 nM 5 min after, and 1.7 nM 90 min after the solution change (n = 8). Reapplication of the original bathing solution 90 min after the initial change reestablished original secretory rate and potential difference. The increases in alkaline secretion and potential difference were comparable in magnitude and profile to those induced by serosal administration of 10 nM prostaglandin E2. Addition of the metabolic inhibitor 2,4-dinitrophenol (100 microM, serosal side) reduced basal alkaline secretion to 30% +/- 7% of the initial rate and abolished the potential difference (n = 8). These data demonstrate that endogenous prostaglandin E production by an isolated preparation of amphibian duodenum accounts for a proportion of alkaline secretion that is equivalent to 50% of metabolism-dependent basal secretion.

  13. 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

  14. Prostaglandin F2α regulates the expression of uterine activation proteins via multiple signalling pathways.

    PubMed

    Xu, Chen; You, Xingji; Liu, Weina; Sun, Qianqian; Ding, Xiaoying; Huang, Ying; Ni, Xin

    2015-01-01

    Prostaglandin F2α (PGF2A) has multiple roles in the birth process in addition to its vital contractile role. Our previous study has demonstrated that PGF2A can modulate uterine activation proteins (UAPs) in cultured pregnant human myometrial smooth muscle cells (HMSMCs). The objective of this study was to define the signalling pathways responsible for PGF2A modulation of UAPs in myometrium. It was found that PGF2A stimulated the expression of (GJA1) connexin 43 (CX43), prostaglandin endoperoxide synthase 2 (PTGS2) and oxytocin receptor (OTR) in cultured HMSMCs. The inhibitors of phospholipase C (PLC) and protein kinase C (PKC) blocked PGF2A-stimulated expression of CX43. The inhibitors of ERK, P38 and NFκB also blocked the effect of PGF2A on CX43 expression, whereas PI3K and calcineurin/nuclear factor of activated T-cells (NFAT) pathway inhibitors did not reverse the effect of PGF2A on CX43. For PTGS2 and OTR, PLC, PI3K, P38 and calcineurin/NFAT signalling pathways were involved in PGF2A action, whereas PKC and NFκB signalling were not involved. In addition, PGF2A activated NFAT, PI3K, NFκB, ERK and P38 signalling pathways. Our data suggest that PGF2A stimulates CX43, PTGS2 and OTR through divergent signalling pathways.

  15. Indomethacin blocks pre-partum nest building behaviour in the pig (Sus scrofa): effects on plasma prostaglandin F metabolite, oxytocin, cortisol and progesterone.

    PubMed

    Gilbert, C L; Burne, T H J; Goode, J A; Murfitt, P J E; Walton, S L

    2002-03-01

    In the pig, nest building occurs in the day preceding parturition (gestation=114--116 days). Nest building behaviour can be induced in pregnant, pseudopregnant and cyclic female pigs following injection of prostaglandin F2alpha. Here we investigated behaviour and endocrine changes after the administration of indomethacin, which inhibits cyclo-oxygenase enzymes and thus prostaglandin synthesis. In experiment 1, pregnant primiparous pigs (gilts) were blood sampled through jugular vein catheters every 20 min from 1000 h on day 113 of pregnancy and behaviour was recorded until birth. Two hours after pre-partum nest building began, animals received 4 mg/kg indomethacin (n=7) or control vehicle (n=8) intramuscularly. Indomethacin-treated animals showed less nest building than controls between 1 and 5 h after injection (P<0.05), during which time they were mostly inactive and lay down for longer than controls. From 5 h before birth until birth there was no significant treatment difference in nest building behaviour. There was a tendency for the start of birth to be delayed in indomethacin-treated animals. Plasma 13,14-dihydro-15-keto-prostaglandin F2 alpha (a major metabolite of prostaglandin F2 alpha) rose during pre-injection nest building and then fell following indomethacin treatment, but was not significantly different between groups when behaviour differed. Plasma oxytocin, cortisol and progesterone were not significantly affected by treatment. In experiment 2, indomethacin-treated non-pregnant gilts (n=7) did not show any changes in activity or posture compared with vehicle-treated controls (n=6) between 90 and 150 min after treatment. These results suggested that indomethacin treatment reversibly and specifically inhibits porcine pre-partum nest building by a mechanism that may involve endogenous prostaglandin F2 alpha synthesis inhibition but is independent of circulating oxytocin, cortisol and progesterone concentrations.

  16. Regulation of cyclic AMP metabolism by prostaglandins in rabbit cortical collecting tubule cells

    SciTech Connect

    Sonnenburg, W.K.

    1987-01-01

    In the rabbit cortical collecting tubule (RCCT), prostaglandin E/sub 1/ (PGE/sub 1/) and prostaglandin E/sub 2/ (PGE/sub 2/) at 1 nM inhibit arginine-vasopressin (AVP)-induced water reabsorption, while 100 nM PGE/sub 1/ and PGE/sub 2/ alone stimulate water reabsorption. Reported here are studies designed to investigate the molecular basis for the biphasic physiological action of PGE/sub 1/ and PGE/sub 2/ in the collecting duct. In freshly isolated RCCT cells, PGE/sub 1/, PGE/sub 2/, and 16,16-dimethyl-PGE/sub 2/ (DM-PGE/sub 2/) stimulated cAMP synthesis at concentrations ranging from 0.1 to 10 M. Other prostaglandins including the synthetic PGE/sub 2/ analogue, sulprostone, failed to stimulate cAMP synthesis. Moreover, sulprostone did not antagonize PGE/sub 2/-stimulated cAMP formation. In contrast, PGE/sub 2/ and sulprostone at concentrations ranging from 1 to 100 nM, inhibited AVP-induced cAMP accumulation in freshly isolated RCCT cells. PGE/sub 2/, PGE/sub 1/, DM-PGE/sub 2/ and sulprostone at 100 nM were equally effective in inhibiting AVP-induced cAMP formation. Moreover sulprostone inhibited AVP-stimulated adenylate cyclase activity. These results suggest that PGE derivatives mediate either inhibition or activation of adenylate cyclase by stimulating different PGE receptors. To further test this concept, PGE/sub 2/ binding to freshly isolated RCCT cell membranes was characterized. Two different classes of PGE/sub 2/ binding were detected. //sup 3/H/PGE/sub 2/ binding to the high affinity class of sites was increased by the GTP-analogue, GTP S, while pertussis toxin pretreatment blocked the stimulatory action. In contrast, //sup 3/H/ PGE/sub 2/ binding to the low affinity class of sites was decreased by GTP S; this inhibitory effect was not blocked by pertussis toxin pretreatment.

  17. Molecular cloning, functional expression, and selective regulation of ovine prostaglandin H synthase-2.

    PubMed

    Zhang, V; O'Sullivan, M; Hussain, H; Roswit, W T; Holtzman, M J

    1996-10-14

    Structural characterization for ovine prostaglandin H synthase-1 (PGHS-1) is extensive, but the corresponding structure for the homologous ovine PGHS-2 isoform is undefined. Accordingly, we isolated a full-length (3.4 kb) ovine PGHS-2 cDNA from a primary-culture cell model (ovine tracheal epithelial cells) originally described as containing both PGHS isoforms. Analysis of ovine PGHS-2 cDNA sequence indicated conservation of critical amino acid residues, but differences in other hydrophilic regions allowed for the development of an anti-peptide antibody highly selective for PGHS-2. Enzymatic activities of the recombinant ovine PGHS isozymes indicated significant differences in response to aspirin-acetylation consistent with the characteristics of endogenous cellular PGHS activities under basal and serum-induced conditions. The results fully account for previous evidence of two distinct PGHS activities in cultured airway epithelial cells and provide for additional definition of PGHS structure-function relationships.

  18. [Polymer materials for biomedical use obtained by radiation methods. IV. The therapeutic system for local release of prostaglandins].

    PubMed

    Rosiak, J; Olejniczak, J

    1989-01-01

    The suitability of a radiation crosslinked polyvinylpyrrolidone++ as a therapeutical system for local prostaglandin monitoring has been studied. The effect of the dose and dose rate of ionizing radiation and of the time of heating the matrix on the content of gel fraction and the degree of hydrogel swelling was determined. The dimensions of a polymer network as dependent on the parameters of the process were calculated. For a chosen way of obtaining the therapeutical system, the release of prostaglandin F2 alpha in vitro was also estimated.

  19. Effect of substrate concentration on inhibition of prostaglandin synthetase of bull seminal vesicles by anti-inflammatory drugs and fenamic acid analogs.

    PubMed

    Cushman, D W; Cheung, H S

    1976-03-26

    Although microsomes of bull seminal vesicle synthesize prostaglandins F2alpha, E2 and D2 from arachidonic acid under suitable assay conditions, prostaglandin E2 is the only significant product at either low concentration of arachidonic acid or high concentration of microsomes. Studies of inhibition of prostaglandin synthesis in vitro by anti-inflammatory drugs at both high (1 mM) and low (1 muM) concentrations of arachidonic acid, suggest three distinct mechanisms of inhibition. Benzydamine and flazalone are non-competitive or weakly competitive with arachidonic acid and, at high concentrations of arachidonic acid, they augment sythesis of prostaglandin E2 while inhibiting production of prostaglandins F2alpha and D2. Niflumic acid and the arylacetic acids naproxen and ibuprofen are competitive inhibiting all products equally, but with 100-500-fold greater potency at the low substrate concentration. The fenamic acids, indomethacin, aspirin, and phenylbutazone also inhibit equally all prostaglandin products, but are only 20--50 times more potent at the low substrate concentration. Studies with analogs of the fenamic acids indicate that the diphenylamine protion of their structure is essential for inhibition of prostaglandin synthesis, whereas the o-carboxyl and m-alkul substitutents greatly enhance inhibitory potency.

  20. 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

    2014-03-07

    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.

  1. 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

  2. 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

  3. Histamine up-regulates phosphodiesterase 4 activity and reduces prostaglandin E2-inhibitory effects in human neutrophils.

    PubMed

    Dasí, F J; Ortiz, J L; Cortijo, J; Morcillo, E J

    2000-11-01

    To investigate whether histamine produces up-regulation of phosphodiesterase (PDE) activity with functional consequences in human peripheral blood neutrophils. PDE activity was studied by a radioisotopic method following anion-exchange chromatography. Reverse transcriptase-polymerase chain reaction (RT-PCR) was used for detection of mRNA transcripts of PDE4 subtypes. Cyclic AMP (cAMP) levels were measured by enzyme-immunoassay, and superoxide generation by cytochrome c reduction. Neutrophils were incubated for 4 h with histamine (1 microM). PDE4 was the only isoenzyme activity increased in treated neutrophils. Kinetic analysis showed a approximately 1.5-fold increase in Vmax without alteration of Km values. cAMP content in treated cells was higher than resting values (0.52+/-0.07 vs. 2.75+/-0.31 pmol/10(6) cells). RT-PCR showed increased expression of mRNA transcripts for PDE4B in histamine-treated cells. Functionally, up-regulation of PDE4 reduced the inhibition by prostaglandin E2 of zymosan-induced superoxide generation. Histamine up-regulates PDE4 activity and produces heterologous desensitisation of human neutrophils.

  4. 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.

  5. Production of prostaglandins by the pseudopregnant rat uterus, in vitro, and the effect of tamoxifen with the identification of 6-keto-prostaglandin F1alpha as a major product.

    PubMed Central

    Fenwick, L; Jones, R L; Naylor, B; Poyser, N L; Wilson, N H

    1977-01-01

    1 Prostaglandin production by rat uterus homogenates has been studied, in vitro, on days 2 to 13 of pseudopregnancy. 2 The highest production of prostaglandins occurred on day 5. 3 The amounts of prostaglandins F and D formed were higher than the amounts of prostaglandin E on every day studied. 4 The ratios of prostglandins F and D to prostaglandin E produced steadily decreased up to day 6. It then increased with the highest values occurring between days 10 and 13, 5 Progesterone levels in peripheral plasma increased rapidly from days 2 to 5, remained high up to day 9, then steadily decreased between days 10 and 13. 6 The anti-oestrogenic drug, tamoxifen administered on day 2, significantly inhibited the increase of prostaglandin production which occurred on day 5. Prostaglandin E production was inhibited more than the production of prostaglandins F and D. 7 Analysis of the uterine extracts by gas chromatography and mass spectrometry showed prostaglandin F2alpha, F1alpha (in trace amounts), E2 and D2 to be present. 8 The major product detected was 6-keto-prostaglandin F1alpha. Its identification forms an addendum to the paper. 9 Also present as a major product was 6(9)-oxy-11,15-dihydroxyprosta-7,13-dienoic acid. PMID:836998

  6. Prostaglandin E2 mediates growth arrest in NFS-60 cells by down-regulating interleukin-6 receptor expression.

    PubMed Central

    de Silva, Kumudika I; Daud, Asif N; Deng, JiangPing; Jones, Stephen B; Gamelli, Richard L; Shankar, Ravi

    2003-01-01

    Interleukin-6 (IL-6), a potent myeloid mitogen, and the immunosuppressive prostanoid prostaglandin E2 (PGE2) are elevated following thermal injury and sepsis. We have previously demonstrated that bone marrow myeloid commitment shifts toward monocytopoiesis and away from granulocytopoiesis during thermal injury and sepsis and that PGE2 plays a central role in this alteration. Here we investigated whether PGE2 can modulate IL-6-stimulated growth in the promyelocytic cell line, NFS-60, by down-regulating IL-6 receptor (IL-6r) expression. Exposure of NFS-60 cells to PGE2 suppressed IL-6-stimulated proliferation as well as IL-6r expression. Receptor down-regulation is functionally significant since IL-6-induced signal transduction through activators of transcription (STAT)-3 is also decreased. Down-regulation of IL-6r correlated with the ability of PGE2 to arrest cells in the G0/G1 phase of the cell cycle. PGE2 appears to signal through EP2 receptors. Butaprost (EP2 agonist) but not sulprostone (EP3 agonist) inhibited IL-6-stimulated proliferation. In addition, an EP2 antagonist (AH6809) alleviated the anti-proliferative effects of PGE2. NFS-60 cells express predominantly EP2 and EP4 receptors. While PGE2 down-regulated both the IL-6r protein and mRNA expression, it had no influence on EP2 or EP4 mRNA expression. The present study demonstrates that PGE2 is a potent down-regulator of IL-6r expression and thus may provide a mechanistic explanation for the granulocytopenia seen in thermal injury and sepsis. PMID:12429018

  7. Prostaglandin E2 receptor EP3 regulates both adipogenesis and lipolysis in mouse white adipose tissue.

    PubMed

    Xu, Hu; Fu, Jia-Lin; Miao, Yi-Fei; Wang, Chun-Jiong; Han, Qi-Fei; Li, Sha; Huang, Shi-Zheng; Du, Sheng-Nan; Qiu, Yu-Xiang; Yang, Ji-Chun; Gustafsson, Jan-Åke; Breyer, Richard M; Zheng, Feng; Wang, Nan-Ping; Zhang, Xiao-Yan; Guan, You-Fei

    2016-12-01

    Among the four prostaglandin E2 receptors, EP3 receptor is the one most abundantly expressed in white adipose tissue (WAT). The mouse EP3 gene gives rise to three isoforms, namely EP3α, EP3β, and EP3γ, which differ only at their C-terminal tails. To date, functions of EP3 receptor and its isoforms in WAT remain incompletely characterized. In this study, we found that the expression of all EP3 isoforms were downregulated in WAT of both db/db and high-fat diet-induced obese mice. Genetic ablation of three EP3 receptor isoforms (EP3(-/-) mice) or EP3α and EP3γ isoforms with EP3β intact (EP3β mice) led to an obese phenotype with increased food intake, decreased motor activity, reduced insulin sensitivity, and elevated serum triglycerides. Since the differentiation of preadipocytes and mouse embryonic fibroblasts to adipocytes was markedly facilitated by either pharmacological blockade or genetic deletion/inhibition of EP3 receptor via the cAMP/PKA/PPARγ pathway, increased adipogenesis may contribute to obesity in EP3(-/-) and EP3β mice. Moreover, both EP3(-/-) and EP3β mice had increased lipolysis in WAT mainly due to the activated cAMP/PKA/hormone-sensitive lipase pathway. Taken together, our findings suggest that EP3 receptor and its α and γ isoforms are involved in both adipogenesis and lipolysis and influence food intake, serum lipid levels, and insulin sensitivity. © The Author (2016). Published by Oxford University Press on behalf of Journal of Molecular Cell Biology, IBCB, SIBS, CAS. All rights reserved.

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

    PubMed

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

    2008-01-25

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

  9. 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.

  10. Prostaglandin E2 receptor EP3 regulates both adipogenesis and lipolysis in mouse white adipose tissue

    PubMed Central

    Xu, Hu; Fu, Jia-Lin; Miao, Yi-Fei; Wang, Chun-Jiong; Han, Qi-Fei; Li, Sha; Huang, Shi-Zheng; Du, Sheng-Nan; Qiu, Yu-Xiang; Yang, Ji-Chun; Gustafsson, Jan-Åke; Breyer, Richard M.; Zheng, Feng; Wang, Nan-Ping; Zhang, Xiao-Yan; Guan, You-Fei

    2016-01-01

    Among the four prostaglandin E2 receptors, EP3 receptor is the one most abundantly expressed in white adipose tissue (WAT). The mouse EP3 gene gives rise to three isoforms, namely EP3α, EP3β, and EP3γ, which differ only at their C-terminal tails. To date, functions of EP3 receptor and its isoforms in WAT remain incompletely characterized. In this study, we found that the expression of all EP3 isoforms were downregulated in WAT of both db/db and high-fat diet-induced obese mice. Genetic ablation of three EP3 receptor isoforms (EP3−/− mice) or EP3α and EP3γ isoforms with EP3β intact (EP3β mice) led to an obese phenotype with increased food intake, decreased motor activity, reduced insulin sensitivity, and elevated serum triglycerides. Since the differentiation of preadipocytes and mouse embryonic fibroblasts to adipocytes was markedly facilitated by either pharmacological blockade or genetic deletion/inhibition of EP3 receptor via the cAMP/PKA/PPARγ pathway, increased adipogenesis may contribute to obesity in EP3−/− and EP3β mice. Moreover, both EP3−/− and EP3β mice had increased lipolysis in WAT mainly due to the activated cAMP/PKA/hormone-sensitive lipase pathway. Taken together, our findings suggest that EP3 receptor and its α and γ isoforms are involved in both adipogenesis and lipolysis and influence food intake, serum lipid levels, and insulin sensitivity. PMID:27436752

  11. 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

  12. beta-Adrenoceptor stimulation up-regulates phosphodiesterase 4 activity and reduces prostaglandin E2-inhibitory effects in human neutrophils.

    PubMed

    Ortiz, J L; Dasí, F J; Cortijo, J; Morcillo, E J

    2000-04-01

    Human neutrophils were treated for 4 h with a combination of salbutamol (1 microM), a beta2-adrenoceptor agonist, and rolipram (30 microM), a selective phosphodiesterase 4 inhibitor, to investigate whether this treatment produces up-regulation of phosphodiesterase activity with functional consequences. Anion-exchange chromatography coupled with the use of selective activators and inhibitors demonstrated that a phosphodiesterase activity with characteristics of the isoenzyme type 4 was increased in drug-treated cells. Kinetic analysis showed a approximately 1.5-fold increase in Vmax without alteration of Km values. The augmented phosphodiesterase activity in drug-treated cells was abolished by actinomycin D. Cyclic AMP content in drug-treated cells was higher than resting values (27.28+/-2.79 pmol/10(6) cells vs. 0.34+/-0.03 pmol/10(6) cells). Reverse transcriptase-polymerase chain reaction showed increased expression of mRNA transcripts for PDE4B and PDE4A in drug-treated cells. Functionally, up-regulation of phosphodiesterase 4 reduced the inhibition by prostaglandin E2 of zymosan-induced superoxide generation.

  13. A New Role for Lipocalin Prostaglandin D Synthase in the Regulation of Brown Adipose Tissue Substrate Utilization

    PubMed Central

    Virtue, Sam; Feldmann, Helena; Christian, Mark; Tan, Chong Yew; Masoodi, Mojgan; Dale, Martin; Lelliott, Chris; Burling, Keith; Campbell, Mark; Eguchi, Naomi; Voshol, Peter; Sethi, Jaswinder K.; Parker, Malcolm; Urade, Yoshihiro; Griffin, Julian L.; Cannon, Barbara; Vidal-Puig, Antonio

    2012-01-01

    In this study, we define a new role for lipocalin prostaglandin D synthase (L-PGDS) in the control of metabolic fuel utilization by brown adipose tissue (BAT). We demonstrate that L-PGDS expression in BAT is positively correlated with BAT activity, upregulated by peroxisome proliferator–activated receptor γ coactivator 1α or 1β and repressed by receptor-interacting protein 140. Under cold-acclimated conditions, mice lacking L-PGDS had elevated reliance on carbohydrate to provide fuel for thermogenesis and had increased expression of genes regulating glycolysis and de novo lipogenesis in BAT. These transcriptional differences were associated with increased lipid content in BAT and a BAT lipid composition enriched with de novo synthesized lipids. Consistent with the concept that lack of L-PGDS increases glucose utilization, mice lacking L-PGDS had improved glucose tolerance after high-fat feeding. The improved glucose tolerance appeared to be independent of changes in insulin sensitivity, as insulin levels during the glucose tolerance test and insulin, leptin, and adiponectin levels were unchanged. Moreover, L-PGDS knockout mice exhibited increased expression of genes involved in thermogenesis and increased norepinephrine-stimulated glucose uptake to BAT, suggesting that sympathetically mediated changes in glucose uptake may have improved glucose tolerance. Taken together, these results suggest that L-PGDS plays an important role in the regulation of glucose utilization in vivo. PMID:22923471

  14. Analysis of 20alpha-hydroxysteroid dehydrogenase expression in the corpus luteum of the buffalo cow: effect of prostaglandin F2-alpha treatment on circulating 20alpha-hydroxyprogesterone levels

    PubMed Central

    2013-01-01

    Background During female reproductive cycles, a rapid fall in circulating progesterone (P4) levels is one of the earliest events that occur during induced luteolysis in mammals. In rodents, it is well recognized that during luteolysis, P4 is catabolized to its inactive metabolite, 20alpha-hydroxyprogesterone (20alpha-OHP) by the action of 20alpha-hydroxysteroid dehydrogenase (20alpha-HSD) enzyme and involves transcription factor, Nur77. Studies have been carried out to examine expression of 20alpha-HSD and its activity in the corpus luteum (CL) of buffalo cow. Methods The expression of 20alpha-HSD across different bovine tissues along with CL was examined by qPCR analysis. Circulating P4 levels were monitored before and during PGF2alpha treatment. Expression of 20alpha-HSD and Nur77 mRNA was determined in CL at different time points post PGF2alpha treatment in buffalo cows. The chromatographic separation of P4 and its metabolite, 20alpha-OHP, in rat and buffalo cow serum samples were performed on reverse phase HPLC system. To further support the findings, 20alpha-HSD enzyme activity was quantitated in cytosolic fraction of CL of both rat and buffalo cow. Results Circulating P4 concentration declined rapidly in response to PGF2alpha treatment. HPLC analysis of serum samples did not reveal changes in circulating 20alpha-OHP levels in buffalo cows but serum from pseudo pregnant rats receiving PGF2alpha treatment showed an increased 20alpha-OHP level at 24 h post treatment with accompanying decrease in P4 concentration. qPCR expression of 20alpha-HSD in CL from control and PGF2alpha-treated buffalo cows showed higher expression at 3 and 18 h post treatment, but its specific activity was not altered at different time points post PGF2alpha treatment. The Nur77 expression increased several fold 3 h post PGF2alpha treatment similar to the increased expression observed in the PGF2alpha-treated pseudo pregnant rats which perhaps suggest initiation of activation of apoptotic pathways in response to PGF2alpha treatment. Conclusions The results taken together suggest that synthesis of P4 appears to be primarily affected by PGF2alpha treatment in buffalo cows in contrast to increased metabolism of P4 in rodents. PMID:24330451

  15. [Changes in the 13,14-dihydro-15-ketoprostaglandin F2alpha and oxytocin level in the 1st trimester following beta-sympathomimetic and intracervical prostaglandin E2 gel administration].

    PubMed

    Osmers, R; Goeschen, K; Fuchs, A R; Dennemark, N

    1988-01-01

    3 ml tylose gel containing 500 micrograms PGE2 was injected into the cervical canal of 23 patients prior to first trimester abortion. 11 patients received 5 mg fenoterol orally before the PGE2-gel application and 12 patients a placebo tablet. The PGFM and oxytocin concentrations in plasma were determined radioimmunologically. The results showed the dominant role of elevated PGFM levels in the clinical prevalence of pain during induced abortion.

  16. Estrous behavior and the estrus-to-ovulation interval in Nelore cattle (Bos indicus) with natural estrus or estrus induced with prostaglandin F2 alpha or norgestomet and estradiol valerate.

    PubMed

    Pinheiro, O L; Barros, C M; Figueiredo, R A; do Valle, E R; Encarnação, R O; Padovani, C R

    1998-02-01

    Estrous behavior and the estrus-to-ovulation interval are essential for estimating the best time to artificially inseminate cattle. Because these parameters are not well characterized in the Nelore breed (Bos indicus), the main purpose of the this study was to determine the estrus-to-ovulation interval in Nelore heifers and cows with natural estrus or with estrus induced by treatments with PGF2 alpha or norgestomet and estradiol valerate (NEV). The cows and heifers were observed continuously (24 h a day) to determine the onset of estrus and to study estrous behavior in the cows. Ten hours after the start of estrus the ovaries were scanned every 2 h by ultrasonography to monitor the dominant follicle until ovulation. Blood samples were collected periodically to determine progesterone levels by RIA. Administration of PGF2 alpha (2 injections, 11 days apart) did not induce estrus in most Nelore females in spite of the presence of functional CL, indicated by progesterone concentrations above 6.0 ng/ml in 25 of 28 animals. Treatment with NEV induced high sexual receptivity in cows (10/11), but only 66% ovulated. Cows with natural or induced estrus exhibited behavioral estrus of 10.9 +/- 1.4 h, and ovulation occurred 26.6 +/- 0.44 h (n = 26) after the onset of estrus. In most of the cows (53.8%) estrus began at night (between 1801 and 600 h), and 34.6% it started and finished during the night. It is concluded that in Nelore females ovulation occurs approximately 26 h after the onset of estrus. Additionally, estrous behavior is shorter than in European breeds, and there is a high incidence of estrus at night, which makes it difficult to detect and, consequently, impairs Al in Nelore cattle. The observation that a high percentage of Nelore females with an active CL did not respond to usual dosages of PGF2 alpha warrants further investigation.

  17. Prostaglandins, renin, aldosterone, and catecholamines in preeclampsia.

    PubMed

    Pedersen, E B; Christensen, N J; Christensen, P; Johannesen, P; Kornerup, H J; Kristensen, S; Lauritsen, J G; Leyssac, P P; Rasmussen, A B; Wohlert, M

    1983-01-01

    Urinary excretion of prostaglandin E2 (PGE2) and F2 alpha (PGF2 alpha), plasma concentrations of renin (PRC), aldosterone (PAC), noradrenaline (PNA) and adrenaline (PA) were determined in the third trimester of pregnancy, 5 days and 3 months after delivery in preeclampsia and normotensive pregnant and non-pregnant control subjects. PGE2 was higher in pregnant control subjects than in non-pregnant subjects, but reduced to non-pregnant level in preeclampsia. PGF2 alpha was the same in preeclampsia and normotensive pregnancy but higher than in the non-pregnant group. PRC and PAC were increased during pregnancy, but considerably lesser in preeclampsia than during normotensive pregnancy. PNA and PA were the same in all three groups. All parameters were normal 3 months after delivery. There were no correlations between any of the hormones and blood pressure in any of the groups. PGE2 was positively correlated to PRC. The lack of renal PGE2 in preeclampsia might be responsible for the decrease in renal blood flow and sodium excretion, and the changes in PRC and PAC are supposed to be secondary to changes in PGE2. It is hypothesised that preeclampsia is a state of prostaglandin deficiency.

  18. Opposite effects of anandamide and N-arachidonoyl dopamine in the regulation of prostaglandin E and 8-iso-PGF formation in primary glial cells.

    PubMed

    Navarrete, Carmen M; Fiebich, Bernd L; de Vinuesa, Amaya García; Hess, Sandra; de Oliveira, Antonio C P; Candelario-Jalil, Eduardo; Caballero, Francisco J; Calzado, Marco A; Muñoz, Eduardo

    2009-04-01

    It is widely accepted that neuroinflammation is a key player in various pathological events associated with brain injury. More specifically, glial activation and the subsequent release of pro-inflammatory cytokines, reactive oxygen species (ROS), and prostaglandins play a role of paramount importance in cerebral damage. In this study, we examined the role of two endocannabinoids, anandamide (AEA) and N-arachidonoyldopamine (NADA) in the regulation of prostaglandin E(2) (PGE(2)) synthesis in primary glial cells. We show that NADA is a potent inhibitor of PGE(2) synthesis in lipopolysaccharide (LPS) stimulated cells, without modifying the expression or enzymatic activity of COX-2 and the production of prostaglandin D(2). We also show that NADA has the ability to prevent the free radical formation in primary microglial cells. The key findings of this investigation are our observation that AEA and NADA have opposite effects on glial cells and, most importantly, the first description of NADA as a potential antioxidative and anti-inflammatory agent acting through a mechanism that involves reduction in the synthesis of microsomal prostaglandin E synthase in LPS-activated microglia. These findings provide new mechanistic insights into the anti-inflammatory activities of NADA in the CNS and its potential to design novel therapeutic strategies to manage neuroinflammatory diseases.

  19. Silica crystals and aluminum salts regulate the production of prostaglandin in macrophages via NALP3 inflammasome-independent mechanisms.

    PubMed

    Kuroda, Etsushi; Ishii, Ken J; Uematsu, Satoshi; Ohata, Keiichi; Coban, Cevayir; Akira, Shizuo; Aritake, Kosuke; Urade, Yoshihiro; Morimoto, Yasuo

    2011-04-22

    Particulates such as silica crystal (silica) and aluminum salts (alum) activate the inflammasome and induce the secretion of proinflammatory cytokines in macrophages. These particulates also induce the production of immunoglobulin E via a T helper 2 (Th2) cell-associated mechanism. However, the mechanism involved in the induction of type 2 immunity has not been elucidated. Here, we showed that silica and alum induced lipopolysaccharide-primed macrophages to produce the lipid mediator prostaglandin E₂ (PGE₂) and interleukin-1β (IL-1β). Macrophages deficient in the inflammasome components caspase 1, NALP3, and ASC revealed that PGE₂ production was independent of the NALP3 inflammasome. PGE₂ expression was markedly reduced in PGE synthase-deficient (Ptges⁻/⁻) macrophages, and Ptges⁻/⁻ mice displayed reduced antigen-specific serum IgE concentrations after immunization with alum or silica. Our results indicate that silica and alum regulate the production of PGE₂ and that the induction of PGE₂ by particulates controls the immune response in vivo. Copyright © 2011 Elsevier Inc. All rights reserved.

  20. Labor-associated regulation of prostaglandin E and F synthesis and action in the ovine amnion and cervix.

    PubMed

    Palliser, Hannah K; Hirst, Jonathan J; Rice, Gregory E; Ooi, Guck T; Dellios, Nicole L; Escalona, Ruth M; Young, I Ross

    2006-01-01

    Prostaglandins (PGs) are key regulators of cervical dilatation and membrane breakdown at the onset of labor. PG synthase and receptor expression has been previously documented in uterine tissues; however, mechanisms governing the changes occurring in the cervix and amnion are less well established. The aim of the current study was to determine the level of expression of PG synthetic enzymes and receptors in these tissues in association with induced labor in sheep. Labor was induced in sheep at 135 days of gestation by continuous fetal dexamethasone infusion. Amnion and cervical tissue was obtained before and after labor for measurement of mRNA encoding enzymes (cytosolic phospholipase A2 [cPLA2], PGH synthase-2 [PGHS-2], PGF synthase [PGFS], and PGE synthase [PGES]) and receptors (FP and EP1-4) by real-time polymerase chain reaction (PCR). cPLA2 expression increased significantly in cervical tissue at labor onset, whereas expression of the other enzymes measured did not change. There was a marked rise in EP3 expression in the cervix, but abundance of this receptor was lower than EP2 and FP expression, which did not change. The amnion exhibited a labor-associated decrease in PGHS-2, PGFS, and FP mRNA expression. The regulation of PG synthesis and action occurring in the amnion and cervix in association with labor appear to differ markedly between the two tissues, indicating tissue-specific roles for PGs. The data support a role for increased PG synthesis and action in the cervix and suggest a decrease in PG production and action in the amnion, in sharp contrast to the pattern reported in human amnion.

  1. Expression and regulation of cytosolic prostaglandin E synthase in mouse uterus during the peri-implantation period.

    PubMed

    Ni, Hua; Sun, Tong; Ma, Xing-Hong; Yang, Zeng-Ming

    2003-03-01

    Prostaglandin E(2) (PGE(2)) is considered important for blastocyst spacing, implantation, and decidualization in rodent uteri. PGE synthase (PGES) catalyzes the isomerization of PGH(2) to PGE(2). Two isoforms of PGES exist: microsomal PGES (mPGES) and cytosolic PGES (cPGES); however, the expression and regulation of cPGES in the mammalian uterus during early pregnancy are still unknown. The aim of this study was to investigate the differential expression of cPGES in mouse uterus during early pregnancy and its regulation under different conditions using in situ hybridization and immunohistochemistry. A strong level of cPGES mRNA signal was exhibited in the stromal cells at the implantation site on Day 5 of pregnancy, whereas cPGES immunostaining was strongly detected in the luminal epithelium. The signals for both cPGES mRNA and immunostaining were strongly detected in the decidualized cells from Days 6-8 of pregnancy. A basal level of cPGES mRNA signal and immunostaining was exhibited in the uterus in delayed implantation. After delayed implantation was terminated by estrogen treatment and embryo implantation was initiated, cPGES mRNA signal was strongly detected in the stroma underlying the luminal epithelium at the implantation site, and cPGES immunostaining was strongly observed in the luminal epithelium surrounding the implanting blastocyst. A strong cPGES mRNA signal and immunostaining were detected in decidualized cells under artificial decidualization, whereas only a basal level of cPGES mRNA signal and immunostaining were observed in the control horn. Our data suggest that cPGES may play an important role during implantation and decidualization.

  2. Prostaglandin E2 Receptor Subtype 2 Regulation of Scavenger Receptor CD36 Modulates Microglial Aβ42 Phagocytosis

    PubMed Central

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

    2016-01-01

    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. PMID:25452117

  3. Molecular cloning and characterization of prostaglandin (PG) transporter in ovine endometrium: role for multiple cell signaling pathways in transport of PGF2alpha.

    PubMed

    Banu, S K; Lee, J; Satterfield, M C; Spencer, T E; Bazer, F W; Arosh, J A

    2008-01-01

    In ruminants, endometrial prostaglandin F(2alpha) (PGF(2alpha)) is the luteolytic hormone. Cellular transport of PGF(2alpha) in the uterine endometrium is critical for regulation of the estrous cycle. Molecular mechanisms responsible for control of PGF(2alpha) transport in endometrium during luteolysis are largely unknown. In the present study, we characterized the prostaglandin transporter (PGT) in ovine endometrium. Ovine PGT cDNA consists of 1935 nucleotides that encode 644 amino acids. In ovine endometria, PGT is highly expressed during the period of luteolysis, between d 14 and 16 of the estrous cycle, in luminal and glandular epithelia. Pharmacological and genomic inhibition of PGT indicates that it is responsible for influx and efflux of PGF(2alpha) in ovine endometrial epithelial cells. Inhibition of PGT during the period of luteolysis prevents the release of oxytocin-induced PGF(2alpha) pulses, and maintains functional corpus luteum and its secretion of progesterone. In ovine endometrial epithelial cells, protein kinase A and protein kinase C pathways are involved in regulating the influx of PGF(2alpha), whereas epidermal growth factor receptor pathways are implicated in regulation of influx and efflux of PGF(2alpha.) The ERK1/2 pathway is associated with efflux of PGF(2alpha), whereas Jun-amino-terminal kinase/stress-activated protein kinase pathways are involved in both efflux and influx of PGF(2alpha.) Phosphatidylinositol 3-kinase pathways are not involved in either influx or efflux of PGF(2alpha) in ovine endometrial epithelial cells. These are the first results to demonstrate a functional role for PGT in regulation of PGF(2alpha) efflux and influx in ovine endometrial cells that influence luteolytic mechanisms in ruminants.

  4. Prostaglandins: pharmacology and clinical application.

    PubMed

    Karim, S M; Hillier, K

    1974-01-01

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

  5. Microvascular effects of selective prostaglandin analogues in the eye with special reference to latanoprost and glaucoma treatment.

    PubMed

    Stjernschantz, J; Selén, G; Astin, M; Resul, B

    2000-07-01

    Prostaglandin F(2alpha) analogues have recently been introduced on the market for glaucoma treatment. While these drugs have a well-documented intraocular pressure reducing effect only a limited number of studies have been published regarding their effects on the microvasculature in the eye. Since many naturally occurring prostaglandins have marked effects on the cardiovascular system it is conceivable that synthetic prostaglandins used as glaucoma drugs may exert microvascular effects in the eye, even if they exhibit receptor selectivity. Latanoprost, the active principle of Xalatan((R)) eye drops, is a selective FP prostanoid receptor agonist, and much of the paper is focused on the microvascular effects of latanoprost and some closely related prostaglandin analogues. The purpose of the paper is to review the literature on the microvascular effects of prostaglandins in the eye, and to present some unpublished data on the effects of selective prostaglandin analogues. Most of the prostaglandin analogues studied exhibit selectivity for the FP prostanoid receptor. Results from studies with the following prostaglandin analogues are presented in the paper: PGF(2alpha)-isopropyl ester (PGF(2alpha)-IE), 17-phenyl-18,19,20-trinor-PGF(2alpha)-isopropyl ester (17-phenyl-PGF(2a)-IE), 15-keto-17-phenyl-18,19, 20-trinor-PGF(2alpha)-isopropyl ester (15-keto-17-phenyl-PGF(2a)-IE), 13,14-dihydro-17-phenyl-18,19,20-trinor-PGF(2alpha)-isopropy l ester (latanoprost), 13,14-dihydro-15R,S-17-phenyl-18,19, 20-trinor-PGF(2alpha)-isopropyl ester (PhXA34), 17-phenyl-18,19, 20-trinor-PGE(2)-isopropyl ester (17-phenyl-PGE(2)-IE), and 19R-hydroxy-PGE(2) (19R-OH-PGE(2)). The regional blood flow has been determined with radioactively labelled microspheres, the blood volume with (51)Cr labelled erythrocytes and the capillary permeability to albumin with (125)I and (131)I labelled albumin. PGF(2alpha)-IE has been shown to exert marked microvascular effects in the rabbit anterior segment

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

    PubMed Central

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

    2016-01-01

    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. In C. albicans-infected cPLA2α−/− or COX-1−/− macrophages, expression of Il10, Nr4a2, and Ptgs2 was lower, and expression of Tnfα 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. In C. 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. albicans acted 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 in Il10, Nr4a2, Ptgs2, and Tnfα expression, was not mediated by cAMP/PKA because it was similar in C. 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 in C. 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. PMID:26841868

  7. 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.

  8. Bovine oviduct epithelial cells downregulate phagocytosis of sperm by neutrophils: prostaglandin E2 as a major physiological regulator.

    PubMed

    Marey, Mohamed A; Liu, Jinghui; Kowsar, Rasoul; Haneda, Shingo; Matsui, Motozumi; Sasaki, Motoki; Takashi, Shimizu; Hayakawa, Hiroyuki; Wijayagunawardane, Missaka P B; Hussein, Fekry M; Miyamoto, Akio

    2014-02-01

    This study aimed to investigate the presence of polymorphonuclear neutrophils (PMNs) in bovine oviduct fluid under physiological conditions and to determine the possible role of bovine oviduct epithelial cells (BOECs) in the regulation of the phagocytic activity of PMNs for sperm. During the pre-ovulatory stage, PMNs were identified in the bovine oviduct fluid in relatively constant numbers. In our experiments, PMNs were incubated for 4 h with the supernatant of cultured BOECs stimulated for 24 h by LH (10 ng/ml). Phagocytosis was then assayed by co-incubation of these PMNs with sperm treated to induce capacitation. The BOEC supernatant significantly suppressed sperm phagocytosis by PMNs, and the LH-stimulated BOEC supernatant further suppressed phagocytosis. Importantly, in the BOEC culture, LH stimulated the secretion of prostaglandin E2 (PGE2), which dose-dependently (10(-6), 10(-7), and 10(-8) M) suppressed sperm phagocytosis by PMNs. Furthermore, a PGEP2 receptor antagonist significantly abrogated the inhibition of phagocytosis by the LH-stimulated BOEC supernatant. Additionally, using scanning electron microscopy, incubation of PMNs with either PGE2 or LH-stimulated BOEC supernatant before phagocytosis was found to prevent the formation of DNA-based neutrophil extracellular traps for sperm entanglement. The results indicate that sperm are exposed to PMNs in the oviduct and PGE2 released into the oviduct fluid after LH stimulation may play a major role in the suppression of the phagocytic activity of PMNs for sperm via interaction with EP2 receptors. Thus, the bovine oviduct provides a PGE2-rich microenvironment to protect sperm from phagocytosis by PMNs, thereby supporting sperm survival in the oviduct. Free Japanese abstract A Japanese translation of this abstract is freely available at http://www.reproduction-online.org/content/147/2/211/suppl/DC1.

  9. The Tpl2 Kinase Regulates the COX-2/Prostaglandin E2 Axis in Adipocytes in Inflammatory Conditions

    PubMed Central

    Berthou, Flavien; Ceppo, Franck; Dumas, Karine; Massa, Fabienne; Vergoni, Bastien; Alemany, Susana; Cormont, Mireille

    2015-01-01

    Bioactive lipid mediators such as prostaglandin E2 (PGE2) have emerged as potent regulator of obese adipocyte inflammation and functions. PGE2 is produced by cyclooxygenases (COXs) from arachidonic acid, but inflammatory signaling pathways controlling COX-2 expression and PGE2 production in adipocytes remain ill-defined. Here, we demonstrated that the MAP kinase kinase kinase tumor progression locus 2 (Tpl2) controls COX-2 expression and PGE2 secretion in adipocytes in response to different inflammatory mediators. We found that pharmacological- or small interfering RNA-mediated Tpl2 inhibition in 3T3-L1 adipocytes decreased by 50% COX-2 induction in response to IL-1β, TNF-α, or a mix of the 2 cytokines. PGE2 secretion induced by the cytokine mix was also markedly blunted. At the molecular level, nuclear factor κB was required for Tpl2-induced COX-2 expression in response to IL-1β but was inhibitory for the TNF-α or cytokine mix response. In a coculture between adipocytes and macrophages, COX-2 was mainly increased in adipocytes and pharmacological inhibition of Tpl2 or its silencing in adipocytes markedly reduced COX-2 expression and PGE2 secretion. Further, Tpl2 inhibition in adipocytes reduces by 60% COX-2 expression induced by a conditioned medium from lipopolysaccharide (LPS)-treated macrophages. Importantly, LPS was less efficient to induce COX-2 mRNA in adipose tissue explants of Tpl2 null mice compared with wild-type and Tpl2 null mice displayed low COX-2 mRNA induction in adipose tissue in response to LPS injection. Collectively, these data established that activation of Tpl2 by inflammatory stimuli in adipocytes and adipose tissue contributes to increase COX-2 expression and production of PGE2 that could participate in the modulation of adipose tissue inflammation during obesity. PMID:26020725

  10. Regulation of chloride secretion across porcine endometrial epithelial cells by prostaglandin E2.

    PubMed

    Deachapunya, C; O'Grady, S M

    1998-04-01

    1. The objective of this study was to investigate the mechanism of PGE2 regulation of Cl- transport across glandular endometrial cells grown in primary culture. 2. Most of the basal short circuit current (Isc) was inhibited by luminal addition of 5-nitro-2-(3-phenylpropylamino)benzoic acid (NPPB) or glibenclamide, suggesting the presence of a basally active Cl- conductance in the apical membrane. 3. Basolateral addition of 10 microM PGE2 increased Isc by 41 +/- 3 microA. A similar response was observed when cells were treated with 8-(4-chlorophenylthio) adenosine 3',5'-cyclic monophosphate (CPT-cAMP). Pretreatment of monolayers with NPPB and glibenclamide blocked the PGE2 and cAMP-mediated increase in Isc, suggesting that the effects of PGE2 and cAMP were dependent on the activity of an apical NPPB- and glibenclamide-sensitive conductance. 4. Addition of 50 nM antiPGE2 antibody to the basolateral bathing solution decreased basal Isc by 20 % and shifted the threshold response to exogenous PGE2. This result suggests autocrine regulation of electrogenic Cl- transport by PGE2. 5. Experiments with amphotericin B-permeabilized monolayers revealed that the apical PGE2-activated, NPPB- and glibenclamide-sensitive conductance was Cl- dependent and that the current-voltage relationship and anion permeation properties (SCN->Br- > Cl- > I-) were characteristic of the cystic fibrosis transmembrane conductance regulator (CFTR). 6. Cultured porcine endometrial epithelial cells were specifically labelled with an antibody to a peptide sequence within the regulatory domain of CFTR. 7. The effect of PGE2 was blocked by basolateral addition of bumetanide and furosemide at concentrations that are selective for inhibition of Na+-K+-2Cl-cotransport activity. The effect of bumetanide on Isc was Cl- dependent, suggesting a role for the bumetanide-sensitive transport pathway in Cl- secretion. 8. PGE2 and cAMP also activated an outwardly rectifying basolateral K+ channel which presumably

  11. 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

  12. The use of prostaglandin pessaries prior to vaginal termination.

    PubMed

    Craft, I

    1973-03-01

    Prosaglandin F2alpha 100 mg pessaries were inserted on 2 occasions within 24 hours of vaginal termination of pregnancy in an attempt to facilitate the subsequent operative procedure. Some degree of cervical dilatation occurred in 8 out of the 10 subjects studied but in only multiparous patients was it of sufficient degree to make evacuation easier. Side effects of uterine cramps, a flushed sensation; and the presence of diarrhea were relatively common. Disadvantages of prostaglandin F2a pessaries for use in vaginal termination of pre.g.nancy (e.g., large amounts are needed to induce cervical dilatation; cervical trauma is affected by parity status, no local specific ccervical softening action) preclude its clinical use.

  13. Prostaglandins produced during class A scavenger receptor-mediated macrophage adhesion differentially regulate cytokine production.

    PubMed

    Nikolic, Dejan M; Vadali, Shanthi; He, Beixiang; Ware, Jerry; Kelly, Thomas; Post, Steven R

    2015-05-01

    Inflammation is associated with modification of the extracellular environment, changes in cytokine expression, and the accumulation of immune cells. Such modifications create ligands that support SR-A-mediated macrophage adhesion and retention. This may be particularly important in settings, such as atherosclerosis and diabetes, as modified lipoproteins and gluc-collagen are ligands for SR-A. SR-A-mediated adhesion requires the PLA2-dependent generation of AA and its metabolism by 12/15 LOX. In contrast, the inhibition of the COX-dependent conversion of AA to PG had no effect on SR-A-mediated adhesion. In this study, macrophages were isolated from SR-A(+/+) and SR-A(-/-) mice and plated on gluc-collagen to test the hypothesis that COX-derived PGs are produced during SR-A-mediated adhesion and regulate macrophage function. SR-A-mediated binding to gluc-collagen induced a rapid but transient increase in PG production, which required the activation of PLA2 and Src kinase but not PI3K. SR-A(+/+) macrophages cultured on gluc-collagen for 24 h secreted a similar amount of TNF-α and 2.5-fold more IL-10 than SR-A(-/-) macrophages. The inhibition of COX substantially increased TNF-α production but reduced IL-10 levels in SR-A(+/+) macrophages. These effects of COX inhibition were reversed by exogenous PGE2 and mimicked by specific antagonism of the EP4 receptor. Thus, in addition to the enhancement of macrophage adhesion, SR-A binding to gluc-collagen stimulates PG production, which in turn, differentially regulates the expression of inflammatory cytokines. © Society for Leukocyte Biology.

  14. Lung Myofibroblasts Are Characterized by Down-Regulated Cyclooxygenase-2 and Its Main Metabolite, Prostaglandin E2

    PubMed Central

    Gabasa, Marta; Royo, Dolores; Molina-Molina, Maria; Roca-Ferrer, Jordi; Pujols, Laura; Picado, Cesar

    2013-01-01

    Background Prostaglandin E2 (PGE2), the main metabolite of cyclooxygenase (COX), is a well-known anti-fibrotic agent. Moreover, myofibroblasts expressing α-smooth muscle actin (α-SMA), fibroblast expansion and epithelial-mesenchymal transition (EMT) are critical to the pathogenesis of idiopathic pulmonary fibrosis (IPF). Our aim was to investigate the expression of COX-2 and PGE2 in human lung myofibroblasts and establish whether fibroblast-myofibroblast transition (FMT) and EMT are associated with COX-2 and PGE2 down-regulation. Methods Fibroblasts obtained from IPF patients (n = 6) and patients undergoing spontaneous pneumothorax (control, n = 6) and alveolar epithelial cell line A549 were incubated with TGF-β1 and FMT and EMT markers were evaluated. COX-2 and α-SMA expression, PGE2 secretion and cell proliferation were measured after IL-1β and PGE2 incubation. Results Myofibroblasts from both control and IPF fibroblast cultures stimulated with IL-1β showed no COX-2 expression. IPF fibroblasts showed increased myofibroblast population and reduced COX-2 expression in response to IL-1β. TGF-β1 increased the number of myofibroblasts in a time-dependent manner. In contrast, TGF-β1 induced slight COX-2 expression at 4 h (without increase in myofibroblasts) and 24 h, but not at 72 h. Both IPF and control cultures incubated with TGF-β1 for 72 h showed diminished COX-2 induction, PGE2 secretion and α-SMA expression after IL-1β addition. The latter decreased proliferation in fibroblasts but not in myofibroblasts. A549 cells incubated with TGF-β1 for 72 h showed down-regulated COX-2 expression and low basal PGE2 secretion in response to IL-1β. Immuno-histochemical analysis of IPF lung tissue showed no COX-2 immuno-reactivity in myofibroblast foci. Conclusions Myofibroblasts are associated with COX-2 down-regulation and reduced PGE2 production, which could be crucial in IPF development and progression. PMID:23755232

  15. Prostaglandin E2 Regulates Its Own Inactivating Enzyme, 15-PGDH, by EP2 Receptor-Mediated Cervical Cell-Specific Mechanisms

    PubMed Central

    Kishore, A. Hari; Owens, David

    2014-01-01

    Context: Prostaglandins play important roles in parturition and have been used to induce cervical ripening and labor. Prior to cervical ripening at term, 15-hydroxyprostaglandin dehydrogenase (15-PGDH) is highly expressed in the cervix and metabolizes cyclooxygenase-2-mediated increases in active prostaglandin E2 (PGE2) to inactive 15-keto PGE2. At term, 15-PGDH gene expression decreases and PGE2 accumulates, leading to cervical ripening and labor. Previously, we found that the cervical isoform of microphthalmia-associated transcription factor (MiTF-CX) serves as a progestational transcription factor that represses IL-8 and hypoxia-mediated increases in cyclooxygenase-2. Objective: We tested the hypothesis that PGE2 regulates its own inactivation through MiTF-CX. Design: We used human cervical stromal cells to investigate the regulation of 15-PGDH. Setting: This was a laboratory-based study using cells from clinical tissue samples. Main Outcome Measures: We evaluated the mechanisms by which PGE2 regulates 15-PGDH in human cervical stromal cells. Results: PGE2 repressed MiTF-CX and 15-PGDH, whereas ectopic overexpression of MiTF-CX induced 15-PGDH expression levels. Stabilization of HIF-1α by deferoxamine resulted in concomitant down-regulation of MiTF-CX and 15-PGDH. Ectopic overexpression of MiTF-CX abrogated PGE2- and deferoxamine-mediated loss of MiTF-CX and 15-PGDH. PGE2-induced loss of MiTF-CX and 15-PGDH was mediated through prostaglandin E2 receptor (EP2) receptors (PTGER2), but not cAMP. Conclusions: The 15-PGDH gene is a MiTF-CX target gene in cervical stromal cells and is down-regulated by PGE2 through EP2 receptors. The findings suggest that EP2 receptor-specific antagonists may be used as an adjunct to present clinical management for the prevention of preterm cervical ripening and preterm labor. PMID:24471568

  16. Growth regulation of primary human keratinocytes by prostaglandin E receptor EP2 and EP3 subtypes.

    PubMed

    Konger, R L; Malaviya, R; Pentland, A P

    1998-02-04

    We examined the contribution of specific EP receptors in regulating cell growth. By RT-PCR and northern hybridization, adult human keratinocytes express mRNA for three PGE2 receptor subtypes associated with cAMP signaling (EP2, EP3, and small amounts of EP4). In actively growing, non-confluent primary keratinocyte cultures, the EP2 and EP4 selective agonists, 11-deoxy PGE1 and 1-OH PGE1, caused complete reversal of indomethacin-induced growth inhibition. The EP3/EP2 agonist (misoprostol), and the EP1/EP2 agonist (17-phenyl trinor PGE2), showed less activity. Similar results were obtained with agonist-induced cAMP formation. The ability of exogenous dibutyryl cAMP to completely reverse indomethacin-induced growth inhibition support the conclusion that growth stimulation occurs via an EP2 and/or EP4 receptor-adenylyl cyclase coupled response. In contrast, activation of EP3 receptors by sulprostone, which is virtually devoid of agonist activity at EP2 or EP4 receptors, inhibited bromodeoxyuridine uptake in indomethacin-treated cells up to 30%. Although human EP3 receptor variants have been shown in other cell types to markedly inhibit cAMP formation via a pertussis toxin sensitive mechanisms, EP3 receptor activation and presumably growth inhibition was independent of adenylyl cyclase, suggesting activation of other signaling pathways.

  17. Mechanism and clinical significance of prostaglandin-induced iris pigmentation.

    PubMed

    Stjernschantz, Johan W; Albert, Daniel M; Hu, Dan-Ning; Drago, Filippo; Wistrand, Per J

    2002-08-01

    The new glaucoma drugs latanoprost, isopropyl unoprostone, travoprost, and bimatoprost cause increased pigmentation of the iris in some patients. The purpose of the present article is to survey the available preclinical and clinical data on prostaglandin-induced iris pigmentation and to assess the phenomenon from a clinical perspective. Most of the data have been obtained with latanoprost, and it appears that there is a predisposition to latanoprost-induced iris pigmentation in individuals with hazel or heterochromic eye color. As latanoprost and travoprost are selective agonists for the prostaglandin F(2alpha) receptor, it is likely that the phenomenon is mediated by this receptor. Several studies indicate that latanoprost stimulates melanogenesis in iridial melanocytes, and transcription of the tyrosinase gene is upregulated. The safety aspects of latanoprost-induced iris pigmentation have been addressed in histopathologic studies, and no evidence of harmful consequences of the side effect has been found. Although a final assessment of the clinical significance of prostaglandin-induced iris pigmentation currently is impossible to make, it appears that the only clear-cut disadvantage is a potential heterochromia between the eyes in unilaterally treated patients because the heterochromia is likely to be permanent, or very slowly reversible.

  18. Inhibition of premature labor in sheep by a combined treatment of nimesulide, a prostaglandin synthase type 2 inhibitor, and atosiban, an oxytocin receptor antagonist.

    PubMed

    Grigsby, P L; Poore, K R; Hirst, J J; Jenkin, G

    2000-09-01

    The aim of this study was to compare the effects of the selective prostaglandin synthase type 2 inhibitor nimesulide, alone or in combination with the oxytocin receptor antagonist atosiban, on the progression of glucocorticoid-induced premature labor in sheep. Effects on circulating maternal and fetal prostaglandin concentrations and on fetal well-being were also examined. Premature labor was induced in ewes with long-term catheterized fetuses by infusion of dexamethasone (1 mg/d) starting at 138 +/- 1 days' gestation. Ewes also received an infusion of either nimesulide and atosiban (20.0 and 4.12 mg/kg per day, respectively; n = 5), nimesulide alone (20.0 mg/kg per day; n = 5), or vehicle only (n = 9). Plasma 13,14-dihydro-15-keto-prostaglandin F(2)(alpha) and prostaglandin E(2) concentrations were measured before and during infusions in plasma samples obtained from the maternal and fetal carotid arteries and the utero-ovarian vein. No fetuses from ewes treated with nimesulide and atosiban were delivered during treatment. These animals were killed electively 98.0 +/- 6.8 hours after the commencement of dexamethasone induction. This was significantly longer than the delivery times for those ewes treated with nimesulide alone (71.2 +/- 3.9 hours; n = 5) and for vehicle-treated ewes (51.4 +/- 1.7 hours; n = 9). Both maternal and fetal plasma 13, 14-dihydro-15-keto-prostaglandin F(2alpha) and prostaglandin E(2) concentrations in nimesulide and atosiban-treated ewes and in nimesulide-treated ewes decreased during treatment. In contrast, vehicle-treated ewes showed a significant increase in maternal and fetal plasma 13,14-dihydro-15-keto-prostaglandin F(2alpha) and prostaglandin E(2) concentrations during dexamethasone induction. Uterine electromyographic activity observed in nimesulide and atosiban-treated ewes was significantly suppressed with respect to activities in both vehicle- and nimesulide-treated ewes during the treatment period. All fetuses were alive at

  19. Preeclampsia -- a state of prostaglandin deficiency? Urinary prostaglandin excretion, the renin-aldosterone system, and circulating catecholamines in preeclampsia.

    PubMed

    Pedersen, E B; Christensen, N J; Christensen, P; Johannesen, P; Kornerup, H J; Kristensen, S; Lauritsen, J G; Leyssac, P P; Rasmussen, A; Wohlert, M

    1983-01-01

    Urinary excretion of prostaglandin E2 (PGE2) and F2 alpha (PGF2 alpha), plasma concentrations of renin, aldosterone, norepinephrine (NE) and epinephrine (E) were determined during pregnancy, 5 days, 3, and 6 months after delivery in preeclampsia, normotensive pregnant, and nonpregnant control subjects. The PGE2 was higher in normotensive pregnant control subjects than in nonpregnant subjects. In preeclampsia, PGE2 was reduced to nonpregnant level. PGF2 alpha was the same in preeclampsia and in normotensive pregnancy, but elevated when compared to the normotensive nonpregnant control group. Plasma concentrations of renin and aldosterone were increased during pregnancy, but considerably less in preeclampsia than during normotensive pregnancy. NE and E were the same as in nonpregnant subjects during both hypertensive and normotensive pregnancy. All parameters were normal 3 months after delivery. There were no correlations between PGE2, PGF2 alpha, plasma concentrations of renin, aldosterone, NE, or E and blood pressure level in third trimester either in preeclampsia or in normotensive pregnancy. PGE2 was positively correlated to plasma concentrations of renin. It is suggested that the lack of renal PGE2 in preeclampsia might be responsible for the decrease in renal blood flow and sodium excretion. It is hypothesized that preeclampsia is a state of prostaglandin deficiency. The changes in the renin-aldosterone system may be secondary to changes in prostaglandin concentration both in preeclampsia and normotensive pregnancy.

  20. ERβ- and Prostaglandin E2-Regulated Pathways Integrate Cell Proliferation via Ras-like and Estrogen-Regulated Growth Inhibitor in Endometriosis

    PubMed Central

    Monsivais, D.; Dyson, M. T.; Yin, P.; Coon, J. S.; Navarro, A.; Feng, G.; Malpani, S. S.; Ono, M.; Ercan, C. M.; Wei, J. J.; Pavone, M. E.; Su, E.

    2014-01-01

    In endometriosis, stromal and epithelial cells from the endometrium form extrauterine lesions and persist in response to estrogen (E2) and prostaglandin E2 (PGE2). Stromal cells produce excessive quantities of estrogen and PGE2 in a feed-forward manner. However, it is unknown how estrogen stimulates cell proliferation and survival for the establishment and persistence of disease. Previous studies suggest that estrogen receptor-β (ERβ) is strikingly overexpressed in endometriotic stromal cells. Thus, we integrated genome-wide ERβ binding data from previously published studies in breast cells and gene expression profiles in human endometriosis and endometrial tissues (total sample number = 81) and identified Ras-like, estrogen-regulated, growth inhibitor (RERG) as an ERβ target. Estradiol potently induced RERG mRNA and protein levels in primary endometriotic stromal cells. Chromatin immunoprecipitation demonstrated E2-induced enrichment of ERβ at the RERG promoter region. PGE2 via protein kinase A phosphorylated RERG and enhanced the nuclear translocation of RERG. RERG induced the proliferation of primary endometriotic cells. Overall, we demonstrated that E2/ERβ and PGE2 integrate at RERG, leading to increased endometriotic cell proliferation and represents a novel candidate for therapeutic intervention. PMID:24992181

  1. ERβ- and prostaglandin E2-regulated pathways integrate cell proliferation via Ras-like and estrogen-regulated growth inhibitor in endometriosis.

    PubMed

    Monsivais, D; Dyson, M T; Yin, P; Coon, J S; Navarro, A; Feng, G; Malpani, S S; Ono, M; Ercan, C M; Wei, J J; Pavone, M E; Su, E; Bulun, S E

    2014-08-01

    In endometriosis, stromal and epithelial cells from the endometrium form extrauterine lesions and persist in response to estrogen (E2) and prostaglandin E2 (PGE2). Stromal cells produce excessive quantities of estrogen and PGE2 in a feed-forward manner. However, it is unknown how estrogen stimulates cell proliferation and survival for the establishment and persistence of disease. Previous studies suggest that estrogen receptor-β (ERβ) is strikingly overexpressed in endometriotic stromal cells. Thus, we integrated genome-wide ERβ binding data from previously published studies in breast cells and gene expression profiles in human endometriosis and endometrial tissues (total sample number = 81) and identified Ras-like, estrogen-regulated, growth inhibitor (RERG) as an ERβ target. Estradiol potently induced RERG mRNA and protein levels in primary endometriotic stromal cells. Chromatin immunoprecipitation demonstrated E2-induced enrichment of ERβ at the RERG promoter region. PGE2 via protein kinase A phosphorylated RERG and enhanced the nuclear translocation of RERG. RERG induced the proliferation of primary endometriotic cells. Overall, we demonstrated that E2/ERβ and PGE2 integrate at RERG, leading to increased endometriotic cell proliferation and represents a novel candidate for therapeutic intervention.

  2. Effect of Prostaglandin I2 Analogs on Cytokine Expression in Human Myeloid Dendritic Cells via Epigenetic Regulation

    PubMed Central

    Kuo, Chang-Hung; Lin, Ching-Hsiung; Yang, San-Nan; Huang, Ming-Yii; Chen, Hsiu-Lin; Kuo, Po-Lin; Hsu, Ya-Ling; Huang, Shau-Ku; Jong, Yuh-Jyh; Wei, Wan-Ju; Chen, Yi-Pin; Hung, Chih-Hsing

    2012-01-01

    Prostaglandin I2 (PGI2) analog is regarded as a potential candidate for treating asthma. Human myeloid dendritic cells (mDCs) play a critical role in the pathogenesis of asthma. However, the effects of PGI2 analog on human mDCs are unknown. In the present study, circulating mDCs were isolated from six healthy subjects. The effects of PGI2 analogs iloprost and treprostinil on cytokine production, maturation and T-cell stimulatory function of human mDCs were investigated. Tumor necrosis factor (TNF)-α and interleukin (IL)-10 were measured by enzyme-linked immunosorbent assay. The expression of costimulatory molecules was investigated by flow cytometry. T-cell stimulatory function was investigated by measuring interferon (IFN)-γ, IL-13 and IL-10 production by T cells cocultured with iloprost-treated mDCs. Intracellular signaling was investigated by Western blot and chromatin immunoprecipitation. We found that iloprost and treprostinil induced IL-10, but suppressed TNF-α production in polyinosinic-polycytidylic acid (poly I:C)-stimulated mDCs. This effect was reversed by the I-prostanoid (IP), E-prostanoid (EP) receptor antagonists or intracellular free calcium (Ca2+) chelator. Forskolin, an adenyl cyclase activator, conferred a similar effect. Iloprost and treprostinil increased intracellular adenosine 3′,5′-cyclic monophosphate (cAMP) levels, and iloprost also increased intracellular Ca2+. Iloprost suppressed poly I:C-induced mitogen-activated protein kinase (MAPK) phospho-p38 and phospho–activating transcription factor (ATF)2 expression. Iloprost downregulated poly I:C-induced histone H3K4 trimethylation in the TNFA gene promoter region via suppressing translocation of histone 3 lysine 4 (H3K4)-specific methyltransferases MLL (mixed lineage leukemia) and WDR5 (WD repeat domain 5). Iloprost-treated mDCs inhibited IL-13, IFN-γ and IL-10 production by T cells. In conclusion, PGI2 analogs enhance IL-10 and suppress TNF-α expression through the IP/EP2/EP4

  3. The role of prostaglandins in human parturition.

    PubMed

    Gibb, W

    1998-06-01

    Parturition is the process of giving birth, and the molecular mechanisms involved are still to be elucidated. Among the various factors involved prostaglandins appear to have an important role. They are synthesized within the human fetal membranes (amnion and chorion) and decidua and act to ripen the cervix, change membrane structure and contract the myometrium. Prostaglandin concentrations increase in amniotic fluid prior to myometrial contractions, and the activity of prostaglandin H synthase (PGHS) increases in the chorion laeve and amnion at labour. This increase is due to increased expression of the PGHS-2 isoenzyme rather than the PGHS-1 isoenzyme. In animal pregnancy, there is also an increase in the expression of the PGHS-2 isoenzyme, and in both human and animal pregnancies this increase appears to occur in the fetal tissues rather than in the maternal tissues. Prostaglandin metabolism also plays an important role in altering prostaglandin output by the human fetal membranes. Prostaglandin dehydrogenase (PGDH) activity decreases in certain cases of preterm labour, and at term it decreases in the area of the chorion laeve covering the cervix. This may allow active prostaglandins produced by the amnion and chorion to access the cervix and myometrium. Recent studies have indicated that glucocorticoids may be important in regulating prostaglandin formation within the human fetal membranes by increasing expression of PGHS-2 in the amnion and decreasing PGDH activity in the chorion. Prostaglandin formation is also important in infection-induced preterm labour and both phospholipase and PGHS-2 activities can be increased by various cytokines. Prostaglandins are important for the onset of both term and preterm parturition and their effects may result from changes in prostaglandin synthesis, prostaglandin metabolism and expression of various prostaglandin receptors.

  4. Down-regulation by prostaglandins of type-II phospholipase A2 expression in guinea-pig alveolar macrophages: a possible involvement of cAMP.

    PubMed Central

    Vial, D; Arbibe, L; Havet, N; Dumarey, C; Vargaftig, B; Touqui, L

    1998-01-01

    We have demonstrated previously that isolated guinea-pig alveolar macrophages (AM) synthesize type-II phospholipase A2 (PLA2-II) through a tumour necrosis factor-alpha (TNF-alpha)-dependent process. This synthesis is enhanced by lipopolysaccharide (LPS) and accompanied by a release of prostaglandin E2 (PGE2) into the medium. Because agents elevating intracellular cAMP, such as PGE2, have been shown to stimulate PLA2-II expression in various cell types, we investigated the modulation of PLA2-II synthesis by cAMP in AM. Surprisingly, incubation of AM with PGE2, dibutyryl-cAMP, cholera toxin or rolipram (an inhibitor of specific cAMP-phosphodiesterase) inhibited both basal and LPS-stimulated PLA2-II expression. The inhibitory effect of PGE2 was observed at concentrations similar to those released by AM. Moreover, treatment of AM with either aspirin or neutralizing PGE2 monoclonal antibody stimulated PLA2-II synthesis. These effects were closely correlated with the ability of these agents to modulate TNF-alpha release, which was decreased by dibutyryl-cAMP and exogenous PGE2, whereas neutralizing PGE2 antibody markedly increased this release. Hence, in contrast to other cell systems, we report that: (i) agents elevating intracellular cAMP levels down-regulate both basal and LPS-induced PLA2-II synthesis, (ii) prostaglandins exert a negative feedback effect on this synthesis, probably through an elevation of intracellular cAMP levels, and (iii) inhibition of TNF-alpha release may account, at least in part, for the down-regulation of PLA2-II expression by endogenously produced prostaglandins and cAMP-elevating agents. PMID:9461495

  5. Differential expression and regulation of cylooxygenases, prostaglandin E synthases and prostacyclin synthase in rat uterus during the peri-implantation period.

    PubMed

    Cong, Jing; Diao, Hong-Lu; Zhao, Yue-Chao; Ni, Hua; Yan, Yun-Qin; Yang, Zeng-Ming

    2006-01-01

    It has been shown that both prostaglandin I2 (PGI2) and PGE2 are essential for mouse implantation, whereas only PGE2 is required for hamster implantation. To date, the expression and regulation of cyclooxygenase (COX) and prostaglandin E synthase (PGES), which are responsible for PGE2 production, have not been reported in the rat. The aim of this study was to examine the expression pattern and regulation of COX-1, COX-2, membrane-associated PGES-1 (mPGES-1), mPGES-2 and cytosolic PGES (cPGES) in rat uterus during early pregnancy and pseudopregnancy, and under delayed implantation. At implantation site on day 6 of pregnancy, COX-1 immunostaining was highly visible in the luminal epithelium, and COX-2 immunostaining was clearly observed in the subluminal stroma. Both mPGES-1 mRNA and protein were only observed in the subluminal stroma surrounding the implanting blastocyst at the implantation site on day 6 of pregancy , but were not seen in the inter-implantation site on day 6 of pregnancy and on day 6 of pseudopregnancy. Our data suggest that the presence of an active blastocyst is required for mPGES-1 expression at the implantation site. When pregnant rats on day 5 were treated with nimesulide for 24 h, mPGES-1 protein expression was completely inhibited. cPGES immunostaining was clearly observed in the luminal epithelium and subluminal stromal cells immediately surrounding the implanting blastocyst on day 6 of pregnancy. mPGES-2 immunostaining was clearly seen in the luminal epithelium at the implantation site. Additionally, immunostaining for prostaglandin I synthase (PGIS) was also strongly detected at the implantation site. In conclusion, our results indicate that PGE2 and PGI2 should have a very important role in rat implantation.

  6. Cyclooxygenase 2 and prostaglandin E2 regulate the attachment of calcium oxalate crystals to renal epithelial cells.

    PubMed

    Miyazawa, Katsuhito; Takahashi, Yoshitaka; Morita, Nobuyo; Moriyama, Manabu T; Kosaka, Takeo; Nishio, Matomo; Yoshimoto, Tanihiro; Suzuki, Koji

    2012-10-01

    To determine the roles of endogenous cyclooxygenase 2 and prostaglandin E(2) in crystal-cell binding, which is considered to be an important step in the development of intratubular nephrocalcinosis. An expression plasmid for human cyclooxygenase 2 was introduced into Madin-Darby canine kidney cells using the lipofection method. Cyclooxygenase activity was measured using thin-layer chromatography, and the prostaglandin E(2) concentration was determined with an enzyme immunoassay. In addition, crystal attachment was evaluated with a liquid scintillation counter using [(14)C] calcium oxalate monohydrate crystals, and immunohistochemistry and an enzyme immunoassay were used to analyze and quantify the expression of hyaluronan, a crystal-binding molecule. Cyclooxygenase 2-overexpressing Madin-Darby canine kidney cells produced about 10-fold more prostaglandin E(2) than wild-type Madin-Darby canine kidney cells, and their hyaluronan production was also upregulated. The attachment of calcium oxalate monohydrate crystals to cyclooxygenase 2-overexpressing Madin-Darby canine kidney cells was significantly reduced compared with their attachment to wild-type and mock-transfected Madin-Darby canine kidney cells. Pre-incubation of the cyclooxygenase 2-overexpressing cells, as well as the mock-transfected and wild-type cells with the cyclooxygenase 2 selective inhibitor etodolac, increased the cellular attachment of calcium oxalate monohydrate crystals in a dose-dependent manner. These findings suggest that cyclooxygenase 2 expression and the resultant increase in endogenous prostaglandin E(2), leading to increased hyaluronan production, help to prevent nephrocalcinosis by inhibiting the attachment of calcium oxalate monohydrate crystals to the surface of renal epithelial cells. © 2012 The Japanese Urological Association.

  7. [Role of prostaglandin E2 in regulation of urine excretion in saluresis, water and osmotic diuresis in rat].

    PubMed

    Bogolepova, A E; Shakhmatova, E I

    2004-11-01

    In the saluresis, water and osmotic diuresis were indicating an increase of prostaglandin E2 excretion and a correlation between this index and diuresis. Unselective blockade of cyclooxygenase by diclofenac-natrium leads to a decrease of diuresis in the observed types of urine-production in rats. Inhibition of inducible cyclooxygenase by celebrex didn't change the value of diuresis after water load or administration of osmotic agent, but decreased the diuretic effect of furosemide.

  8. Transcriptional regulation of microsomal prostaglandin E synthase 1 by the proto-oncogene, c-myc, in the pathogenesis of inflammation and cancer.

    PubMed

    Ramanan, M; Pilli, V S; Aradhyam, G K; Doble, M

    2017-01-22

    Pro-inflammatory molecules play a key role in the progression of various types of cancers highlighting the importance of studying the pathways that regulate the inflammatory cytokine production. To this end, prostaglandins have been reported to correlate with exacerbated cancer phenotypes that may be prevented by using anti-inflammatory drugs in humans. To understand how the prostaglandin E synthase 1 (mPGES1) may be regulated we analyzed its promoter sequence and identified myc-binding sites. Functional validation was performed by mutating the sites that led to attenuated promoter activation of mPGES1. The known c-myc inhibitor (10058-F4) also blocked PGE2 activity, indicating the importance of c-Myc in PGE2 synthesis. Isocoumarin analogs were able to reduce the expressions of both c-myc as well as mPGES1 and also inhibit the production of PGE2. Based on these data and the well-established role of c-myc in oncogenesis, we have demonstrated an additional role of c-myc in exacerbating cancers via PGE2 production, which may provide a therapeutic opportunity to treat these diseases. Copyright © 2016 Elsevier Inc. All rights reserved.

  9. Intrauterine inhibition of prostaglandin transporter protein blocks release of luteolytic PGF2alpha pulses without suppressing endometrial expression of estradiol or oxytocin receptor in ruminants.

    PubMed

    Lee, JeHoon; McCracken, John A; Banu, Sakhila K; Arosh, Joe A

    2013-08-01

    In ruminants, prostaglandin F2 alpha (PGF2(alpha)) is synthesized and released in a pulsatile pattern from the endometria luminal epithelial (LE) cells during the process of luteolysis. Prostaglandin transporter (PGT) is a 12-transmembrane solute carrier organic anion transporter protein that facilitates transport of PGF2(alpha). The present study determined the effects of inhibition of PGT protein on pulsatile release of luteolytic PGF2(alpha) and the underlined cell-signaling mechanisms. The results indicate that intrauterine inhibition of the PGT protein inhibits the pulsatile release of PGF2(alpha) from the endometrium and maintains a functional corpus luteum. Surprisingly, inhibition of PGT-mediated luteolytic pulses is not associated with spatial regulation of estrogen and oxytocin receptors in the LE of the endometrium and is also not accompanied by decreased biosynthesis of PGF2(alpha) or increased catabolism of PGF2(alpha) by the endometrium. Importantly, PGT inhibitor increases expression of pERK1/2 proteins in the LE of the endometrium. Knock down of ERK1/2 genes in LE cells reverses the inhibitory effects of PGT inhibitor on release of PGF2(alpha). In conclusion, intrauterine inhibition of PGT inhibits the pulsatile release of PGF2(alpha) from the endometrium without modulating spatial expressions of estrogen and oxytocin receptor proteins and metabolism of PGF2(alpha) at the time of luteolysis. Activation of ERK1/2 pathways and interactions between ERK1/2 and PGT protein appear to be important cell-signaling mechanisms that control PGT-mediated efflux transport function. PGT emerges as an important final component in the luteolytic machinery that controls the release of luteolytic pulses of PGF2(alpha) from the endometrium in sheep.

  10. The induced prostaglandin E2 pathway is a key regulator of the respiratory response to infection and hypoxia in neonates

    PubMed Central

    Hofstetter, Annika O.; Saha, Sipra; Siljehav, Veronica; Jakobsson, Per-Johan; Herlenius, Eric

    2007-01-01

    Infection during the neonatal period commonly induces apnea episodes, and the proinflammatory cytokine IL-1β may serve as a critical mediator between these events. To determine the mechanism by which IL-1β depresses respiration, we examined a prostaglandin E2 (PGE2)-dependent pathway in newborn mice and human neonates. IL-1β and transient anoxia rapidly induced brainstem-specific microsomal prostaglandin E synthase-1 (mPGES-1) activity in neonatal mice. Furthermore, IL-1β reduced respiratory frequency during hyperoxia and depressed hypoxic gasping and autoresuscitation in mPGES-1 wild-type mice, but not in mPGES-1 knockout mice. In wild-type mice, PGE2 induced apnea and irregular breathing patterns in vivo and inhibited brainstem respiratory rhythm generation in vitro. Mice lacking the EP3 receptor (EP3R) for PGE2 exhibited fewer apneas and sustained brainstem respiratory activity, demonstrating that PGE2 exerts its respiratory effects via EP3R. In human neonates, the infectious marker C-reactive protein was correlated with elevated PGE2 in the cerebrospinal fluid, and elevated central PGE2 was associated with an increased apnea frequency. We conclude that IL-1β adversely affects breathing and its control by mPGES-1 activation and PGE2 binding to brainstem EP3 receptors, resulting in increased apnea frequency and hypoxia-induced mortality. PMID:17535900

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

    PubMed

    Seebacher, Frank; Franklin, Craig E

    2003-08-07

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

  12. Prostaglandins, catecholamines, renin and aldosterone during hypertensive and normotensive pregnancy.

    PubMed

    Pedersen, E B; Christensen, N J; Christensen, P; Johannesen, P; Kornerup, H J; Kristensen, S; Lauritsen, J G; Leyssac, P P; Rasmussen, A B; Wohlert, M

    1982-01-01

    Urinary excretion of prostaglandin E2 (PGE2) and F2 alpha (PGF2 alpha), plasma concentrations of renin (PRC), aldosterone (PAC), noradrenaline (PNA) and adrenaline (PA) were determined in the third trimester of pregnancy, 5 days and 3 months after delivery in preeclampsia and normotensive pregnant and non-pregnant control subjects. PGE2 was higher in pregnant control subjects than in non-pregnant subjects, but reduced to non-pregnant level in preeclampsia. PGF2 alpha was the same in preeclampsia and normotensive pregnancy but higher than in the non-pregnant group. PRC and PAC were increased during pregnancy, but considerably lesser in preeclampsia than during normotensive pregnancy. PNA and PA were the same in all three groups. All parameters were normal 3 months after delivery. There were no correlations between any of the hormones and blood pressure in any of the groups. PGE2 was positively correlated to PRC. The lack of renal PGE2 in preeclampsia might be responsible for the decrease in renal blood flow and sodium excretion, and the changes in PRC and PAC are supposed to be secondary to changes in PGE2. It is hypothesised that preeclampsia is a state of prostaglandin deficiency.

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

    PubMed Central

    Seebacher, Frank; Franklin, Craig E

    2003-01-01

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

  14. Differential regulation of prostaglandin EP and FP receptors in pregnant sheep myometrium and endometrium during spontaneous term labor.

    PubMed

    Ma, X; Wu, W X; Nathanielsz, P W

    1999-11-01

    In the present study, we characterized the mRNA abundance of prostaglandin E(2) receptor subtypes (EP1 and EP3, which stimulate excitatory responses; EP2 and EP4, which stimulate inhibitory responses) and the FP receptor in pregnant sheep myometrium and endometrium in relation to parturition. Myometrial and endometrial poly(A) RNA was extracted from control ewes at 143-147 days gestational age (dGA, n = 6) and from ewes in spontaneous term labor at 145-147 dGA (n = 6), and was subjected to Northern blot analysis for FP, EP1, EP2, EP3, and EP4 mRNA. Myometrial EP3, EP4, and FP mRNA abundance increased during labor (P<0.05); EP2 mRNA did not change. EP1 mRNA was not detectable in the myometrium. Endometrial EP2 and EP4 mRNA remained unchanged during labor. EP3 mRNA was expressed at a very low level, and EP1 and FP mRNA were not detected in endometrium in any animals studied. In conclusion, there is differential expression in myometrium and endometrium of EP subtypes and FP receptor in relation to labor. Increases in EP3 and FP, together with increased prostaglandin production from intrauterine tissues, may lead to the switch in the myometrial contraction pattern that occurs during labor. These differences within and between myometrium and endometrium may result from different anatomical location, such as longitudinal or circular layers of myometrium, or vascular location.

  15. Evidence for a spatial and temporal regulation of prostaglandin-endoperoxide synthase 2 expression in human amnion in term and preterm parturition.

    PubMed

    Lee, Deug-Chan; Romero, Roberto; Kim, Jung-Sun; Yoo, Wonsuk; Lee, JoonHo; Mittal, Pooja; Kusanovic, Juan Pedro; Hassan, Sonia S; Yoon, Bo Hyun; Kim, Chong Jai

    2010-09-01

    Prostaglandin-endoperoxide synthase 2 (PTGS2) is a key enzyme involved in parturition. PTGS2 mRNA was found to be differentially expressed between placental amnion (amnion overlying the placental disc) and reflected amnion (amnion of the extraplacental chorioamniotic membranes) in term placentas. The aim was to evaluate the spatial and temporal regulation of PTGS2 expression in the amnion and the chorion-decidua. PTGS2 expression was analyzed in the amnion and chorion-decidua obtained from 32 women: term not in labor (n = 12), term in labor (n = 12), and preterm labor (n = 8), by immunoblotting and densitometry. Prostaglandin E(2) (PGE(2)) in the amnion and chorion-decidua was measured by a specific immunoassay. Compared to preterm labor cases, PTGS2 expression increased at term before the onset of labor far more prominently in placental amnion (4.5-fold; P = 0.002) than in reflected amnion (1.4-fold; P = 0.007). There was a significant increase in PTGS2 expression in reflected amnion (2.9-fold; P < 0.01) but not in placental amnion with labor at term. PTGS2 expression was higher in reflected amnion than in chorion-decidua in labor at term (2.9-fold; P < 0.01). PTGS2 was barely detected in amnion and chorion-decidua with preterm labor. Expression of PGE(2) showed a good correlation with PTGS2 expression (r = 0.722; P < 0.001). PTGS2 expression in the amnion shows a distinct spatial and temporal regulation. Spontaneous labor at term and pathological preterm labor clearly differ in amniotic PTGS2 and PGE(2) abundance. Our observations underscore the biological significance of the amnion and amniotic fluid in human parturition.

  16. Changes in the expression of prostaglandin E and F synthases at induced and spontaneous labour onset in the sheep.

    PubMed

    Palliser, H K; Ooi, G T; Hirst, J J; Rice, G; Dellios, N L; Escalona, R M; Young, I R

    2004-03-01

    The differential production of prostaglandin (PG) F(2 alpha) and PGE(2) within the uterine compartment may play a role in controlling myometrial contraction. We hypothesized that the enzymes downstream of PG endoperoxide synthase-2 (PGHS-2) determine the ratio of PGF(2 alpha) and PGE(2) in the utero-ovarian vein plasma and the time of normal and preterm labour onset. The aim of this study was to simultaneously determine the expression of PGF and PGE synthases (PGFS and PGES) in gestational tissues at spontaneous and induced-preterm labour in sheep. Myometrial, endometrial and placental tissue were obtained from ewes in dexamethasone-induced preterm labour, age-matched control ewes, and ewes in spontaneous term labour for analysis of mRNA expression by real-time PCR. PGFS mRNA expression was significantly increased following dexamethasone-induced and spontaneous labour onset in placentome (P<0.01) but was unchanged in the myometrium and endometrium. In contrast, PGES mRNA expression remained unchanged or decreased. PGHS-2 mRNA expression was increased in all tissues examined in both dexamethasone-induced and spontaneous labour (P<0.001). Plasma PGE(2) and PGF(2 alpha) concentrations rose in both dexamethasone-induced and spontaneous labour with the ratio of PGF(2 alpha):PGE(2) increased with labour onset (P<0.05). These results are consistent with the hypothesis that the increased expression, of PGFS is responsible for the increased PGF(2 alpha):PGE(2) ratio and this, together with increased PGHS-2 expression, accounts for myometrial activity at labour onset. The findings point to PGFS expression as a key factor in regulating the uterotonic process in the sheep.

  17. [Plasma hormone concentrations in induced abortion with local prostaglandin administration in the 1st trimester].

    PubMed

    Rath, W; König, A; Ulbrich, R; Hilgers, R; Kuske, R; Kuhn, W

    1983-01-01

    Abortion was performed by curettage on 71 women with pregnancies between the 7th and the 13th week of gestation seven to eight hours after intracervical application of a tylose gel containing 3mg prostaglandin F2 alpha. Prior to the application of the prostaglandin and immediately before the surgical intervention a sonographic examination for determining the vitality of the pregnancy was carried out.--Plasma progesteron, estradiol and HPL levels were determined radioimmunologically prior to the application of prostaglandin, at four-hour intervals on the day of intervention, and 24, 48 and 72 hours after the intervention. In 22 women a complete or an incomplete abortion occurred; in two cases a blighted ovum was observed; 47 pregnancies, according to sonographic examination, remained intact until curettage. After seven to eight hours duration of the effect of the prostaglandin gel, progesterone levels were found to be reduced to 60.5 per cent and 17-beta-estradiol to 31.4 per cent of the initial values, whereas the HPL values fell below the specificity of the testing procedure (12.5 ng/ml). Comparative investigations of the pregnancies which, according to sonographic findings, remained intact until curettage and those which were aborted after the application of prostaglandin did not, in spite of low plasma progesterone and estradiol levels in the abortive group, reveal any statistically significant differences. The abortive effect--even with local application--of the prostaglandins was confirmed. Conclusions regarding the effective mechanism of the prostaglandins upon the fetoplacental unit and the function of the corpus luteum remain subject to speculation.

  18. Preparation for induction of labour of the unfavourable cervix with Foley catheter compared with vaginal prostaglandin.

    PubMed

    Thomas, I L; Chenoweth, J N; Tronc, G N; Johnson, I R

    1986-02-01

    Ripening of the unfavourable cervix prior to induction of labour using traction on a Foley catheter (32 patients) was compared with 40 mg of prostaglandin F2 alpha in Tylose gel applied to the external cervical os and held in place for 12 hours with a vaginal diaphragm (25 patients). Each patient in the above groups had a modified Bishop score of 0-3 and was randomly allocated to one or other group. Comparison was made with a further 25 patients in whom the cervical score was 4-6. Timing of amniotomy and commencement of Syntocinon infusion were equivalent for all patients. Prostaglandins conferred no advantage over Foley catheter in terms of amniotomy-delivery interval, operative delivery rate, and condition of the baby one minute after birth. The disadvantages of prostaglandins for cervical ripening are a longer preparation-delivery interval, and cost ($77 versus $4.75 for the Foley catheter). Currently, prostaglandins are not officially approved for use in Australia for induction of labour. It is suggested, therefore, that the Foley catheter is preferable for ripening the unfavourable cervix as a prelude to amniotomy.

  19. Prostaglandins and reproduction in female farm animals.

    PubMed

    Weems, C W; Weems, Y S; Randel, R D

    2006-03-01

    Prostaglandins impact on ovarian, uterine, placental, and pituitary function to regulate reproduction in female livestock. They play important roles in ovulation, luteal function, maternal recognition of pregnancy, implantation, maintenance of gestation, microbial-induced abortion, parturition, postpartum uterine and ovarian infections, and resumption of postpartum ovarian cyclicity. Prostaglandins have both positive and negative effects on reproduction; they are used to synchronize oestrus, terminate pseudopregnancy in mares, induce parturition, and treat retained placenta, luteinized cysts, pyometra, and chronic endometritis. Improved therapeutic uses for prostaglandins will be developed when we understand better their involvement in implantation, maintenance of luteal function, and establishment and maintenance of pregnancy.

  20. Stretch magnitude- and frequency-dependent cyclooxygenase 2 and prostaglandin E2 up-regulation in human endometrial stromal cells: possible implications in endometriosis.

    PubMed

    Li, Xiaochuan; Gong, Xianghui; Zhu, Lan; Leng, Jinhua; Fan, Qingbo; Sun, Dawei; Lang, Jinghe; Fan, Yubo

    2012-11-01

    Endometriosis, with a prevalence rate ranging from 6% to 10%, is the major contributor to pelvic pain and subfertility, and considerably reduces the quality of life in affected women. However, the pathogenesis of this disease remains largely unknown. The present study aimed to uncover the role of hyperperistalsis in the pathogenesis of endometriosis, by exploring the response of human endometrial stromal cells (ESCs) to the cyclic stretch in vitro. ESCs isolated from 18 different endometrium biopsies undergoing hysterectomy for myoma were subjected to uniaxial cyclic stretches with different magnitude and frequency using the Uniaxial Tension System. Expression of cyclooxygenase-2 (COX-2) and microsomal prostaglandin E2 synthase-1 (mPGES-1) in stretched and unstretched ESCs were assessed by realtime quantitative polymerase chain reaction and Western blot. Production of prostaglandin E2 (PGE(2)) in the culture medium was measured by enzyme-linked immunosorbent assay. The cyclic stretch mimicking hyperperistalsis in endometriosis (5% elongation at 4 cycles/min) stimulated quick up-regulations of COX-2 and mPGES-1 simultaneously on both transcriptional and translational levels, and delayed PGE(2) overproduction was also noted in ESCs. As the stretch magnitude or frequency increased, so did overexpression of COX-2 and PGE(2) (P < 0.05). By contrast, the cyclic stretch mimicking physiological peristalsis (3% elongation at 2 cycles/min) did not induce significant COX-2, mPGES-1 or PGE(2) production within 12 h. Both COX-2 and mPEGS-1 are PGE(2) synthases, and the aberrant COX-2 and PGE(2) production play important roles in the pathogenesis of endometriosis. Therefore, the present findings revealed that increased stretch stimuli from the hyperperistalsis of endometriosis were capable of causing the aberrant COX-2 and PGE(2) expression in the endometrium by mechanotransduction, in a magnitude and frequency-dependent manner. It implied possible roles of hyperperistalsis in

  1. Reactive oxygen species (ROS) production triggered by prostaglandin D2 (PGD2) regulates lactate dehydrogenase (LDH) expression/activity in TM4 Sertoli cells.

    PubMed

    Rossi, Soledad P; Windschüttl, Stefanie; Matzkin, María E; Rey-Ares, Verónica; Terradas, Claudio; Ponzio, Roberto; Puigdomenech, Elisa; Levalle, Oscar; Calandra, Ricardo S; Mayerhofer, Artur; Frungieri, Mónica B

    2016-10-15

    Reactive oxygen species (ROS) regulate testicular function in health and disease. We previously described a prostaglandin D2 (PGD2) system in Sertoli cells. Now, we found that PGD2 increases ROS and hydrogen peroxide (H2O2) generation in murine TM4 Sertoli cells, and also induces antioxidant enzymes expression suggesting that defense systems are triggered as an adaptive stress mechanism that guarantees cell survival. ROS and specially H2O2 may act as second messengers regulating signal transduction pathways and gene expression. We describe a stimulatory effect of PGD2 on lactate dehydrogenase (LDH) expression via DP1/DP2 receptors, which is prevented by the antioxidant N-acetyl-L-cysteine and the PI3K/Akt pathway inhibitor LY 294002. PGD2 also enhances Akt and CREB/ATF-1 phosphorylation. Our results provide evidence for a role of PGD2 in the regulation of the oxidant/antioxidant status in Sertoli cells and, more importantly, in the modulation of LDH expression which takes place through ROS generation and the Akt-CREB/ATF-1 pathway. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

  2. MicroRNA 21 Is a Homeostatic Regulator of Macrophage Polarization and Prevents Prostaglandin E2-Mediated M2 Generation

    PubMed Central

    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. PMID:25706647

  3. Signal transduction pathway regulating prostaglandin EP3 receptor-induced neurite retraction: requirement for two different tyrosine kinases.

    PubMed Central

    Aoki, J; Katoh, H; Yasui, H; Yamaguchi, Y; Nakamura, K; Hasegawa, H; Ichikawa, A; Negishi, M

    1999-01-01

    We reported previously that activation of the prostaglandin E receptor EP3 subtype triggered neurite retraction through the small GTPase Rho-, and its target, RhoA-binding kinase alpha (ROKalpha)-, dependent pathway in EP3 receptor-expressing PC12 cells. Here we examined the involvement of tyrosine kinases in this pathway in nerve growth factor-differentiated PC12 cells. Tyrphostin A25, a tyrosine kinase inhibitor, blocked neurite retraction and cell rounding induced by activation of the EP3 receptor, however, it failed to block neurite retraction and cell rounding induced by microinjection of constitutively active RhoA, RhoAV14, indicating that a tyrphostin-sensitive tyrosine kinase was involved in the pathway from the EP3 receptor to Rho activation. On the other hand, genistein, another tyrosine kinase inhibitor, blocked neurite retraction and cell rounding induced by both activation of the EP3 receptor and microinjection of RhoAV14. However, genistein did not block neuronal morphological changes induced by microinjection of a constitutively active mutant of ROKalpha. These results indicate that two different tyrosine kinases, tyrphostin A25-sensitive and genistein-sensitive kinases, are involved in the EP3 receptor-mediated neurite retraction acting upstream and downstream of Rho, respectively. PMID:10333476

  4. Estrogen receptor-related receptor alpha mediates up-regulation of aromatase expression by prostaglandin E2 in prostate stromal cells.

    PubMed

    Miao, Lin; Shi, Jiandang; Wang, Chun-Yu; Zhu, Yan; Du, Xiaoling; Jiao, Hongli; Mo, Zengnan; Klocker, Helmut; Lee, Chung; Zhang, Ju

    2010-06-01

    Estrogen receptor-related receptor alpha (ERRalpha) is an orphan member of the nuclear receptor superfamily of transcription factors. ERRalpha is highly expressed in the prostate, especially in prostate stromal cells. However, little is known about the regulation and function of ERRalpha, which may contribute to the progression of prostatic diseases. We previously found that prostaglandin E2 (PGE2) up-regulated the expression of aromatase in prostate stromal cells. Here we show that PGE2 also up-regulates the expression of ERRalpha, which, as a transcription factor, further mediates the regulatory effects of PGE2 on the expression of aromatase. ERRalpha expression was up-regulated by PGE2 in prostate stromal cell line WPMY-1, which was mediated mainly through the protein kinase A signaling pathway by PGE2 receptor EP2. Suppression of ERRalpha activity by chlordane (an antagonist of ERRalpha) or small interfering RNA knockdown of ERRalpha blocked the increase of expression and promoter activity of aromatase induced by PGE2. Overexpression of ERRalpha significantly increased aromatase expression and promoter activity, which were further augmented by PGE2. Chromatin immunoprecipitation assay demonstrated that ERRalpha directly bound to the aromatase promoter in vivo, and PGE2 enhanced the recruitment of ERRalpha and promoted transcriptional regulatory effects on aromatase expression in WPMY-1. 17Beta-estradiol concentration in WPMY-1 medium was up-regulated by ERRalpha expression, and that was further increased by PGE2. Our results provided evidence that ERRalpha contributed to local estrogen production by up-regulating aromatase expression in response to PGE2 and provided further insights into the potential role of ERRalpha in estrogen-related prostatic diseases.

  5. Prostaglandins in labor--a translational approach.

    PubMed

    Khan, Abdul H; Carson, Ray J; Nelson, Scott M

    2008-05-01

    The mechanisms involved in the initiation of human labor are largely unknown. Understanding the molecular pathways is fundamental in both the development of effective therapeutic strategies and intervention to prevent preterm labor. Prostaglandins are bioactive lipids and members of the eicosanoids family, derived from arachidonic acid, which act in a paracrine or autocrine manner and function via binding to specific G-protein-coupled receptors, activating intracellular signaling and gene transcription. Prostaglandins have a central role in the maintenance of pregnancy and initiation of labor, with the change from uterine quiescence to a contractile state facilitated by differential expression of prostaglandin receptors within the myometrium and fetal membranes. Clinical evidence for the key role of prostaglandins in human parturition is evident from their successful exploitation as exogenous agents for the induction of labor and the role of prostaglandin synthase inhibitors as a preventative therapy for preterm labor. This review aims to focus on prostaglandin synthesis and metabolism and how differential regulation of prostaglandins and their receptors in gestational tissues interact in the initiation of labor.

  6. Prostaglandins in reproductive physiology*

    PubMed Central

    Craig, Gillian M.

    1975-01-01

    The role of prostaglandins in reproductive physiology is reviewed with particular emphasis on their possible importance in ovulation in humans. A possible interaction between gonadal steroids, biogenic amines and prostaglandins at hypothalamic-pituitary level, in relation to the release of luteinizing hormone releasing factor, and LH, is discussed. Anomalies regarding the role of oestrogens in LH release are noted, and it is suggested that high oestrogen levels may release prostaglandins from the uterus and/or centrally in humans, in connection with the mid-cycle LH surge and ovulation. A hypothetical role for prostaglandins in sexual behaviour and premenstrual changes is discussed. The hypotheses open up new areas for clinical research to establish the role of prostaglandins in human endocrinology. The need for measurement of prostaglandin metabolites in blood and urine is emphasized. PMID:1089972

  7. 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

  8. HtrA3 is regulated by 15-deoxy-{Delta}12,14-prostaglandin J2 independently of PPAR{gamma} in clear cell renal cell carcinomas

    SciTech Connect

    Theoleyre, Sandrine; Mottier, Stephanie; Masson, Damien; Denis, Marc G.

    2010-04-09

    Peroxisome proliferator-activated receptor gamma (PPAR{gamma}) ligands have been shown to possess anti-proliferative effects in many types of cancer. In clear cell renal cell carcinoma (CCRCC), the targets involved in these effects are not known. In this study, we demonstrated that, in CCRCC cell lines, the endogenous PPAR{gamma} ligand 15-deoxy-{Delta}12,14-prostaglandin J2 (15dPGJ2) induces the expression, both at the mRNA and the protein levels, of the HtrA3 gene. This gene belongs to the High-Temperature Requirement Factor A family of serine proteases that repress signaling by TGF-{beta} family members and inhibit cell migration. Rosiglitazone or ciglitazone, synthetic PPAR{gamma} agonists, did not induce HtrA3 expression, and the PPAR{gamma} antagonist GW9662 did not prevent 15dPGJ2 induction, suggesting that the up-regulation of HtrA3 by 15dPGJ2 is independent of PPAR{gamma}. The MEK/ERK inhibitor PD98059 dramatically repressed HtrA3 induction. Altogether, these data indicate that 15dPGJ2 is able to stimulate the expression of HtrA3 through an indirect mechanism involving the MEK/ERK pathway but independent of PPAR{gamma}. Our results provide a better understanding of the mechanisms involved in the regulation of HtrA3, a potential tumor suppressor gene.

  9. Prostaglandins and Inflammation

    PubMed Central

    Ricciotti, Emanuela; FitzGerald, Garret A.

    2011-01-01

    Prostaglandins are lipid autacoids derived from arachidonic acid. They both sustain homeostatic functions and mediate pathogenic mechanisms, including the inflammatory response. They are generated from arachidonate by the action of cyclooxygenase (COX) isoenzymes and their biosynthesis is blocked by nonsteroidal anti-inflammatory drugs (NSAIDs), including those selective for inhibition of COX-2. Despite the clinical efficacy of NSAIDs, prostaglandins may function in both the promotion and resolution of inflammation. This review summarizes insights into the mechanisms of prostaglandin generation and the roles of individual mediators and their receptors in modulating the inflammatory response. Prostaglandin biology has potential clinical relevance for atherosclerosis, the response to vascular injury and aortic aneurysm. PMID:21508345

  10. Prostaglandin (PG) FP and EP1 receptors mediate PGF2alpha and PGE2 regulation of interleukin-1beta expression in Leydig cell progenitors.

    PubMed

    Walch, Laurence; Clavarino, Emanuela; Morris, Patricia L

    2003-04-01

    Prostaglandins (PG) mediate IL-1beta regulation of several interleukin mRNAs in progenitor Leydig cells. PGE(2) and PGF(2alpha) potently reverse indomethacin (INDO; a cyclooxygenase inhibitor) inhibition of IL-1beta autoinduction. IL-1beta increases PGE(2) and PGF(2alpha) production. To determine the PG receptors involved in this regulation, this study established by RT-PCR and Western analyses which specific receptors for PGE(2) (EP receptors) and PGF(2alpha) (FP receptors) are expressed in progenitors. Pharmacological characterization of receptors involved in PGE(2) and PGF(2alpha) regulation of IL-1beta mRNA levels was ascertained using real-time PCR analyses. FP, EP(1), EP(2), and EP(4) receptor mRNAs and proteins, and an EP(3) receptor subtype were detected. IL-1beta treatment (24-h) significantly decreased EP(1) receptor levels; INDO abrogated this down-regulation. FP, EP(2), and EP(4) receptor levels increased after IL-1beta and IL-1beta + INDO. A selective FP agonist, cloprostenol (0.1 micro M), and PGF(2alpha) (10 micro M) had similar effects on IL-1beta mRNA levels in progenitors treated with IL-1beta + INDO. None of the EP(2)/EP(4) agonists [butaprost, misoprostol, or 11-deoxy PGE(1) (10 micro M)] affected IL-1beta mRNA levels. In contrast, EP(1)/EP(3) agonists (17-phenyl trinor PGE(2) and sulprostone) increased IL-1beta mRNAs in a dose-dependent manner. EP(1) receptor subtype-selective antagonist, SC-51322, blocked IL-1beta-induced and [IL-1beta + INDO + 17-phenyl trinor PGE(2)]-induced increases in IL-1beta mRNAs. Taken together, our data demonstrate that FP and EP(1) receptors mediate PGF(2alpha) and PGE(2) induction of progenitor IL-1beta expression.

  11. Sequential down-regulation of E-cadherin with squamous cell carcinoma progression: loss of E-cadherin via a prostaglandin E2-EP2 dependent posttranslational mechanism.

    PubMed

    Brouxhon, Sabine; Kyrkanides, Stephanos; O'Banion, M Kerry; Johnson, Renee; Pearce, David A; Centola, Gina M; Miller, Jen-nie H; McGrath, Kieran H; Erdle, Brandon; Scott, Glynis; Schneider, Sandra; VanBuskirk, JoAnne; Pentland, Alice P

    2007-08-15

    The incidence of skin cancer is on the rise, with over 1 million new cases yearly. Although it is known that squamous cell cancers (SCC) are caused by UV light, the mechanism(s) involved remains poorly understood. In vitro studies with epithelial cells or reports examining malignant skin lesions suggest that loss of E-cadherin-mediated cell-cell contacts may contribute to SCCs. Other studies show a pivotal role for cyclooxygenase-dependent prostaglandin E2 (PGE2) synthesis in this process. Using chronically UV-irradiated SKH-1 mice, we show a sequential loss of E-cadherin-mediated cell-cell contacts as lesions progress from dysplasia to SCCs. This E-cadherin down-regulation was also evident after acute UV exposure in vivo. In both chronic and acute UV injury, E-cadherin levels declined at a time when epidermal PGE2 synthesis was enhanced. Inhibition of PGE2 synthesis by indomethacin in vitro, targeted deletion of EP2 in primary mouse keratinocyte (PMK) cultures or deletion of the EP2 receptor in vivo abrogated this UV-induced E-cadherin down-regulation. In contrast, addition of PGE2 or the EP2 receptor agonist butaprost to PMK produced a dose- and time-dependent decrease in E-cadherin. We also show that UV irradiation, via the PGE2-EP2 signaling pathway, may initiate tumorigenesis in keratinocytes by down-regulating E-cadherin-mediated cell-cell contacts through its mobilization away from the cell membrane, internalization into the cytoplasm, and shuttling through the lysosome and proteasome degradation pathways. Further understanding of how UV-PGE2-EP2 down-regulates E-cadherin may lead to novel chemopreventative strategies for the treatment of skin and other epithelial cancers.

  12. The prostaglandin E2 receptor, EP2, regulates survivin expression via an EGFR/STAT3 pathway in UVB-exposed mouse skin.

    PubMed

    Chun, Kyung-Soo; Langenbach, Robert

    2011-06-01

    We previously reported that cycloogenase (COX)-2-generated prostaglandin E2 (PGE2) had anti-apoptotic effects in UVB-exposed mouse skin that involved EP2-mediated signaling (Chun et al., Cancer Res. 2007; 67: 2015). Because survivin is a regulator of cell survival, the possible involvement of COX-2 and EP2 in survivin expression following UVB exposure of mouse skin was investigated. In wild type mice, UVB exposure time-dependently increased the levels of survivin and phosphorylated-signal transducer and activator of transcription 3 (p-STAT3), a transcription factor that regulates survivin expression; and COX-2- or EP2-deficiency significantly reduced their induction. Topical application of the COX-2 inhibitor, celecoxib, also reduced UVB-induced survivin levels. To further investigate the roles of PGE2 and EP2 in the regulation of survivin, indomethacin was used to inhibit UVB-induced endogenous PG production. UVB-induced survivin levels were reduced by indomethacin, and PGE2 and the EP2 agonist, butaprost, partially restored survivin levels. The epidermal growth factor receptor (EGFR) is a downstream effector of EP2 and EGFR inhibition (AG1478) significantly reduced UVB activation of STAT3 and survivin levels. UVB-induced epidermal apoptosis in COX-2-/- mice was reduced by butaprost and EGFR inhibition blocked butaprost’s protective effects. Furthermore, butaprost in the absence of UVB exposure time-dependently increased p-EGFR, p-STAT3, and survivin levels in naïve mouse skin, whereas the EP4 agonist, PGE1 alcohol, did not significantly increase p-STAT3 or survivin levels. These data suggest that COX-2-generated PGE2 regulates survivin expression in mouse skin, in part, via an EP2-mediated EGFR/STAT3 pathway. Therefore, targeting the EP2/survivin pathway may provide a strategy for the chemoprevention/chemotherapy of skin cancer.

  13. 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.

  14. 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.

  15. Regulation of activator protein-1 by 8-iso-prostaglandin E2 in a thromboxane A2 receptor-dependent and -independent manner

    SciTech Connect

    Weber, Thomas J.; Markillie, Lye MENG.

    2003-05-01

    The thromboxane (TX) A{sub 2} receptor (TP) encompasses two alternatively spliced forms, termed the platelet/placental (TP-P) and endothelial (TP-E) type receptors. Experimental evidence suggests that TP activity may be modulated by novel ligands, termed the isoprostanes, that paradoxically act as TP agonists in smooth muscle and TP antagonists in platelet preparations. Here we have investigated whether prototypical isoprostanes 8-iso-prostaglandin (PG)F{sub 2{alpha}} and 8-iso-PGE{sub 2} regulate the activity of TP isoforms expressed in Chinese hamster ovary (CHO) cells using activator protein-1 (AP-1)-luciferase activity as a reporter. AP-1-luciferase activity was increased by a TP agonist [9,11-dideoxy-9{alpha},11{alpha}-methanoepoxy PGF{sub 2{alpha}} (U46619)] in CHO cells transfected with the human TP-P and TP-E receptors, and this response was fully inhibited by TP antagonists [1S-[1{alpha},2{beta}(Z),3{alpha},5{alpha}

  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. 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).

  18. Differential effect of acetylsalicylic acid and dipyrone on prostaglandin production in human fibroblast cultures.

    PubMed Central

    Lüthy, C.; Multhaupt, M.; Oetliker, O.; Perisic, M.

    1983-01-01

    Human skin fibroblasts incubated with arachidonic acid in culture show basal release of prostaglandins. They produce the same prostaglandins after stimulation with bradykinin. Basal release of prostaglandins I2 (6-oxo-PGF1 alpha), F2 alpha and E2 is inhibited dose-dependently by both acetylsalicylic acid (ASA) and dipyrone (P less than 0.05). The examined dose-range was 10(-7) to 10(-4) M for both drugs. During the first 5 min after removal of the drugs from the incubation medium, bradykinin-stimulated release remains dose-dependently inhibited (P less than 0.001) in ASA-, but not in dipyrone-treated cultures. The difference between the effects of ASA and of dipyrone is highly significant (P less than 0.0001), whereas the dipyrone-treated cultures are not different from controls. The findings are consistent with cyclo-oxygenase inhibition by ASA as well as by dipyrone. However, the data demonstrate rapid reversibility of the effect of dipyrone. This suggests that in contrast to ASA, dipyrone does not inhibit cyclo-oxygenase by binding covalently to the enzyme. PMID:6418250

  19. Prostaglandin E2 activates and utilizes mTORC2 as a central signaling locus for the regulation of mast cell chemotaxis and mediator release.

    PubMed

    Kuehn, Hye Sun; Jung, Mi-Yeon; Beaven, Michael A; Metcalfe, Dean D; Gilfillan, Alasdair M

    2011-01-07

    Prostaglandin (PG) E(2), a potent mediator produced in inflamed tissues, can substantially influence mast cell responses including adhesion to basement membrane proteins, chemotaxis, and chemokine production. However, the signaling pathways by which PGE(2) induces mast cell chemotaxis and chemokine production remains undefined. In this study, we identified the downstream target of phosphatidylinositol 3-kinase, mammalian target of rapamycin (mTOR), as a key regulator of these responses. In mouse bone marrow-derived mast cells, PGE(2) was found to induce activation of mTORC1 (mTOR complexed to raptor) as indicated by increased p70S6K and 4E-BP1 phosphorylation, and activation of mTORC2 (mTOR complexed to rictor), as indicated by increased phosphorylation of AKT at position Ser(473). Selective inhibition of the mTORC1 cascade by rapamycin or by the use of raptor-targeted shRNA failed to decrease PGE(2)-mediated chemotaxis or chemokine generation. However, inhibition of the mTORC2 cascade through the dual mTORC1/mTORC2 inhibitor Torin, or through rictor-targeted shRNA, resulted in a significant attenuation in PGE(2)-mediated chemotaxis, which was associated with a comparable decrease in actin polymerization. Furthermore, mTORC2 down-regulation decreased PGE(2)-induced production of the chemokine monocyte chemoattractant protein-1 (CCL2), which was linked to a significant reduction in ROS production. These findings are consistent with the conclusion that activation of mTORC2, downstream of PI3K, represents a critical signaling locus for chemotaxis and chemokine release from PGE(2)-activated mast cells.

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

    PubMed

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

    2015-02-15

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

  1. [Relationship between the onset of labor and prostaglandins in rabbit tissues before and after delivery (author's transl)].

    PubMed

    Makimura, N; Kato, K; Nagata, I; Seki, K

    1981-03-01

    1) The studies were performed to elucidate the mechanism of onset of labor. It was investigated in relation to the movement of prostaglandins in individual tissues of pregnant rabbits before and after labor with the onset of labor. 2) The rabbit uterus duplex used is convenient material to investigate the movement of PGs in the same rabbit at the different term. 3) The concentrations of PGs were measured by RIA. 4) The concentrations of PGs in blood and amniotic fluid were not essential to explain account for the mechanism of onset labor. 5) From the results of the PGs values before and after labor, we have been considered that the relative PGs at the onset of labor were PG E1 and PG E2 in the placenta. We infer that PG F2 alpha plays a leading role in uterine contraction, because the large amount of PG F2 alpha presented in decidual parietalis during delivery, and PG E1 and PG E2 play a role in uterine contraction, too.

  2. Autocrine/paracrine prostaglandin E2 production by non-small cell lung cancer cells regulates matrix metalloproteinase-2 and CD44 in cyclooxygenase-2-dependent invasion.

    PubMed

    Dohadwala, Mariam; Batra, Raj K; Luo, Jie; Lin, Ying; Krysan, Kostyantyn; Pold, Mehis; Sharma, Sherven; Dubinett, Steven M

    2002-12-27

    Tumor cyclooxygenase-2 (COX-2) expression is known to be associated with enhanced tumor invasiveness. In the present study, we evaluated the importance of the COX-2 product prostaglandin E2 (PGE2) and its signaling through the EP4 receptor in mediating non-small cell lung cancer (NSCLC) invasiveness. Genetic inhibition of tumor COX-2 led to diminished matrix metalloproteinase (MMP)-2, CD44, and EP4 receptor expression and invasion. Treatment of NSCLC cells with exogenous 16,16-dimethylprostaglandin E2 significantly increased EP4 receptor, CD44, and MMP-2 expression and matrigel invasion. In contrast, anti-PGE2 decreased EP4 receptor, CD44, and MMP-2 expression in NSCLC cells. EP4 receptor signaling was found to be central to this process, because antisense oligonucleotide-mediated inhibition of tumor cell EP4 receptors significantly decreased CD44 expression. In addition, agents that increased intracellular cAMP, as is typical of EP4 receptor signaling, markedly increased CD44 expression. Moreover, MMP-2-AS treatment decreased PGE2-mediated CD44 expression, and CD44-AS treatment decreased MMP-2 expression. Thus, PGE2-mediated effects through EP4 required the parallel induction of both CD44 and MMP-2 expression because genetic inhibition of either MMP-2 or CD44 expression effectively blocked PGE2-mediated invasion in NSCLC. These findings indicate that PGE2 regulates COX-2-dependent, CD44- and MMP-2-mediated invasion in NSCLC in an autocrine/paracrine manner via EP receptor signaling. Thus, blocking PGE2 production or activity by genetic or pharmacological interventions may prove to be beneficial in chemoprevention or treatment of NSCLC.

  3. Autocrine/Paracrine Prostaglandin E2 Production by Non-small Cell Lung Cancer Cells Regulates Matrix Metalloproteinase-2 and CD44 in Cyclooxygenase-2-dependent Invasion*

    PubMed Central

    Dohadwala, Mariam; Batra, Raj K.; Luo, Jie; Lin, Ying; Krysan, Kostyantyn; Põld, Mehis; Sharma, Sherven; Dubinett, Steven M.

    2006-01-01

    Tumor cyclooxygenase-2 (COX-2) expression is known to be associated with enhanced tumor invasiveness. In the present study, we evaluated the importance of the COX-2 product prostaglandin E2 (PGE2) and its signaling through the EP4 receptor in mediating non-small cell lung cancer (NSCLC) invasiveness. Genetic inhibition of tumor COX-2 led to diminished matrix metalloproteinase (MMP)-2, CD44, and EP4 receptor expression and invasion. Treatment of NSCLC cells with exogenous 16,16-dimethylprostaglandin E2 significantly increased EP4 receptor, CD44, and MMP-2 expression and matrigel invasion. In contrast, anti-PGE2 decreased EP4 receptor, CD44, and MMP-2 expression in NSCLC cells. EP4 receptor signaling was found to be central to this process, because antisense oligonucleotide-mediated inhibition of tumor cell EP4 receptors significantly decreased CD44 expression. In addition, agents that increased intracellular cAMP, as is typical of EP4 receptor signaling, markedly increased CD44 expression. Moreover, MMP-2-AS treatment decreased PGE2-mediated CD44 expression, and CD44-AS treatment decreased MMP-2 expression. Thus, PGE2-mediated effects through EP4 required the parallel induction of both CD44 and MMP-2 expression because genetic inhibition of either MMP-2 or CD44 expression effectively blocked PGE2-mediated invasion in NSCLC. These findings indicate that PGE2 regulates COX-2-dependent, CD44- and MMP-2-mediated invasion in NSCLC in an autocrine/paracrine manner via EP receptor signaling. Thus, blocking PGE2 production or activity by genetic or pharmacological interventions may prove to be beneficial in chemoprevention or treatment of NSCLC. PMID:12393872

  4. Advanced Glycation End-Products Induce Apoptosis in Pancreatic Islet Endothelial Cells via NF-κB-Activated Cyclooxygenase-2/Prostaglandin E2 Up-Regulation

    PubMed Central

    Lan, Kuo-Cheng; Chiu, Chen-Yuan; Kao, Chia-Wei; Huang, Kuo-How; Wang, Ching-Chia; Huang, Kuo-Tong; Tsai, Keh-Sung

    2015-01-01

    Microvascular complications eventually affect nearly all patients with diabetes. Advanced glycation end-products (AGEs) resulting from hyperglycemia are a complex and heterogeneous group of compounds that accumulate in the plasma and tissues in diabetic patients. They are responsible for both endothelial dysfunction and diabetic vasculopathy. The aim of this study was to investigate the cytotoxicity of AGEs on pancreatic islet microvascular endothelial cells. The mechanism underlying the apoptotic effect of AGEs in pancreatic islet endothelial cell line MS1 was explored. The results showed that AGEs significantly decreased MS1 cell viability and induced MS1 cell apoptosis in a dose-dependent manner. AGEs dose-dependently increased the expressions of cleaved caspase-3, and cleaved poly (ADP-ribose) polymerase in MS1 cells. Treatment of MS1 cells with AGEs also resulted in increased nuclear factor (NF)-κB-p65 phosphorylation and cyclooxygenase (COX)-2 expression. However, AGEs did not affect the expressions of endoplasmic reticulum (ER) stress-related molecules in MS1 cells. Pretreatment with NS398 (a COX-2 inhibitor) to inhibit prostaglandin E2 (PGE2) production reversed the induction of cleaved caspase-3, cleaved PARP, and MS1 cell viability. Moreover, AGEs significantly increased the receptor for AGEs (RAGE) protein expression in MS1 cells, which could be reversed by RAGE neutralizing antibody. RAGE Neutralizing antibody could also reverse the induction of cleaved caspase-3 and cleaved PARP and decreased cell viability induced by AGEs. These results implicate the involvement of NF-κB-activated COX-2/PGE2 up-regulation in AGEs/RAGE-induced islet endothelial cell apoptosis and cytotoxicity. These findings may provide insight into the pathological processes within the pancreatic islet microvasculature induced by AGEs accumulation. PMID:25898207

  5. Prostaglandin E2 and IL-23 plus IL-1β differentially regulate the Th1/Th17 immune response of human CD161(+) CD4(+) memory T cells.

    PubMed

    Barrie, Arthur; Khare, Anupriya; Henkel, Matthew; Zhang, Yingze; Barmada, M Michael; Duerr, Richard; Ray, Anuradha

    2011-08-01

    Prostaglandin E2 (PGE2), interleukin (IL)-23, and IL-1beta (β) propagate inflammatory bowel disease (IBD) by enhancing the development and function of IL-17 producing CD4(+) T helper (Th17) cells. CD4(+) T cells that express the C-type lectin-like receptor CD161 have been proposed to be the physiologic pool of circulating Th17 cells implicated in IBD. We sought to understand how PGE2, alone and in combination with IL-23 and IL-1β, modulate human peripheral CD161(+) CD4(+) memory T cells. We found that CD161(+) cells comprise a significant proportion of human peripheral CD4(+) memory T cells. PGE2 and IL-23 plus IL-1β synergistically induced early IL-17A secretion from CD161(+) CD4(+) memory T cells and the selective enrichment of IL-17A(+) CD161(+) CD4(+) memory T cells in culture. Conversely, IL-23 plus IL-1β partially opposed the PGE2-mediated repression of early interferon gamma (IFN-γ) secretion from CD161(+) cells, as well as the PGE2-mediated depletion of IFN-γ(+) CD161(+) cells. Our results suggest that PGE2 and IL-23 plus IL-1β induce the Th17 immune response preferentially in CD161(+) CD4(+) memory T cells, while divergently regulating their ability to express IFN-γ. We hypothesize that Th17-mediated chronic inflammation in IBD depends on the net response of CD161(+) CD4(+) memory T cells to both PGE2 and IL-23 plus IL-1β. © 2011 Wiley Periodicals, Inc.

  6. Regulation of cytosolic COX-2 and prostaglandin E2 production by nitric oxide in activated murine macrophages.

    PubMed

    Patel, R; Attur, M G; Dave, M; Abramson, S B; Amin, A R

    1999-04-01

    Murine macrophages (RAW 264.7) when stimulated with LPS show 90% distribution of cyclooxygenase-2 (COX-2) in the nuclear fraction and approximately 10% in the cytosolic fraction. Further analysis of this cytosolic fraction at 100,000 x g indicates that the COX-2 is distributed both in the 100,000 x g soluble fraction and membrane fraction. Stimulation of RAW 264.7 cells with LPS in the presence of inducible nitric oxide synthase inhibitor L-NMMA at concentrations that inhibit nitrite accumulation by /=85% with higher concentrations of L-NMMA shows 1) up-regulation of PGE2 production, 2) accumulation of COX-2 protein in the 100,000 x g soluble and membrane fractions of the cytosolic fraction, and 3) with no significant effects on the accumulation of COX-2 mRNA. These experiments suggest that low concentrations of nitric oxide (10-15% of the total) attenuate PGE2 production in response to LPS in RAW 264.7 cells. This inhibition is, in part, due to decreased expression of cytosolic COX-2 protein.

  7. The biochemistry of prostaglandins: a primer.

    PubMed

    O'Neill, C

    1994-06-01

    The membranes of cells serve to endow structural integrity, compartmentalize regions of the cell and allow the generation of a stable intracellular milieu. The lipid component of the membrane forms a matrix for structurally and functionally important proteins. It is also increasingly obvious that these lipids form substrates for the synthesis of a range of molecules which have a central role in cellular communication and regulation. The prostaglandins were the first class of such molecules described and to some extent may serve as an archetype for an understanding of the various classes of lipid mediators. The release of arachidonic acid from lipids (phospholipids in particular) is achieved by lipases (phospholipase A2). Arachidonic acid itself may act directly on cells to modify function. For instance, it may modulate ion channel function. However, it is more often a substrate for cyclooxygenase which produces prostaglandin H2, being the precursor for further prostaglandin and thromboxane synthesis, or for lipoxygenase, to produce the precursor for leukotrienes (a related class of mediators). The prostaglandins may act intracellularly, are readily released from cells to act in an autocrine or paracrine fashion, and may enter the blood vessels or lymphatics to exert endocrine effects. Target cells may contain receptors with relative specificity for various members of the prostaglandin family, thus eliciting some specificity of action by the mediators.

  8. Inhibition of prostaglandin synthesis and its effect on uterine activity during established premature labor in sheep.

    PubMed

    Scott, J E; Grigsby, P L; Hirst, J J; Jenkin, G

    2001-01-01

    Continuous infusion of the selective prostaglandin synthase type-2 inhibitor nimesulide, together with the oxytocin receptor antagonist atosiban, inhibits glucocorticoid induction of labor in sheep. We evaluated the effectiveness of this treatment commencing after the onset of premature labor when prostaglandin concentrations are already significantly elevated. Premature labor was induced in chronically cannulated fetuses by constant fetal dexamethasone infusion. After the onset of active labor in each ewe, defined as uterine electromyographic (EMG) activity twice basal levels, ewes received combined nimesulide and atosiban (20.0 and 4.12 mg/kg per day, respectively; n = 6) or vehicle (n-methyl-2-pyrrolidone and saline each 1 mL/hour; n = 4) infusions for 48 hours. Maternal and fetal plasma PGFM (13,14-dihydro-15-keto PGF2alpha, the stable metabolite of prostaglandin (PG) F2alpha) and PGE2 concentrations were measured before, during, and after infusions. Four nimesulide- and atosiban-treated ewes successfully completed the 48-hour infusion period with no deliveries occurring during inhibitor treatment, or up to 6 hours after inhibitor treatment. Delivery was delayed in two other ewes, compared with control animals. Uterine EMG activity in nimesulide- and atosiban-treated ewes (n = 4) was significantly reduced during the 48-hour inhibitor treatment period. Maternal and fetal prostaglandin concentrations were significantly decreased in inhibitor-treated ewes during and after the infusions. The combination of nimesulide and atosiban treatment for 48 hours successfully inhibited the progression of active premature labor to delivery. This study further supports the potential value of this treatment regime for the inhibition of premature labor.

  9. Prostaglandin E₂ down-regulates the expression of CD25 on bovine T cells, and this effect is mediated through the EP4 receptor.

    PubMed

    Maślanka, Tomasz; Spodniewska, Anna; Barski, Dariusz; Jasiecka, Agnieszka; Zuśka-Prot, Monika; Ziółkowski, Hubert; Markiewicz, Włodzimierz; Jaroszewski, Jerzy Jan

    2014-08-15

    A crucial event in the initiation of an immune response is the activation of T cells, which requires IL-2 binding to its high-affinity IL-2 receptor for optimal signaling. The IL-2 receptor α-chain (CD25) is needed for the high affinity binding of IL-2 to effector cells and is potently induced after T cell activation. The aim of this research has been to determine whether prostaglandin E2 (PGE2) affects the CD25 expression on bovine T cells, and if it does, then which of the PGE2 receptor (EP) subtype(s) mediate(s) this effect. Herein, we report that exposure of peripheral blood mononuclear cells (PBMC) to PGE2 considerably reduces the percentage and absolute counts of CD25(+)CD4(+), CD25(+)CD8(+) and CD25(+)WC1(+) T cells, significantly increases the value of these parameters with respect of CD25(-)CD4(+), CD25(-)CD8(+) and CD25(-)WC1(+) T cells, and does not affect counts of the total populations of CD4(+), CD8(+) and WC1(+) T cells. These results indicate that PGE2 down-regulates the CD25 expression on bovine T cells. Moreover, we show that the selective blockade of EP4 receptor, but not EP1 and EP3 receptors, prevents this effect. Interestingly, the exposure of PBMC to a selective EP2 receptor agonist leads to a substantial increase in the percentage and absolute number of CD25(+)CD4(+), CD25(+)CD8(+) and CD25(+)WC1(+) T cells. In conclusions, the PGE2-induced down-regulation of CD25 expression on bovine CD4(+), CD8(+) and WC1(+) T cells should be considered as immunosuppressive and anti-inflammatory action, because these lymphocytes primarily represent effector cells and adequate CD25 expression is essential for their correct functioning. The PGE2-mediated down-regulation of the CD25 expression on bovine T cells is mediated via the EP4 receptor, although selective activation of the EP2 receptor up-regulates the CD25 expression on these cells. Thus, with respect to the effect of PGE2 on the CD25 expression on bovine T cells, EP4 receptor serves as an

  10. 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.

  11. Adenylate cyclase of human articular chondrocytes. Responsiveness to prostaglandins and other hormones.

    PubMed Central

    Houston, J P; McGuire, M K; Meats, J E; Ebsworth, N M; Russell, R G; Crawford, A; Mac Neil, S

    1982-01-01

    Adenylate cyclase [ATP pyrophosphate lyase (cyclizing), EC 4.6.1.1] was shown to be present in cultured human articular chondrocytes. Optimal conditions of incubation time, protein and substrate concentrations and pH were determined in whole cell lysates. Maximal activity occurred at pH 8.5 with no decrease in activity up to pH 10.0. Adenylate cyclase activity of particulate membrane preparations was enhanced by the addition of crude cytosol preparations. The prostaglandins E1, E2, F1 alpha, F2 alpha, D2, B1, B2, A1 and A2, as well as adrenaline and isoprenaline, stimulated adenylate cyclase derived from either adult or foetal chondrocytes. No significant stimulation was observed in the presence of human calcitonin or glucagon. Bovine parathyroid hormone always significantly stimulated the adenylate cyclase derived from foetal chondrocytes, but not from adult chondrocytes. Preincubation of the chondrocytes in culture with indomethacin and with or without supernatant medium from cultured mononuclear cells increased the responsiveness of the adenylate cyclase to prostaglandin E1. PMID:7159397

  12. Effects of prostaglandins on histophysiology of male reproductive organs and fertility in rats.

    PubMed

    Chinoy, N J; Sharma, J D; Seethalakshmi, L; Sanjeevan, A G

    1980-01-01

    The effects of subcutaneous injections of prostaglandins F2 alpha and E1 (PGF2 alpha and E1) on the histophysiology of male reproductive organs of mature albino rats and their fertility rate were studied. Although most of the androgensensitive biochemical parameters were reduced by PG treatment, the level of cholesterol and activities of 3 beta and 17 beta hydroxy steroid dehydrogenases were not significantly altered in the testis. These results indicate a probable decline in target organ response to androgen and/or in conversion of testosterone to its metabolites. The reduction in fertility rate of prostaglandin-treated male rats has been correlated with the altered morphology of the epididymal spermatozoa as well as with their reduced density and motility. The weights of testis and epididymis were significantly reduced but those of seminal vesicle (SV) and ventral prostate (VP) were increased by PG treatment. The height of the germinal/secretory epithelium, the tubular diameter of testis, and the epididymis were decreased, but Leydig cell diameter was not affected. The reduced fructose in SV and the corresponding increase in its weight suggest that there is hypertrophy but no hyperplasia. On the other hand, in VP there probably occur both hypertrophy and hyperplasia. It is evident from the results that PGF2 alpha and E1 exert a definite growth promoting effect particularly in SV and VP together with the antiandrogenic and partial antifertility effects.

  13. Regulation of Nur77 gene expression by prostanoids in cementoblastic cells.

    PubMed

    Moldovan, Sanda M; Nervina, Jeanne M; Tetradis, Sotirios; Camargo, Paulo M

    2009-05-01

    The inflammatory cytokine interleukin-1 (IL-1) decreases mineralisation by immortalized mouse-derived cementoblastic cells (OC-CM cells), whilst various prostanoids, including fluprostenol (flup) increase it. Subtraction hybridisation conducted on flup minus IL-1-treated OC-CM cells revealed that one of the primary response genes preferentially induced by flup is the transcription factor Nur77. The objective of this study was to examine the signal transduction cascades regulating prostanoid induction of Nur77 gene expression in OC-CM cells. Confluent OC-CM cells were treated with prostaglandin E(2) (PGE(2)), prostaglandin F(2alpha) (PGF(2alpha)), specific activators of the various EP prostanoid receptors and of the FP prostanoid receptor, and direct activators/inhibitors of the cyclic AMP-protein kinase A (PKA), protein kinase C (PKC) and intracellular calcium pathways. Nur77 gene expression was examined by mRNA extraction and Northern blot analysis. PGE(2) and PGF(2alpha) treatment of OC-CM cells significantly increased Nur77 mRNA expression in a time- and dose-dependent fashion. Both the EP1 prostanoid receptor-specific activator 16,16-dimethyl-PGE(2) and the FP prostanoid receptor-specific activator flup significantly increased Nur77 gene expression by OC-CM cells as compared to vehicle-treated controls. Increase in Nur77 gene expression was also observed when direct activators of the PKA, PKC and intracellular calcium pathways were used to treat OC-CM cells. Direct inhibition of the PKA, PKC and intracellular calcium pathways abrogated Nur77 gene expression induced by OC-CM cell treatment with PGE(2) and PGF(2alpha). Nur77 is a primary gene expressed by OC-CM cells and its induction appears to be mediated by the PKA, PKC and intracellular calcium pathways. Nur77 may affect expression of downstream target genes in OC-CM cells and partially regulate cementoblast cell function.

  14. 15-Deoxy-{delta}{sup 12,14}-prostaglandin J{sub 2} down-regulates CXCR4 on carcinoma cells through PPAR{gamma}- and NF{kappa}B-mediated pathways

    SciTech Connect

    Richard, Cynthia Lee; Lowthers, Erica Lauren; Blay, Jonathan

    2007-10-01

    The chemokine receptor CXCR4 plays a key role in the metastasis of colorectal cancer and its growth at metastatic sites. Here, we have investigated the mechanisms by which CXCR4 on cancer cells might be regulated by eicosanoids present within the colorectal tumor microenvironment. We show that prostaglandins PGE{sub 2}, PGA{sub 2}, PGD{sub 2}, PGJ{sub 2} and 15dPGJ{sub 2} each down-regulates CXCR4 receptor expression on human colorectal carcinoma cells to differing degrees. The most potent of these were PGD{sub 2} and its metabolites PGJ{sub 2} and 15dPGJ{sub 2}. Down-regulation was most rapid with the end-product 15dPGJ{sub 2} and was accompanied by a marked reduction in CXCR4 mRNA. 15dPGJ{sub 2} is known to be a ligand for the nuclear receptor PPAR{gamma}. Down-regulation of CXCR4 was also observed with the PPAR{gamma} agonist rosiglitazone, while 15dPGJ{sub 2}-induced CXCR4 down-regulation was substantially diminished by the PPAR{gamma} antagonists GW9662 and T0070907. These data support the involvement of PPAR{gamma}. However, the 15dPGJ{sub 2} analogue CAY10410, which can act on PPAR{gamma} but which lacks the intrinsic cyclopentenone structure found in 15dPGJ{sub 2}, down-regulated CXCR4 substantially less potently than 15dPGJ{sub 2}. The cyclopentenone grouping is known to inhibit the activity of NF{kappa}B. Consistent with an additional role for NF{kappa}B, we found that the cyclopentenone prostaglandin PGA{sub 2} and cyclopentenone itself could also down-regulate CXCR4. Immunolocalization studies showed that the cellular context was sufficient to trigger a focal nuclear pattern of NF{kappa}B p50 and that 15dPGJ{sub 2} interfered with this p50 nuclear localization. These data suggest that 15dPGJ{sub 2} can down-regulate CXCR4 on cancer cells through both PPAR{gamma} and NF{kappa}B. 15dPGJ{sub 2}, present within the tumor microenvironment, may act to down-regulate CXCR4 and impact upon the overall process of tumor expansion.

  15. Fatty acid and prostaglandin metabolism in children with diabetes mellitus. II. The effect of evening primrose oil supplementation on serum fatty acid and plasma prostaglandin levels.

    PubMed

    Arisaka, M; Arisaka, O; Yamashiro, Y

    1991-07-01

    Our previous study demonstrated that levels of dihomo-gamma-linolenic acid (DGLA) and arachidonic acid in serum total lipids decreased in association with increased plasma levels of prostaglandins E2 (PGE2) and F2 alpha (PGF2 alpha) in patients with insulin-dependent diabetes mellitus. In this study, 11 children with insulin-dependent diabetes mellitus completed a double-blind, placebo-controlled study to assess the effect of dietary supplementation with gamma-linolenic acid (GLA) on serum essential fatty acid and plasma PGE2 and PGF2 alpha levels. GLA was given as the seed oil from the evening primrose (EPO) and all patients received either EPO capsules (containing 45 mg of GLA and 360 mg of linoleic acid) or indistinguishable placebo capsules for 8 months. Initially patients took 2 capsules daily for 4 months then 4 capsules daily for a further 4 months. All patients were assessed at the start of the study, after 4 months and at the end of the study, by measuring serum essential fatty acid and plasma PGE2 and PGF2 alpha levels. After administration of 4 capsules daily the DGLA levels increased and PGE2 levels decreased significantly (p less than 0.01) in the EPO compared with the placebo group. Neither fatty acid nor PGE2 and PGF2 alpha levels were altered by administration of 2 EPO capsules daily. This suggests that the altered essential fatty acid and PG metabolism in diabetes may be reversed by direct GLA supplementation.

  16. Gastroprotective Activities of Sennoside A and Sennoside B via the Up-Regulation of Prostaglandin E2 and the Inhibition of H+/K+-ATPase

    PubMed Central

    Hwang, In Young; Jeong, Choon Sik

    2015-01-01

    Sennoside A (erythro) and sennoside B (threo) are dianthrone glycosides and diastereomers. We investigated their abilities to prevent the gastric lesions associated with diseases, such as, gastritis and gastric ulcer. To elucidate their gastroprotective effects, the inhibitions of HCl•EtOH-induced gastritis and indomethacin-induced gastric ulcers were assessed in rats. It was observed that both sennoside A and sennoside B increased prostaglandin E2 (PGE2) levels and inhibited H+/K+-ATPase (proton pump). In a rat model, both compounds reduced gastric juice, total acidity and increased pH, indicating that proton pump inhibition reduces gastric acid secretion. Furthermore, sennoside A and B increased PGE2 in a concentration-dependent manner. In a gastric emptying and intestinal transporting rate experiment, both sennoside A and sennoside B accelerated motility. Our results thus suggest that sennoside A and sennoside B possess significant gastroprotective activities and they might be useful for the treatment of gastric disease. PMID:26336586

  17. Dissociation of bradykinin-induced prostaglandin formation from phosphatidylinositol turnover in Swiss 3T3 fibroblasts: evidence for G protein regulation of phospholipase A/sub 2/

    SciTech Connect

    Burch, R.M.; Axelrod, J.

    1987-09-01

    In Swiss 3T3 fibroblasts bradykinin stimulated inositol phosphate (InsP) formation and prostaglandin E/sub 2/ (PGE/sub 2/) synthesis. The EC/sub 50/ values for stimulation of PGE/sub 2/ synthesis and InsP formation by bradykinin were similar, 200 pM and 275 pM, respectively. Guanosine-5'-(..gamma..-thio)triphosphate stimulated PGE/sub 2/ synthesis and InsP formation, and guanosine-5'-(..beta..-thio)diphosphate inhibited both PGE/sub 2/ synthesis and InsP formation stimulated by bradykinin. Neither bradykinin-stimulated PGE/sub 2/ synthesis nor InsP formation was sensitive to pertussis toxin. Phorbol ester, dexamethasone, and cycloheximide distinguished between bradykinin-stimulated PGE/sub 2/ synthesis and InsP formation. Phorbol 12-myristate 13-acetate enhanced bradykinin-stimulated PGE/sub 2/ synthesis but inhibited bradykinin-stimulated InsP formation. Pretreatment of cells with dexamethasone for 24 hr inhibited bradykinin-stimulated PGE/sub 2/ synthesis but was without effect on bradykinin-stimulated InsP formation. Cycloheximide inhibited on bradykinin-stimulated InsP formation. When bradykinin was added to cells prelabeled with (/sup 3/H) choline, the phospholipase A/sub 2/ products lysophosphatidylcholine and glycerophosphocholine were generated. The data suggest that bradykinin receptors are coupled by GTP-binding proteins to both phospholipase C and phospholipase A/sub 2/ and that phospholipase A/sub 2/ is the enzyme that catalyzes release of arachidonate for prostaglandin synthesis.

  18. Effects of flunixin meglumine and prostaglandin F2 α treatments on the development and quality of bovine embryos in vitro.

    PubMed

    Kim, S-S; Bang, J-I; Fakruzzaman, M; Lee, K-L; Ko, D-H; Ghanem, N; Wang, Z; Kong, I-K

    2014-12-01

    Assisted reproduction procedures, such as embryo transfer (ET) and artificial insemination (AI), in cattle could induce the secretion of prostaglandin F2 -alpha (PGF2 α) from uterine horns which may in turn interrupt embryo development and implantation. This study investigated the effect of flunixin meglumine (FM), prostaglandin F2 alpha (PGF2α) and FM combined with PGF2α supplementation in culture medium (IVC-II) on the development and quality of in vitro produced bovine embryos. The development rate of embryos was significantly higher in the FM group (33.3%) than in control (24.3%), PGF2 α (23.9%) and FM + PGF2 α groups (24.5%). The percentage of hatched blastocysts was also higher (p < 0.05) in the FM group (41.2%) than in the control (27.8%) and PGF2 α groups (19.8%). While, there was no significant difference in total cell number in all experimental groups, the number of apoptotic cells was significantly higher in the PGF2 α group (8.2 ± 6.6) than in the control (4.7 ± 3.2), FM (4.7 ± 2.5) and FM + PGF2 α (4.9 ± 3.4) groups. Detected by real-time PCR, secreted vesicle seminal protein 1 (SSLP1) and prostaglandin G/H synthase 2 (PTGS2) gene expression decreased (p < 0.05) in the PGF2 α group. However, SSLP1 and PTGS2 gene expression in the FM + PGF2 α group returned to their baseline levels, similar to the control and FM groups. Caspase 3 (CAPS3) gene expression increased in the PGF2 α group compared with other groups (p < 0.05). In conclusion, addition of FM in vitro culture significantly improved embryo development as well as alleviated the negative impact of PGF2 α.

  19. Prostaglandins in semen and their relationship to male fertility: a study of 145 men.

    PubMed

    Cosentino, M J; Emilson, L B; Cockett, A T

    1984-01-01

    Prostaglandin (PG) F2 alpha and PGE were measured in 163 semen samples from 145 men attending our male infertility clinic. In addition, each semen sample was analyzed for 13 different fertility parameters. Blood plasma levels of testosterone, follicle-stimulating hormone, and luteinizing hormone were also determined in many of the patients. The data obtained were then analyzed using multiple regression analyses on each PG for all of the parameters studied. The results indicate seminal PGF2 alpha and PGE concentrations were 2.78 +/- 0.24 micrograms/ml and 46.0 +/- 4.5 micrograms/ml, respectively. The seminal parameters that were significant predictors of seminal PGF2 alpha included: Ca++ concentration (P less than 0.001), Zn++ concentration (P less than 0.01), and percentage of tapered sperm (P less than 0.05). The seminal parameters that were significant predictors of seminal PGE included: Ca++ concentration (P less than 0.01) and sperm motility (P less than 0.05). Plasma testosterone was also a significant predictor of seminal PGE (P less than 0.05). These results suggest that seminal PGs are important to the human male fertility potential in that their levels are significantly interdependent with specific parameters of male fertility.

  20. Peripheral group II metabotropic glutamate receptors (mGluR2/3) regulate prostaglandin E2-mediated sensitization of capsaicin responses and thermal nociception.

    PubMed

    Yang, Dongni; Gereau, Robert W

    2002-08-01

    Previous studies have shown that group II metabotropic glutamate receptors (mGluRs) are present on the peripheral terminals of primary sensory neurons, suggesting that they might be involved in nociception. In this study, we investigated the modulation of nociception by peripheral group II mGluRs and the molecular basis of this modulation. Subcutaneous injection of a group II mGluR agonist, 2R,4R 4-aminopyrrolidine-2,4-dicarboxylate (APDC), did not alter thermal sensitivity but blocked prostaglandin E2 (PGE2)-induced thermal hyperalgesia. This effect was blocked by (2s)-2-amino-2-[(1s,2s)-2-carboxycycloprop-1-yl]-3-(xanth-9-yl) propanoic acid, a selective group II mGluR antagonist. In cultured primary sensory neurons, APDC blocked PGE2-induced potentiation of capsaicin responses, which was abolished when neurons were pretreated with pertussis toxin. Similar potentiating effects induced by forskolin but not 8-bromo-cAMP were also blocked by the activation of group II mGluRs. These results indicate that peripheral group II mGluRs act via inhibition of adenylyl cyclase to reverse the sensitization of capsaicin receptors and the thermal hyperalgesia induced by PGE2, and suggest that peripheral group II mGluRs might be targeted for therapeutic intervention in inflammatory pain states.

  1. The syndecan-4/protein kinase Cα pathway mediates prostaglandin E2-induced extracellular regulated kinase (ERK) activation in endothelial cells and angiogenesis in vivo.

    PubMed

    Corti, Federico; Finetti, Federica; Ziche, Marina; Simons, Michael

    2013-05-03

    Prostaglandin E2 (PGE2) is regarded as the main mediator of inflammatory symptoms. In addition, it also plays an important role in tumor growth and angiogenesis. In this study, we examined the mechanism of PGE2-induced angiogenic response. We show that in the absence of proteoglycan syndecan-4 (Sdc4), PGE2-induced ERK activation is decreased significantly, as is endothelial cell migration and cord formation in a two-dimensional Matrigel assay. In vivo, PGE2-induced angiogenesis is reduced dramatically in Sdc4(-/-) mice. The mechanism was traced to Sdc4-dependent activation of protein kinase Cα (PKCα). Transduction of an Sdc4 S183E mutant (a cytoplasmic domain mutation that blocks Sdc4-dependent PKCα activation) into Sdc4(-/-) endothelial cells was not able to rescue the loss of PGE2-induced ERK activation, whereas a transduction with full-length Sdc4 resulted in full rescue. Furthermore, PGE2-induced angiogenesis was also reduced in PKCα(-/-) mice. Taken together, these results demonstrate that PGE2-induced activation of angiogenesis is mediated via syndecan-4-dependent activation of PKCα.

  2. Linoleic Acid-Induced Growth Inhibition of Human Gastric Epithelial Adenocarcinoma AGS Cells is Associated with Down-Regulation of Prostaglandin E2 Synthesis and Telomerase Activity

    PubMed Central

    Choi, Yung Hyun

    2014-01-01

    Background: Linoleic acid is the most abundant polyunsaturated fatty acid in human nutrition and found in most vegetable oils and certain food products. In the present study, we investigated the effects of linoleic acid on the growth of human epithelial adenocarcinoma AGS cells. Methods: MTT assay, flow cytometry, RT-PCR and Western-blot analyses were used to investigate the effects and underlying mechanisms of linoleic acid on AGS cells. The effects of this compound were also tested on prostaglandin E2 (PGE2) production and telomerase activity. Results: Our data indicated that growth inhibition of AGS cells by linoleic acid treatment was associated with induction of apoptosis. Linoleic acid treatment decreased the expression levels of the cyclooxygenase (COX)-2 mRNA and protein without causing significant changes in the COX-1 levels, which was correlated with the inhibition of PGE2 synthesis. Linoleic acid treatment also decreased the expression of human telomerase reverse transcriptase (hTERT), a main determinant of the telomerase enzymatic activity, and activity of telomerase, with inhibiting the expression of c-myc in a concentration-dependent manner. Conclusions: Taken together, our results indicate that linoleic acid inhibits the production of PGE2 and activity of telomerase by suppressing COX-2 and hTERT expression. PMID:25337570

  3. The ω6-fatty acid, arachidonic acid, regulates the conversion of white to brite adipocyte through a prostaglandin/calcium mediated pathway

    PubMed Central

    Pisani, Didier F.; Ghandour, Rayane A.; Beranger, Guillaume E.; Le Faouder, Pauline; Chambard, Jean-Claude; Giroud, Maude; Vegiopoulos, Alexandros; Djedaini, Mansour; Bertrand-Michel, Justine; Tauc, Michel; Herzig, Stephan; Langin, Dominique; Ailhaud, Gérard; Duranton, Christophe; Amri, Ez-Zoubir

    2014-01-01

    Objective Brite adipocytes are inducible energy-dissipating cells expressing UCP1 which appear within white adipose tissue of healthy adult individuals. Recruitment of these cells represents a potential strategy to fight obesity and associated diseases. Methods/Results Using human Multipotent Adipose-Derived Stem cells, able to convert into brite adipocytes, we show that arachidonic acid strongly inhibits brite adipocyte formation via a cyclooxygenase pathway leading to secretion of PGE2 and PGF2α. Both prostaglandins induce an oscillatory Ca++ signaling coupled to ERK pathway and trigger a decrease in UCP1 expression and in oxygen consumption without altering mitochondriogenesis. In mice fed a standard diet supplemented with ω6 arachidonic acid, PGF2α and PGE2 amounts are increased in subcutaneous white adipose tissue and associated with a decrease in the recruitment of brite adipocytes. Conclusion Our results suggest that dietary excess of ω6 polyunsaturated fatty acids present in Western diets, may also favor obesity by preventing the “browning” process to take place. PMID:25506549

  4. Regulation of metalloproteinases and NF-kappaB activation in rabbit synovial fibroblasts via E prostaglandins and Erk: contrasting effects of nabumetone and 6MNA.

    PubMed

    Pillinger, Michael H; Dinsell, Victoria; Apsel, Beth; Tolani, Sonia N; Marjanovic, Nada; Chan, Edwin S L; Gomez, Paul; Clancy, Robert; Chang, Lih-Fan; Abramson, Steven B

    2004-07-01

    1 Nabumetone is a prodrug that is converted in vivo into 6-methoxy-2-naphthylacetic acid (6MNA), a cyclooxygenase inhibitor with anti-inflammatory properties. We tested the effects of nabumetone and 6MNA on the inflammatory responses of synovial fibroblasts (SFs). 2 Brief exposures to 6MNA (50-150 microm) had no effect on IL-1beta/TNF-alpha (each 20 ng ml(-1))-stimulated Erk activation. Longer exposures depleted prostaglandin E1 (PGE1) as much as 70%, and stimulated Erk as much as 300%. Nabumetone (150 microm) inhibited Erk activation by 60-80%. 6MNA (50-150 microm) stimulated (approximately 200%) and nabumetone (150 microm) inhibited (approximately 50%) matrix metalloproteinase (MMP)-1, but not MMP-13 secretion from SFs. 3 6MNA stimulation of MMP-1 secretion was inhibited approximately 30% by PGE1 (1 microm) and approximately 80% by the Erk pathway inhibitor UO126 (10 microm), confirming that PGE depletion and Erk activation mediate MMP-1 secretion by 6MNA. 4 Consistent with its role as an Erk inhibitor, nabumetone (150 microm) abrogated 6MNA enhancement of MMP-1 secretion. 5 UO126 (10 microm) and nabumetone (150 microm) inhibited (approximately 70 and 40%, respectively), but 6MNA (150 microm) enhanced (approximately 40%), NF-kappaB activation. 6 Our data indicate that 6MNA shares with other COX inhibitors several proinflammatory effects on synovial fibroblasts. In contrast, nabumetone demonstrates anti-inflammatory and potentially arthroprotective effects that have not been previously appreciated.

  5. The relationship between spontaneous rupture of membranes, labor, and microbial invasion of the amniotic cavity and amniotic fluid concentrations of prostaglandins and thromboxane B2 in term pregnancy.

    PubMed

    Romero, R; Baumann, P; Gomez, R; Salafia, C; Rittenhouse, L; Barberio, D; Behnke, E; Cotton, D B; Mitchell, M D

    1993-06-01

    The purpose of this study was to examine the relationship between rupture of membranes, labor, and microbial invasion of the amniotic cavity and amniotic fluid concentrations of eicosanoids in patients with spontaneous rupture of membranes at term. Amniotic fluid was retrieved by transabdominal amniocentesis from patients with rupture of membranes and patients with intact membranes at term. Studies to determine the microbial state of the amniotic cavity included culture for bacteria and mycoplasmas, Gram stain, amniotic fluid white blood cell count, and Limulus amebocyte lysate. Eicosanoids (prostaglandin E2, prostaglandin F2 alpha and its stable metabolite, 6-keto-prostaglandin F1 alpha, and thromboxane B2) were determined with sensitive and specific radioimmunoassays validated for human amniotic fluid. Statistical inference was conducted with analysis of variance and linear contrast. (1) Spontaneous rupture of membranes at term was associated with a significant increase in amniotic fluid concentrations of all eicosanoids measured in this study except 6-keto-prostaglandin F1 alpha. (2) Early labor in patients with rupture of membranes was associated with a significant increase in the amniotic fluid concentration of all eicosanoids. (3) A significant increase in amniotic fluid eicosanoids in women with microbial invasion of the amniotic cavity could not be documented. Whereas preterm labor in the absence of microbial invasion of the amniotic cavity is not associated with a significant increase in amniotic fluid concentrations of prostaglandins, a clear increase was documented in women with early labor after spontaneous rupture of membranes. These observations suggest that there are fundamental differences in the biochemistry of term and preterm parturition.

  6. Canine placenta: a source of prepartal prostaglandins during normal and antiprogestin-induced parturition.

    PubMed

    Kowalewski, Mariusz Pawel; Beceriklisoy, Hakki Bülent; Pfarrer, Christiane; Aslan, Selim; Kindahl, Hans; Kücükaslan, Ibrahim; Hoffmann, Bernd

    2010-03-01

    Expression of cyclooxygenase 2 (COX2, now known as PTGS2), prostaglandin E2 synthase (PTGES, PGES), and prostaglandin F2alpha synthase (PGFS), of the respective receptors PTGFR (FP), PTGER2 (EP2), and PTGER4 (EP4) and of the progesterone receptor (PGR, PR) was assessed by real-time PCR, immunohistochemistry (IHC), or in situ hybridization (ISH) in utero/placental tissue samples collected from three to five bitches on days 8-12 (pre-implantation), 18-25 (post-implantation), and 35-40 (mid-gestation) of pregnancy and during the prepartal luteolysis. Additionally, ten mid-pregnant bitches were treated with the antiprogestin aglepristone (10 mg/kg bw (2x/24 h)); ovariohysterectomy was 24 and 72 h after the second treatment. Plasma progesterone and 15-ketodihydro-PGF2alpha (PGFM) concentrations were determined by RIA. Expression of the PGR was highest before implantation and primarily located to the endometrium; expression in the placenta was restricted to the decidual cells. PTGS2 was constantly low expressed until mid-gestation; a strong upregulation occurred at prepartal luteolysis concomitant with an increase in PGFM. PGFS was upregulated after implantation and significantly elevated through early and mid-gestation. PTGES showed a gradual increase and a strong prepartal upregulation. PTGFR, PTGER2, and PTGER4 were downregulated after implantation; a gradual upregulation of PTGFR and PTGER2 occurred towards parturition. ISH and IHC co-localized PGFS, PTGFR, PTGES, and PTGS2 in the trophoblast and endometrium. The changes following application of aglepristone were in the same direction as those observed from mid-gestation to prepartal luteolysis. These data suggest that the prepartal increase of PGF2alpha results from a strong upregulation of PTGS2 in the fetal trophoblast with the withdrawal of progesterone having a signalling function and the decidual cells playing a key role in the underlying cell-to-cell crosstalk.

  7. 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.

  8. The influence of inhibited prostaglandin biosynthesis on post-ovulatory oviductal ova transport in sows.

    PubMed

    Hultén, F; Tantasuparuk, W; Englund, P; Kindahl, H; Einarsson, S

    2000-04-15

    Changes in prostaglandin and progesterone concentrations after ovulation seem to affect reproductive functions in the sow. The influence of lowered prostaglandin levels on ova transport velocity through the isthmus part of the oviduct, and on progesterone concentrations, was studied during the second estrus after weaning in thirteen purebred Yorkshire multiparous sows. To determine the time of ovulation transrectal ultrasonographic examination was performed. In the second estrus, six sows were given intravenous injections of flunixin meglumine (2.2 mg/kg body weight) every sixth hour from 4 to 8 h after time of ovulation until about 48 h after ovulation, at which time the sows were slaughtered. Blood samples were collected every second hour from about 12 h before ovulation until slaughter. Progesterone and prostaglandin F2alpha (PGF2alpha) metabolite levels were determined. Immediately after slaughter the isthmus part of the oviducts were cut into 3 equally long segments and the number of ova in each segment, and in the upper part of the uterine horns, was determined. Before start of treatment, PGF2alpha metabolite levels were similar in the 2 groups (P=0.84). In the treatment group, PGF2alpha values dropped to below the detection limit immediately after start of treatment, whereas in the control group the concentrations were quite stable throughout the sampling period (P=0.005). Ova recovery rate was 94% in the treatment group and 95 % in the control group. At time of slaughter, in the treatment group ova had on average passed 2.1 segments whereas in the control group the ova had passed 2.5 segments (P=0.57). The progesterone levels increased continuously in both groups after ovulation but there was no difference in the mean progesterone concentrations between the two groups before (P=0.96) or after (P=0.58) ovulation. It can be concluded that the transport of ova through the isthmus part of the oviduct is unaffected by an inhibition of prostaglandin synthesis

  9. Prostaglandins, Lysosomes, and Radiation Injury

    DTIC Science & Technology

    1980-01-01

    SCIENTIFIC REPORT Prostaglandins, lysosomes, and radiation injury 7 P. J. Trocha <G. N. Catravas DTI.C A DEFENSE NUCLEAR AGENCY -LL ARMED FORCES...been shown to be altered with tissue injury . Yet no studies have been performed to monitor lysosomal enzyme activi- ties and PG levels simultaneously...nd R. Pi olm. Raven Pra& New Yort- D 980. Prostaglandins, Lysosomes, and Radiation Injury Paul J. Trocha and George N. Catravas Armed Forces

  10. [Value of prostaglandins in andrology].

    PubMed

    Kreysel, C O

    1994-05-20

    In humans, the highest concentration of prostaglandins is found in the seminal fluid, where they are stored. They probably act as hormones by exercising--via receptors--an influence on cell function. Views on the role of prostaglandins in fertility vary. An explanation for this may be the methodological differences discussed. It remains for future research to establish the true functions of this highly versatile class of compounds in the area of fertility.

  11. 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

  12. Expression of the prostaglandin E(2) (PGE(2)) receptor subtype EP(4) and its regulation by PGE(2) in osteoblastic cell lines and adult rat bone tissue.

    PubMed

    Weinreb, M; Machwate, M; Shir, N; Abramovitz, M; Rodan, G A; Harada, S

    2001-03-01

    Prostaglandins E (especially PGE(2)) stimulate bone formation and increase bone mass in several species including man. The mechanism for this effect, the target cells, and the receptors involved are not known. Specific cell-surface receptors for PGE(2) (EP(1-4)) have been cloned and characterized. EP(4) was reported to be the major receptor in embryonic and neonatal bone tissue in mice, especially in preosteoblasts; however, no data are available regarding its expression in adult bone. This study examines the expression of EP(4) in bone tissue of young adult rats, in which PGE(2) is markedly anabolic, and in various osteoblastic cell lines. Using northern blot analysis, we found that osteoblastic cell lines RCT-1, RCT-3, TRAB-11, and RP-1, primary osteoblastic cells harvested from fetal rat calvaria, as well as tibiae and calvariae of 5-week-old rats express 3.8 kb EP(4) messenger RNA (mRNA). Treatment of periosteal cells (RP-1) in vitro with 10(-6) mol/L PGE(2) increased the levels of both EP(4) mRNA and EP(4) protein, peaking at 1-2 h. Similarly, systemic administration of an anabolic dose of PGE(2) (3-6 mg/kg) to young adult rats upregulated the expression of EP(4) in the tibia and calvaria, also peaking at 1-2 h. Using in situ hybridization, we found increased expression of EP(4) in bone marrow cells of the tibial metaphysis in response to systemic PGE(2) treatment. The preosteoblastic nature of these EP(4)-expressing cells was suggested by the fact that dexamethasone-treated bone marrow stromal cells in culture express EP(4) mRNA, which is upregulated by PGE(2). Northern blot analysis failed to detect both basal and PGE(2)-induced EP(2) mRNA in the bone samples or cell lines tested. Taken together, these data implicate EP(4) as the major cyclic AMP-related PGE(2) receptor subtype expressed in bone tissue and osteoblastic cells and indicate that this receptor is upregulated by its ligand, PGE(2).

  13. Differential regulation of phosphorylation of the cAMP response element-binding protein after activation of EP2 and EP4 prostanoid receptors by prostaglandin E2.

    PubMed

    Fujino, Hiromichi; Salvi, Sambhitab; Regan, John W

    2005-07-01

    The EP2 and EP4 prostanoid receptors are G-protein-coupled receptors whose activation by their endogenous ligand, prostaglandin (PG) E2, stimulates the formation of intracellular cAMP. We have previously reported that the stimulation of cAMP formation in EP4-expressing cells is significantly less than in EP2-expressing cells, despite nearly identical levels of receptor expression (J Biol Chem 277:2614-2619, 2002). In addition, a component of EP4 receptor signaling, but not of EP2 receptor signaling, was found to involve the activation of phosphatidylinositol 3-kinase (PI3K). In this study, we report that PGE2 stimulation of cells expressing either the EP2 or EP4 receptor results in the phosphorylation of the cAMP response element binding protein (CREB) at serine-133. Pretreatment of cells with N-[2-(4-bromocinnamylamino)ethyl]-5-isoquinoline (H-89), an inhibitor of protein kinase A (PKA), attenuated the PGE2-mediated phosphorylation of CREB in EP2-expressing cells, but not in EP4-expressing cells. Pretreatment of cells with wortmannin, an inhibitor of PI3K, had no effects on the PGE2-mediated phosphorylation of CREB in either EP2- or EP4-expressing cells, although it significantly increased the PGE2-mediated activation of PKA in EP4-expressing cells. However, combined pretreatment with H-89 and wortmannin blocked PGE2-mediated phosphorylation in EP2-expressing cells as well as in EP2-expressing cells. PGE2-mediated intracellular cAMP formation was not affected by pretreatment with wortmannin, or combined treatment with wortmannin and H-89, in either the EP2- or EP4-expressing cells. These findings suggest that PGE2 stimulation of EP4 receptors, but not EP2 receptors, results in the activation of a PI3K signaling pathway that inhibits the activity of PKA and that the PGE2-mediated phosphorylation of CREB by these receptors occurs through different signaling pathways

  14. Prostaglandins in swine reproduction.

    PubMed

    Kingston, D J

    1982-05-01

    A review is presented of the roles of prostaglandins in swine reproduction. PGE and PGF are both produced in the ovary. PGE is thought to mediate steroidogenic activity of L.H. on the development of the granulosa cells leading to increased progesterone production in the preovulatory phase of the oestrus cycle. PGF2 acts on the theca cells leading to increased oestradiol and oestrus manifestation. The PG blocker indomethacin prevents oocyte rupture, but not maturation. The L.H. surges in the follicular phase stimulate ovarian PG production which initiates oestrus and ovulation. The uterus produces PGF2alpha. Disorders leading to abortion usually result in excess PGF2alpha production at the endometrium leading to luteolysis. With normal gestation circulatory progesterone levels fall during the last two weeks of pregnancy associated with increased circulatory foetal corticoid levels. The foetal corticoids are thought to trigger endometrial PGF2alpha levels leading to luteolysis and parturition. The use of exogenous PGF2alpha for induction of oestrus and abortion, parturition, semen collection and resolution of anoestrus is reviewed.

  15. 15-deoxy-Delta12,14-prostaglandin J2 up-regulates death receptor 5 gene expression in HCT116 cells: involvement of reactive oxygen species and C/EBP homologous transcription factor gene transcription.

    PubMed

    Su, Rong-Ying; Chi, Kwan-Hwa; Huang, Duen-Yi; Tai, Ming-Hui; Lin, Wan-Wan

    2008-10-01

    Although 15-deoxy-Delta(12,14)-prostaglandin J(2) (15dPGJ(2)) was reported to up-regulate death receptor 5 (DR5) protein expression and sensitize TRAIL-induced cytotoxicity, its action mechanism remains unclear. Using HCT116 colon cancer cells, we found that sensitization of TRAIL-induced cytotoxicity by 15dPGJ(2) resulted from up-regulation of DR5 via gene transcription but was not associated with PPAR-gamma activation. Moreover, 15dPGJ(2) induced GRP78, XBP1, and C/EBP homologous transcription factor (CHOP) expression in HCT116 cells, confirming that 15dPGJ(2) is an endoplasmic reticulum stress inducer. Knockdown of the CHOP gene by siRNA attenuated DR5 up-regulation and the sensitized cytotoxicity in colon cancer HCT116 and SW480. With deletion plasmids of DR5 promoters, we found that the CHOP-binding site was involved in activating the DR5 gene by 15dPGJ(2). A mechanistic study showed the contributions of reactive oxygen species (ROS) and intracellular calcium in CHOP and DR5 gene up-regulation. 15dPGJ(2) was also found to induce DR5 in two prostate cancer cell lines, LNCaP and PC3. Although in LNCaP DR5 up-regulation was accompanied by CHOP expression by 15dPGJ(2), no significant increase in CHOP expression or DR5 promoter activity was observed in PC3 cells. Intriguingly, 15dPGJ(2) induced ROS and calcium production in PC3 cells. This inability to induce CHOP was not due to the p53-null in PC3 cells, as similar extents of increase in CHOP protein were found due to 15dPGJ(2) in both wild-type and p53-null HCT116 cells. In summary, the effect of up-regulation of DR5 by 15dPGJ(2) in colon cancer cells is independent of PPAR-gamma and p53 but relies on CHOP induction through gene transcription involving ROS and calcium.

  16. Tartrazine and the prostaglandin system.

    PubMed

    Gerber, J G; Payne, N A; Oelz, O; Nies, A S; Oates, J A

    1979-04-01

    The effect of tartrazine on prostaglandin production was evaluated in several in vitro systems in order to elucidate the interrelationship between aspirin-sensitive asthma and tartrazine. Unlike the nonsteroidal anti-inflammatory drugs, tartrazine did not inhibit cyclooxygenase activity in sheep seminal vesicles, guinea pig lung microsomes, and human platelets. Tartrazine had no effect on the activation of acyl hydrolase, which is the rate-limiting step in prostaglandin production. The major metabolite of tartrazine, sulfanilic acid, also had no inhibitory effect on the sheep seminal vesicle cyclooxygenase. In view of these findings, if there is a cross-sensitivity between tartrazine and aspirin in aspirin-sensitive asthmatics, it is unlikely to be on the basis of prostaglandin inhibition.

  17. Occurrence of prostaglandins and other eicosanoids in parasites and their role in host-parasite interaction.

    PubMed

    Szkudliński, J

    2000-01-01

    Prostaglandins have been already pretty well recognized as metabolic regulators in vertebebrata tissues mainly in mammals. I.ess reports concerned the occurrence of prostaglandins in invertebrates. In the present review we summarise literature data about the presence of prostaglandins and other eicosanoids in various groups of parasites and their possible role in host-parasite interaction. Prostaglandins have also been found in very primitive organisms as bacteria, varions plants and protozoa. We summarise that prostaglandins seem to be a very ancient group, going back to the roots of evolution. They are as universal in cell physiology as DNA in genetics. In host-parasiter eicosanoids also parasitic origin, play an important role as a modulators of hosts immune responsiveness.

  18. Corticotropin-releasing hormone interacts with interleukin-1β to regulate prostaglandin H synthase-2 expression in human myometrium during pregnancy and labor.

    PubMed

    Markovic, Danijela; Bari, Muhammad F; Lu, Buyu; Vatish, Manu; Grammatopoulos, Dimitris K

    2013-07-01

    The onset of labor appears to involve the activation of myometrial inflammatory pathways, and transcription factors such as nuclear factor-κB (NF-κB) control expression of the contraction-associated proteins required to induce a procontractile phenotype. These responses might involve CRH, which integrates immune and neuroendocrine systems. In human myometrium we investigated cyclooxygenase 2 (PGHS2) expression and regulation by CRH and the proinflammatory cytokine IL-1β before and after labor. Myometrial tissues obtained from pregnant women at term before (n = 12) or during labor (n = 10) and pathological cases of choriamnionitis-associated term labor (n = 5) were used to isolate primary myocytes and investigate in vitro, CRH effects on basal and IL-1β regulated p65 activation and PGHS2 expression. In nonlaboring myometrial cells, CRH was unable to induce NF-κB nuclear translocation; however, it altered the temporal dynamics of IL-1β-driven NF-κB nuclear entry by initially delaying entry and subsequently prolonging retention. These CRH-R1-driven effects were associated with a modest inhibitory action in the early phase (within 2 hours) of IL-1β stimulated PGHS2 mRNA expression, whereas prolonged stimulation for 6-18 hours augmented the IL-1β effects. The early-phase effect required intact protein kinase A activity and was diminished after the onset of labor. The presence of chorioamnionitis led to exaggerated PGHS2 mRNA responses to IL-1β but diminished effects of CRH. CRH is involved in the inflammatory regulation of PGHS2 expression before and during labor; these actions might be important in priming and preparing the myometrium for labor and cellular adaptive responses to inflammatory mediators.

  19. Corticotropin-Releasing Hormone Interacts With Interleukin-1β to Regulate Prostaglandin H Synthase-2 Expression in Human Myometrium During Pregnancy and Labor

    PubMed Central

    Markovic, Danijela; Bari, Muhammad F.; Lu, Buyu; Grammatopoulos, Dimitris K.

    2013-01-01

    Context: The onset of labor appears to involve the activation of myometrial inflammatory pathways, and transcription factors such as nuclear factor-κB (NF-κB) control expression of the contraction-associated proteins required to induce a procontractile phenotype. These responses might involve CRH, which integrates immune and neuroendocrine systems. Objectives: In human myometrium we investigated cyclooxygenase 2 (PGHS2) expression and regulation by CRH and the proinflammatory cytokine IL-1β before and after labor. Design: Myometrial tissues obtained from pregnant women at term before (n = 12) or during labor (n = 10) and pathological cases of choriamnionitis-associated term labor (n = 5) were used to isolate primary myocytes and investigate in vitro, CRH effects on basal and IL-1β regulated p65 activation and PGHS2 expression. Results: In nonlaboring myometrial cells, CRH was unable to induce NF-κB nuclear translocation; however, it altered the temporal dynamics of IL-1β-driven NF-κB nuclear entry by initially delaying entry and subsequently prolonging retention. These CRH-R1-driven effects were associated with a modest inhibitory action in the early phase (within 2 hours) of IL-1β stimulated PGHS2 mRNA expression, whereas prolonged stimulation for 6–18 hours augmented the IL-1β effects. The early-phase effect required intact protein kinase A activity and was diminished after the onset of labor. The presence of chorioamnionitis led to exaggerated PGHS2 mRNA responses to IL-1β but diminished effects of CRH. Conclusions: CRH is involved in the inflammatory regulation of PGHS2 expression before and during labor; these actions might be important in priming and preparing the myometrium for labor and cellular adaptive responses to inflammatory mediators. PMID:23666959

  20. IL-33 Signaling Regulates Innate IL-17A and IL-22 Production via Suppression of Prostaglandin E2 during Lung Fungal Infection.

    PubMed

    Garth, Jaleesa M; Reeder, Kristen M; Godwin, Matthew S; Mackel, Joseph J; Dunaway, Chad W; Blackburn, Jonathan P; Steele, Chad

    2017-09-15

    Members of the IL-1 family play protective and regulatory roles in immune defense against the opportunistic mold Aspergillus fumigatus In this study, we investigated the IL-1 family member IL-33 in lung defense against A. fumigatus IL-33 was detected in the naive lung, which further increased after exposure to A. fumigatus in a dectin-1-independent manner. Mice deficient in the receptor for IL-33 (Il1rl1(-/-)) unexpectedly demonstrated enhanced lung clearance of A. fumigatus IL-33 functioned as a negative regulator of multiple inflammatory cytokines, as IL-1α, IL-1β, IL-6, IL-17A, and IL-22 were significantly elevated in fungal-exposed Il1rl1(-/-) mice. Subsequently, IL-33 administration to normal mice attenuated fungal-induced IL-17A and IL-22, but not IL-1α, IL-1β, or IL-6, production. IL-33-mediated regulation of IL-17A and IL-22 did not involve the modulation of IL-23 but rather PGE2; PGE2 was significantly increased in fungal-exposed Il1rl1(-/-) mice, and normal mice produced less PGE2 after fungal exposure when administered IL-33, suggesting that IL-33-mediated regulation of IL-17A and IL-22 occurred at the level of PGE2 This was confirmed by in vivo cyclooxygenase 2 inhibition, which attenuated fungal-induced IL-17A and IL-22, as well as IL-1α, IL-1β, and IL-6, production in Il1rl1(-/-) mice, resulting in impaired fungal clearance. We also show that a PGE2 receptor agonist increased, whereas a PGE2 synthase inhibitor decreased, the levels of IL-17A and IL-22 but not IL-1α, IL-1β, or IL-6. This study establishes novel mechanisms of innate IL-17A/IL-22 production via PGE2 and regulation of the PGE2/IL-17A/IL-22 axis via IL-33 signaling during lung fungal exposure. Copyright © 2017 by The American Association of Immunologists, Inc.

  1. Regulation of Activator Protein-1 by 8-iso-Prostaglandin E{sub 2} in a Thromboxane A{sub 2} Receptor-Dependent and -Independent Manner

    SciTech Connect

    Weber, Thomas J.; Markillie, Lye MENG.

    2003-05-01

    The thromboxane A{sub 2} (TXA{sub 2}) receptor (TP) is represented by two alternatively spliced forms, termed the platelet/placental (TP-P) and endothelial (TP-E) type receptors. Experimental evidence suggests that TP isoforms may be regulated by novel ligands termed the isoprostanes, which paradoxically act as TP agonists in smooth muscle and TP antagonists in platelet preparations. Here we have investigated whether prototypical isoprostanes (8-iso-PG{sub 2{sub {alpha}}} and 8-iso-PGE{sub 2}) regulate the activity of TP isoforms expressed in Chinese Hamster Ovary (CHO) cells using activator protein-1 (AP-1)-luciferase activity as a reporter. AP-1-luciferase activity was increased by a TP agonist (U46619) in CHO cells transfected with the human TP-P and TP-E receptors and this response was fully inhibited by TP antagonists (ISAP, SQ29,548). AP-1-luciferase activity was potently (nM) increased by 8-iso-PGE2 in CHO TP-P and TP-E cells, and this response was partially inhibited by cotreatment of cells with TP antagonists, while 8-iso-PGF{sub 2{sub {alpha}}} was without effect. Cyclooxygenase inhibitors did not abolish 8-iso-PGE{sub 2} mediated AP-1-luciferase activity, indicating that this response is not dependent on de novo TXA2 biosynthesis. Interestingly, 8-iso-PGE{sub 2}-mediated AP-1-luciferase activity was near maximal in naive cells between 1-10 nM concentrations, and this response was not inhibited by TP antagonist or reproduced by agonists for TP or EP1/EP3 receptors. These observations (1) support a role for novel ligands in the regulation of TP-dependent signaling, (2) indicate that TP-P and TP-E couple to AP-1, (3) provide further evidence that isoprostanes function as TP agonists in a cell-type specific fashion, and (4) indicate that additional targets regulated by 8-iso-PGE{sub 2} couple to AP-1.

  2. 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.

  3. Expression of programmed cell death1 in T follicular helper cells is regulated by prostaglandin E2 secreted by HBV-infected HepG2.2.1.5 cells.

    PubMed

    Sui, Zhefeng; Shi, Ying; Gao, Zhiling; Yang, Deguang; Wang, Zhihao

    2017-06-01

    The present study aimed to investigate the distribution of T follicular helper (Tfh)-cell subsets in patients with hepatitis B virus (HBV) and determine the underlying mechanism of HBV regulation of Tfh cells. The frequency of peripheral blood Tfh subsets was analyzed using flow cytometry. The expression level of programmed cell death‑1 (PD‑1) and prostaglandin E2 (PGE2) was quantified using reverse transcription‑quantitative polymerase chain reaction and western blotting. The PGE2 level in culture supernatant was detected using enzyme‑linked immunosorbent assay. A Transwell chamber was used to co‑culture Tfh cells with HepG2 and HepG2.2.1.5. The percentage of inducible T‑cell costimulator (ICOS)+ and total Tfh cells was high at the immune activation (IA) group; however, it was reduced in the immune tolerance (IT), responders with HBsAg seroconversion (RP) and healthy control (HC) groups. The percentage of PD‑1+ Tfh cells was significantly higher in IA and IT compared with RP and HC. The ratio of PD‑1+/total Tfh cells was positively correlated with the load of HBV DNA; therefore, this ratio may act as an indicator for HBV replication. The expression level of PD‑1 in Tfh cells was higher in the HepG2.2.1.5 co‑cultured group compared with the HepG2 group, this may be due to the high PGE2 expression level in HBV‑infected HepG2.2.1.5 cells. The findings of the present study revealed an imbalanced distribution of PD‑1+ Tfh cells in patients with HBV at different immune phases. Additionally, HBV may upregulate the expression of PD‑1 in Tfh cells by promoting HepG2.2.1.5 to secret PGE2. Identifying the effect of HBV on Tfh‑cell subsets is crucial for improving immuno-based therapy for HBV.

  4. 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

  5. Pathophysiological role of prostaglandin E2-induced up-regulation of the EP2 receptor in motor neuron-like NSC-34 cells and lumbar motor neurons in ALS model mice.

    PubMed

    Kosuge, Yasuhiro; Miyagishi, Hiroko; Yoneoka, Yuki; Yoneda, Keiko; Nango, Hiroshi; Ishige, Kumiko; Ito, Yoshihisa

    2017-07-04

    Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease characterized by selective degeneration of motor neurons. The primary triggers for motor neuronal death are still unknown, but inflammation is considered to be an important factor contributing to the pathophysiology of ALS both clinically and in ALS models. Prostaglandin E2 (PGE2) and its corresponding four E-prostanoid receptors play a pivotal role in the degeneration of motor neurons in human and transgenic models of ALS. It has also been shown that PGE2-EP2 signaling in glial cells (astrocytes or microglia) promotes motor neuronal death in G93A mice. The present study was designed to investigate the levels of expression of EP receptors in the spinal motor neurons of ALS model mice and to examine whether PGE2 alters the expression of EP receptors in differentiated NSC-34 cells, a motor neuron-like cell line. Immunohistochemical staining demonstrated that EP2 and EP3 immunoreactivity was localized in NeuN-positive large cells showing the typical morphology of motor neurons in mice. Semi-quantitative analysis showed that the immunoreactivity of EP2 in motor neurons was significantly increased in the early symptomatic stage in ALS model mice. In contrast, the level of EP3 expression remained constant, irrespective of age. In differentiated NSC-34 cells, bath application of PGE2 resulted in a concentration-dependent decrease of MTT reduction. Although PGE2 had no effect on cell survival at concentrations of less than 10 μM, pretreatment with 10 μM PGE2 significantly up-regulated EP2 and concomitantly potentiated cell death induced by 30 μM PGE2. These results suggest that PGE2 is an important effector for induction of the EP2 subtype in differentiated NSC-34 cells, and that not only EP2 up-regulation in glial cells but also EP2 up-regulation in motor neurons plays a pivotal role in the vulnerability of motor neurons in ALS model mice. Copyright © 2017 Elsevier Ltd. All rights

  6. Prostaglandin dehydrogenase and the initiation of labor.

    PubMed

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

    1999-01-01

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

  7. Role of prostaglandins in hypertension.

    PubMed

    Colina-Chourio, J A; Godoy-Godoy, N; Avila-Hernández, R M

    2000-04-01

    The role of prostaglandins (PGs) in hypertension (HT) is reviewed, emphasising their biochemical characteristics, physiological effects and functions, especially in the cardiovascular area, and the current evidence of their participation in the antihypertensive activity of a balanced mechanism to maintain normal blood pressure. Also, the clinical use of PGs and the future of such autacoids in the treatment of HT and other diseases or conditions is mentioned.

  8. Prostaglandins for preventing postpartum haemorrhage.

    PubMed

    Tunçalp, Özge; Hofmeyr, G Justus; Gülmezoglu, A Metin

    2012-08-15

    Prostaglandins have mainly been used for postpartum haemorrhage (PPH) when other measures fail. Misoprostol, a new and inexpensive prostaglandin E1 analogue, has been suggested as an alternative for routine management of the third stage of labour. To assess the effects of prophylactic prostaglandin use in the third stage of labour. We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (7 January 2011). We updated this search on 25 May 2012 and added the results to the awaiting classification section. Randomised trials comparing a prostaglandin agent with another uterotonic or no prophylactic uterotonic (nothing or placebo) as part of management of the third stage of labour. The primary outcomes were blood loss 1000 mL or more and the use of additional uterotonics. Two review authors independently assessed eligibility and trial quality and extracted data. We included 72 trials (52,678 women). Oral or sublingual misoprostol compared with placebo is effective in reducing severe PPH (oral: seven trials, 6225 women, not totalled due to significant heterogeneity; sublingual: risk ratio (RR) 0.66; 95% confidence interval (CI) 0.45 to 0.98; one trial, 661 women) and blood transfusion (oral: RR 0.31; 95% CI 0.10 to 0.94; four trials, 3519 women).Compared with conventional injectable uterotonics, oral misoprostol was associated with higher risk of severe PPH (RR 1.33; 95% CI 1.16 to 1.52; 17 trials, 29,797 women) and use of additional uterotonics, but with a trend to fewer blood transfusions (RR 0.84; 95% CI 0.66 to 1.06; 15 trials; 28,213 women). Additional uterotonic data were not totalled due to heterogeneity. Misoprostol use is associated with significant increases in shivering and a temperature of 38º Celsius compared with both placebo and other uterotonics. Oral or sublingual misoprostol shows promising results when compared with placebo in reducing blood loss after delivery. The margin of benefit may be affected by whether other components of the

  9. Recovery of Prostaglandins in Human Cutaneous Inflammation*

    PubMed Central

    Greaves, Malcolm W.; Søndergaard, Jørgen; McDonald-Gibson, Wendy

    1971-01-01

    An in-vivo skin perfusion technique has been used to study the pharmacological activity in inflamed skin of patients with allergic contact eczema. Perfusates from 35 out of 45 patients contained a smooth-muscle-contracting agent with prostaglandin-like properties. Solvent partition followed by thinlayer chromatography revealed this activity to be due to a mixture of prostaglandins E and F. This direct evidence supports the view that prostaglandins mediate inflammation in man. PMID:5572386

  10. Prostaglandins as PPARγ Modulators in Adipogenesis

    PubMed Central

    Fujimori, Ko

    2012-01-01

    Adipocytes and fat cells play critical roles in the regulation of energy homeostasis. Adipogenesis (adipocyte differentiation) is regulated via a complex process including coordinated changes in hormone sensitivity and gene expression. PPARγ is a ligand-dependent transcription factor and important in adipogenesis, as it enhances the expression of numerous adipogenic and lipogenic genes in adipocytes. Prostaglandins (PGs), which are lipid mediators, are associated with the regulation of PPARγ function in adipocytes. Prostacyclin promotes the differentiation of adipocyte-precursor cells to adipose cells via activation of the expression of C/EBPβ and δ. These proteins are important transcription factors in the activation of the early phase of adipogenesis, and they activate the expression of PPARγ, which event precedes the maturation of adipocytes. PGE2 and PGF2α strongly suppress the early phase of adipocyte differentiation by enhancing their own production via receptor-mediated elevation of the expression of cycloxygenase-2, and they also suppress the function of PPARγ. In contrast, PGD2 and its non-enzymatic metabolite, Δ12-PGJ2, activate the middle-late phase of adipocyte differentiation through both DP2 receptors and PPARγ. This paper focuses on potential roles of PGs as PPARγ modulators in adipogenesis and regulators of obesity. PMID:23319937

  11. Prostaglandin release in canine acute haemorrhagic pancreatitis.

    PubMed Central

    Glazer, G; Bennett, A

    1976-01-01

    Acute haemorrhagic pancreatitis was induced in greyhound dogs by a bile salt/trypsin injection into the main pancreatic duct. Prostaglandin-like activity in the pancreatic venous blood, right atrial blood, and arterial blood was measured by bioassay. Activity rose significantly in the pancreatic venous blood of test dogs but not in controls. Chromatographic analysis of the peritoneal exudate from the dogs with pancreatitis showed high levels of prostaglandin E-like material (mean 43 ng/ml prostaglandin E2 equivalents). It seems likely that prostaglandins contribute to the induced pancreatitis. PMID:1269976

  12. Prostaglandin E, pessaries for induction of labour.

    PubMed

    Pearce, J M; Shepherd, J H; Sims, C D

    1979-03-17

    Vaginal pessaries containing 3 mg of prostaglandin E2 were used to induce labour in 200 patients with variable induction features. Prostaglandin-induced labour was augmented where necessary by synthetic oxytocin. There was on failed induction. Only 23% of patients with favourable induction features and 53% of patients with unfavourable features needed oxytocin. There were no adverse fetal or maternal effects. The prostaglandin E2 pessary was as effective in inducing labour as 350 microgram extra-amniotic prostaglandin E2 in tylose in a comparable group of 200 patients in which there were 4 failed inductions.

  13. [Prolonged pregnancy--prostaglandins as the cause of labor onset].

    PubMed

    Rath, W

    1994-01-01

    The causes of prolonged pregnancy are still largely unknown and their investigation requires a detailed observation of potential birth-initiating stimuli on the endocrine and biomolecular level. A large number of clinical and biochemical studies point to the central importance of prostaglandins for the beginning of human birth. The main places of origin of the intensified prostaglandin formation and release are the amnion and the decidua which has "macrophage-like" properties and functions. The superordinate regulation and trigger mechanisms for intensified uterine prostaglandin production has not been sufficiently investigated either. Possible factors currently being debated include local changes in estrogen and progesterone biosynthesis in fetal membranes and decidua, subclinical inflammatory reactions with the activation of macrophages and the consecutive release of cytokines, and a loss of maternal immune tolerance with a time-determined rejection reaction. In addition, the substances inhibiting and stimulating prostaglandin synthesis have been detected in the amniotic fluid, fetal membranes and decidua. The fetus itself also plays an important part in the initiation of labor. Prolongation may be due to anatomic functional disturbances of the one hand which prevent the activation of the fetal hypothalamic-hypophyseal-adrenal axis and the release of the birth-initiating stimuli originating in the fetus; on the other hand, an elevated immune tolerance with a delayed rejection reaction or the lack of "bacterial stimulus" may inhibit the activation of the macrophages and hence the formation of cytokines. The consequences would be the development and release of a quantity of prostaglandins from the fetal membranes and decidua insufficient to overcome the pregnancy-maintaining safety systems.(ABSTRACT TRUNCATED AT 250 WORDS)

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

    PubMed Central

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

    2013-01-01

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

  15. Role of seminal prostaglandins in male fertility. I. Relationship of prostaglandin E and 19-OH prostaglandin E with seminal parameters.

    PubMed

    Isidori, A; Conte, D; Laguzzi, G; Giovenco, P; Dondero, F

    1980-01-01

    Prostaglandin (PG) E and 19-OH PGE, now considered to be the most important of the human seminal prostaglandins, were assayed in infertile and normal men. In the 15 volunteers PGE and 19-OH PGE levels were 23-89 microgram/ml, respectively. In the 4 groups of infertile patients in whom either PGE or 19-OH PGE levels were increased or decreased with respect to normal, sperm concentration and motility were significantly reduced. The negative effects of low levels of seminal prostaglandins on sperm concentration and motility might be correlated respectively with decreased adenylcyclase and testicular androgen activity. The negative effects of high levels of prostaglandins on the seminal fluid might be due either to an inhibition in testicular DNA synthesis or to a decreased sensitivity of the receptors to high titers of prostaglandins.

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

    PubMed

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

    2013-10-01

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

  17. Time related changes in luteal prostaglandin synthesis and steroidogenic capacity during pregnancy, normal and antiprogestin induced luteolysis in the bitch.

    PubMed

    Kowalewski, Mariusz Pawel; Beceriklisoy, Hakki Bülent; Aslan, Selim; Agaoglu, Ali Reha; Hoffmann, Bernd

    2009-11-01

    In nonpregnant and pregnant dogs the corpora lutea (CL) are the only source of progesterone (P4) which shows an almost identical secretion pattern until the rapid decrease of P4 prior to parturition. For the nonpregnant dog clear evidence has been obtained that physiological luteal regression is devoid of a functional role of the PGF2alpha-system and seems to depend on the provision of StAR. Yet in pregnant dogs the rapid prepartal luteal regression, coinciding with an increase of PGF2alpha, may be indicative for different regulatory mechanisms. To assess this situation and by applying semi-quantitative Real Time (Taq Man) RT-PCR, expression patterns were determined for the following factors in CL of pregnant and prepartal dogs and of mid-pregnant dogs treated with the antiprogestin Aglepristone: cyclooxygenase 2 (Cox2), prostaglandin E2 synthase (PGES), prostaglandin F2alpha synthase (PGFS), its receptors (EP2, EP4 an FP), the steroidogenic acute regulatory protein (StAR), 3beta-hydroxysteroid-dehydrogenase (3betaHSD) and the progesterone receptor (PR). Peripheral plasma P4 concentrations were determined by RIA. CL were collected via ovariohysterectomy from pregnant bitches (n=3-5) on days 8-12 (Group 1, pre-implantation period), days 18-25 (Group 2, post-implantation period), days 35-40 (Group 3, mid-gestation period) and during the prepartal progesterone decline (Group 4). Additionally, CL were obtained from groups of 5 mid-pregnant dogs (days 40-45) 24h, respectively 72h after the second treatment with Aglepristone. Expression of Cox2 and PGES was highest during the pre-implantation period, that of PGFS and FP during the post-implantation period. EP4 and EP2 revealed a constant expression pattern throughout pregnancy with a prepartal upregulation of EP2. 3betaHSD and StAR decreased significantly from the pre-implatation period to prepartal luteolysis, it was matched by the course of P4 concentrations. Expression of the PR was higher during mid-gestation and

  18. Dietary supplementation with safflower seeds differing in fatty acid composition differentially influences serum concentrations of prostaglandin F metabolite in postpartum beef cows.

    PubMed

    Grant, Mark H J; Alexander, Brenda M; Hess, Bret W; Bottger, Jeff D; Hixon, Doug L; Van Kirk, Edward A; Nett, Terry M; Moss, Gary E

    2005-01-01

    Synthesis and secretion of prostaglandin F2alpha (PGF2alpha) is elevated following parturition and exerts divergent effects on the re-establishment of fertile estrous cycles in cows. The objective of these experiments was to determine if oil seed supplements differing in fatty acid composition differentially influence serum concentrations of the specific PGF2alpha metabolite, PGFM. Safflower seed supplements were formulated to provide 5% of dry-matter intake as fat. In Trial 1, 24 multiparous beef cows were individually fed control (beet pulp-soybean meal) or cracked high-linoleate safflower seed (78% 18:2n-6) supplements for 80 d postpartum. Linoleate supplemented cows had greater (P < 0.001) serum concentrations of PGFM than control cows. In Trial 2, primiparous beef cows (n = 36) were individually fed control (cracked corn-soybean meal), cracked high-linoleate (76% 18:2n-6) or -oleate (72% 18:1n-9) safflower seed supplements for 92 d postpartum. As in Trial 1, serum concentrations of PGFM were greater (P < or = 0.04) in linoleate than control or oleate supplemented cows. Serum concentrations of PGFM, however, did not differ (P = 0.40) among oleate and control supplemented cows. Although potential impacts on reproductive performance remain to be proven, dietary oil supplements high in linoleate, but not oleate, increased serum concentrations of PGFM compared to control supplements.

  19. Effect of cardiorespiratory fitness on vascular regulation and oxidative stress in postmenopausal women.

    PubMed

    Pialoux, Vincent; Brown, Allison D; Leigh, Richard; Friedenreich, Christine M; Poulin, Marc J

    2009-11-01

    Increasing evidence exists suggesting an important role for oxidative stress in the pathogenesis and progression of hypertension in women via a decrease of NO production after menopause. Regular physical training has been shown to upregulate antioxidant enzymatic systems, which may slow down the usual increase of oxidative stress in postmenopausal women. The aims of this study were to determine the impact of fitness status on enzymatic antioxidant efficiency, oxidative stress, and NO production and to determine the associations among oxidative stress, enzymatic antioxidant and NO production, mean arterial blood pressure (MABP), and cerebrovascular conductance (CVC) in postmenopausal women (n=40; 50 to 90 years old). Physical fitness, physical activity, resting MABP, and CVC were measured. End product of NO, lipid peroxidation (malondialdehyde and 8-iso-prostaglandin F2alpha), DNA oxidation (8-hydroxy-2'-deoxyguanosine), protein nitration (nitrotyrosine), antioxidant glutathione peroxidase, and catalase activities were measured in plasma. We identified significant negative associations between oxidative stress and indices of physical fitness (malondialdehyde: r=-0.33, P<0.05; 8-iso-prostaglandin F2alpha: r=-0.39, P<0.05; 8-hydroxy-2'-deoxyguanosine: r=-0.35, P<0.05) and physical activity (malondialdehyde: r=-0.30, P<0.05; 8-iso-prostaglandin F2alpha: r=-0.41, P<0.01; 8-hydroxy-2'-deoxyguanosine: r=-0.39, P<0.05). Conversely, glutathione peroxidase was positively correlated with fitness level (r=0.55; P<0.01). Finally, MABP and CVC were significantly associated with 8-hydroxy-2'-deoxyguanosine (MABP: r=0.36, P<0.05; CVC: r=-0.36, P<0.05), nitrotyrosine (MABP: r=0.39, P<0.05; CVC: r=-0.32, P<0.05), and the end product of NO (MABP: r=-0.57, P<0.01; CVC: r=0.44, P<0.01). These findings demonstrate that, after menopause, fitness level and regular physical activity mediate against oxidative stress by maintaining antioxidant enzyme efficiency. Furthermore, these results

  20. Influence of polychlorinated biphenyls and their hydroxylated metabolites on prostaglandins secretion from epithelial cells of bovine oviduct, in vitro.

    PubMed

    Wrobel, Michal H; Mlynarczuk, Jaroslaw; Kotwica, Jan

    2010-04-11

    Polychlorinated biphenyls (PCBs) markedly stimulate bovine uterine contractions and prostaglandin (PG) F2alpha secreted from both, myometrial and endometrial cells is essentially involved in this process. Since contractions of the oviduct are crucial for gametes and embryo transport, therefore the goal of this study was to investigate the influence of PCBs on PGF2alpha and PGE2 secretion from oviductal epithelium. Epithelial cells of the oviduct, from cows and heifers on days 1-5 of estrous cycle, were treated with PCBs: technical mixture (Aroclor 1248; Ar 1248), individual congeners (PCB 30 and PCB 153) and hydroxylated metabolites (PCB 30-OH and PCB 50-OH). Viability of the cells after treatment with PCBs (10 and 100 ng/ml) was determined after 24, 48 and 72 h. The concentration of PGFM (metabolite of PGF2alpha) and PGE2 in culture medium was determined after 2 and 48 h of incubation with PCBs (0.1, 1 and 10 ng/ml). None of the PCBs affected (P>0.05) cell viability, whereas all of them, except PCB 30 after 48 h of treatment, increased (P<0.05-0.01) PGF2alpha secretion from epithelial cells. All PCBs also stimulated (P<0.05) the PGE2 secretion after 2h of incubation, but this effect was less evident or there was no effect after 48 h of treatment. We conclude that oviductal secretion of PGF2alpha and PGE2 is affected by PCBs and this can be a part of the mechanism by means of which PCBs may affect the contractions of bovine oviduct.

  1. The effect of progesterone on oxytocin-stimulated intracellular Ca2+ mobilisation and prostaglandin secretion in porcine endometrium.

    PubMed

    Kotwica, G; Oponowicz, A; Kurowicka, B; Franczak, A; Bogacka, I

    2010-01-01

    We have studied in the porcine endometrium the expression of oxytocin receptor (OTR) mRNA and the effect of progesterone (P4) on oxytocin/oxytocin receptor (OT/OTR) function concerning intracellular Ca2+ mobilisation ([Ca2+]i), prostaglandin F2alpha (PGF2alpha) and E2 (PGE2; PG) secretion. Tissue was taken from cyclic and early pregnant pigs (days 14-16). A higher expression of OTR mRNA (P < 0.05) was observed in the endometrium of cyclic than pregnant pigs. The stimulatory (P < 0.05) effect of OT (10(-7) M) on [Ca2+]i mobilisation was noticed within 15-60 s and 30-60 s in endometrial stromal cells of cyclic and pregnant pigs, respectively. In the presence of P4 (10(-5) M) basal and OT-stimulated [Ca2+]i concentrations decreased in stromal cells during luteolysis and pregnancy. In stromal cells P4 delayed mobilisation of [Ca2+]i in response to OT by 15 s during luteolysis and had no effect during pregnancy. In cyclic and pregnant epithelial cells OT stimulated mobilisation of [Ca2+]i in 45 s and 60 s, respectively. Oxytocin increased (P < 0.05) PGF2alpha secretion during luteolysis and pregnancy and PGE2 during luteolysis from endometrial slices. Progesterone did not inhibit this stimulatory effect. During luteolysis OT increased (P < 0.05) PGF2alpha in epithelial and stromal cells and PGE2 secretion in epithelial cells. In the presence of P4 this effect of OT was reduced only in stromal cyclic cells (6 h culture). The presence of P4 decreased the effect of OT on [Ca2+]i mobilisation only in stromal cells. We found that, in most conditions, P4 did not inhibit the OT-stimulated secretion of PG in the porcine endometrium.

  2. Subcellular distribution of the different platelet proteins phosphorylated on exposure of intact platelets to ionophore A23187 or to prostaglandin E1. Possible role of a membrane phosphopolypeptide in the regulation of calcium-ion transport.

    PubMed Central

    Fox, J E; Say, A K; Haslam, R J

    1979-01-01

    Exposure of 32P-labelled human platelets to ionophore A23187 results in an increased incorporation of 32P into polypeptides with apparent mol.wts. of 47 000 (P47) and 20 000 (P20), whereas exposure to prostaglandin E1 results in increased labelling of polypeptides with apparent mol.wts. of 24 000 (P24) and 22 000 (P22) [Haslam, Lynham & Fox (1979) Biochem. J. 178, 397-406]. Labelled platelets that had been incubated with ionophore A23187 or prostaglandin E1 were sonicated and rapidly separated into three fractions by differential centrifugation. Electron microscopy and measurement of marker enzymes indicated that the 1300-19 000 gav. particulate fraction was enriched in granules, mitochondria and plasma membranes, that the 19 000-90 000 gav. particulate fraction was enriched in both intracellular and plasma membranes and that the 90 000 gav. supernatant contained only soluble proteins. 32P-labelled phosphopolypeptide P47 was present almost exclusively in the 90 000 gav. supernatant, whereas phosphopolypeptide P20 was largely dephosphorylated under fractionation conditions that protected other phosphopolypeptides. 32P-labelled phosphopolypeptide P24 was enriched in both particulate fractions, but particularly in the 19 000-90 000 gav. fraction, and may therefore be present in both the intracellular and plasma membranes. Phosphopolypeptide P22 appeared to be similarly distributed. Both particulate fractions were capable of the ATP-dependent oxalate-stimulated uptake of Ca2+. When the 19 000-90 000 gav. membrane fraction was prepared from platelets that had been incubated with ionophore A23187, active uptake of Ca2+ did not occur, but when this fraction was isolated from platelets that had been exposed to prostaglandin E1, uptake of Ca2+ was significantly greater than observed with the corresponding membranes from control platelets. It is suggested that phosphorylation of polypeptide P24 (or P22) by a cyclic AMP-dependent protein kinase may promote the active

  3. Prostaglandin E2-induced inflammation: Relevance of prostaglandin E receptors.

    PubMed

    Kawahara, Kohichi; Hohjoh, Hirofumi; Inazumi, Tomoaki; Tsuchiya, Soken; Sugimoto, Yukihiko

    2015-04-01

    Prostaglandin E2 (PGE2) is one of the most typical lipid mediators produced from arachidonic acid (AA) by cyclooxygenase (COX) as the rate-limiting enzyme, and acts on four kinds of receptor subtypes (EP1-EP4) to elicit its diverse actions including pyrexia, pain sensation, and inflammation. Recently, the molecular mechanisms underlying the PGE2 actions mediated by each EP subtype have been elucidated by studies using mice deficient in each EP subtype as well as several compounds highly selective to each EP subtype, and their findings now enable us to discuss how PGE2 initiates and exacerbates inflammation at the molecular level. Here, we review the recent advances in PGE2 receptor research by focusing on the activation of mast cells via the EP3 receptor and the control of helper T cells via the EP2/4 receptor, which are the molecular mechanisms involved in PGE2-induced inflammation that had been unknown for many years. We also discuss the roles of PGE2 in acute inflammation and inflammatory disorders, and the usefulness of anti-inflammatory therapies that target EP receptors. This article is part of a Special Issue entitled "Oxygenated metabolism of PUFA: analysis and biological relevance". Copyright © 2014 Elsevier B.V. All rights reserved.

  4. The role of prostaglandins and endothelium-derived relaxation factor in the regulation of cerebral blood flow and cerebral oxygen utilization in the piglet: operationalizing the concept of an essential circulation.

    PubMed

    Meadow, W; Rudinsky, B; Bell, A; Lozon, M; Randle, C; Hipps, R

    1994-06-01

    The brain is considered an "essential" organ, defined as one whose blood supply is preferentially maintained vis-à-vis other less-essential circulations during periods of reduced systemic cardiac output (CO). We asked whether the actions of either prostaglandins or endothelium-derived relaxation factor might underlie the essential qualities of the cerebral circulation; that is, would the absence of one or the other impair the ability of the brain to preferentially redirect systemic blood flow during a period of reduced systemic CO. We compared hemodynamics in the cerebral and systemic circulations in 33 anesthetized piglets under three conditions that reduced systemic CO equivalently: endothelium-derived relaxation factor inhibition with the substituted L-arginine analog N-nitro-L-arginine (NNLA; 25 mg/kg), prostaglandin inhibition with indomethacin (INDO; 5 mg/kg), and inflation of a left atrial balloon (LAB) catheter. NNLA, INDO, and LAB each reduced CO to an equivalent value (approximately 30% from baseline). NNLA and INDO, but not LAB elevated systemic blood pressure, cerebral perfusion pressure (CPP), systemic vascular resistance (SVR), and cerebral vascular resistance (CVR). Cerebral blood flow (CBF) was preserved after NNLA and LAB but fell after INDO (-35%). Despite the equivalent reduction in CO noted during the three experimental protocols, the proportion of systemic blood flow directed toward the brain (CBF/CO) rose significantly during LAB and NNLA (+30%) but fell significantly during INDO (-12%). Similarly, relative cerebral vascular resistance (CVR/SVR) fell significantly during LAB and NNLA but rose during INDO.(ABSTRACT TRUNCATED AT 250 WORDS)

  5. 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.

  6. A Michaelis-Menten-style model for the autocatalytic enzyme prostaglandin H synthase.

    PubMed

    Tien, Joseph H; Hazelton, William D; Sparks, Rachel; Ulrich, Cornelia M

    2005-07-01

    Prostaglandin H synthase (PGHS) is an autocatalytic enzyme which plays a key role in the arachidonic acid metabolic pathway. PGHS mediates the formation of prostaglandin H2, the precursor for a number of prostaglandins which are important in a wide variety of biological processes, including inflammation, blood clotting, renal function, and tumorigenesis. Here we present a Michaelis-Menten-style model for PGHS. A stability analysis determines when the reaction becomes self-sustaining, and can help explain the regulation of PGHS activity in vivo. We also consider a quasi-steady-state approximation (QSSA) for the model, and present conditions under which the QSSA is expected to be a good approximation. Applying the QSSA for this model can be useful in computationally intensive modeling endeavors involving PGHS.

  7. 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. © 2012 Wiley Periodicals, Inc.

  8. Separation, identification, and estimation of prostaglandins.

    PubMed

    Shaw, J E; Ramwell, P W

    1969-01-01

    The procedures which may be and are being used to provide a basis for the analysis of submicrogram quantitities of prostaglandins are surveyed. Discussion is focused on the following: 1) sources of standards; 2) properties (effect of different pH values, effect of blood, metabolism, solubility); 3) extraction; 4) detection; 5) estimation (ultraviolet, optical rotatory dispersion, densitometry, radioimmunoassay, enzymatic assay, isotopic methods, bioassay); 6) separation of prostaglandins (separation of PGE, PGF, and PGA with PGB compounds, separation of PGA and PGB compounds, and separation of individual prostaglandins); and 6) structural identification. Methods of prostaglandin analysis, with the required sensitivity for application to individual tissue and fluid specimens, are still in the developmental state. Although prostaglandins may be ubiquitous throughout the animal kingdom, no systematic study of their distribution has been made to date. Recent work has shown that PGE1 has a potent effect on the formation of 3',5' cyclic adenosine monophosphate (cyclic AMP) which is widely believed to be an intracellular intermediate in hormone action.

  9. PTGER1 and PTGER2 receptors mediate regulation of progesterone synthesis and type 1 11β-hydroxysteroid dehydrogenase activity by prostaglandin E2 in human granulosa–lutein cells

    PubMed Central

    Chandras, C; Harris, T E; López Bernal, A; Abayasekara, D R E; Michael, A E

    2007-01-01

    In luteinizing granulosa cells, prostaglandin E2 (PGE2) can exert luteotrophic actions, apparently via the cAMP signalling pathway. In addition to stimulating progesterone synthesis, PGE2 can also stimulate oxidation of the physiological glucocorticoid, cortisol, to its inactive metabolite, cortisone, by the type 1 11β-hydroxysteroid dehydrogenase (11βHSD1) enzyme in human granulosa–lutein cells. Having previously shown these human ovarian cells to express functional G-protein coupled, E-series prostaglandin (PTGER)1, PTGER2 and PTGER4 receptors, the aim of this study was to delineate the roles of PTGER1 and PTGER2 receptors in mediating the effects of PGE2 on steroidogenesis and cortisol metabolism in human granulosa–lutein cells. PGE2-stimulated concentration-dependent increases in both progesterone production and cAMP accumulation (by 1·9±0·1- and 18·7±6·8-fold respectively at 3000 nM PGE2). While a selective PTGER1 antagonist, SC19220, could partially inhibit the steroidogenic response to PGE2 (by 55·9±4·1% at 1000 nM PGE2), co-treatment with AH6809, a mixed PTGER1/PTGER2 receptor antagonist, completely abolished the stimulation of progesterone synthesis at all tested concentrations of PGE2 and suppressed the stimulation of cAMP accumulation. Both PGE2 and butaprost (a preferential PTGER2 receptor agonist) stimulated concentration-dependent increases in cortisol oxidation by 11βHSD1 (by 42·5±3·1 and 40·0±3·0% respectively, at PGE2 and butaprost concentrations of 1000 nM). Co-treatment with SC19220 enhanced the ability of both PGE2 and butaprost to stimulate 11βHSD1 activity (by 30·2±0·2 and 30·5±0·6% respectively), whereas co-treatment with AH6809 completely abolished the 11βHSD1 responses to PGE2 and butaprost. These findings implicate the PTGER2 receptor–cAMP signalling pathway in the stimulation of progesterone production and 11βHSD1 activity by PGE2 in human granulosa–lutein cells. PMID:17761898

  10. Prevotella intermedia induces prostaglandin E2 via multiple signaling pathways.

    PubMed

    Guan, S-M; Fu, S-M; He, J-J; Zhang, M

    2011-01-01

    Prostaglandin E(2) (PGE(2)) plays important roles in the bone resorption of inflammatory diseases such as rheumatoid arthritis and periodontitis via specific prostaglandin receptors (i.e., EP1-EP4). In this study, the authors examined whether Prevotella intermedia regulates PGE(2) production and EP expression in human periodontal ligament fibroblasts (hPDLs); they also explored the potential signaling pathways involved in PGE(2) production. P. intermedia induced PGE(2) production and cyclooxygenase-2 (COX-2) expression in a dose- and time-dependent manner. Indomethacin and NS-398 completely abrogated the P. intermedia-induced PGE(2) production without modulating COX-2 expression. Specific inhibitors of extracellular signal-regulated kinase, c-Jun N-terminal kinase, p38, phosphatidylinositol 3-kinase, and protein kinase C--but not c-AMP and protein kinase A--significantly attenuated the P. intermedia-induced COX-2 and PGE(2) expression. P. intermedia reduced EP1 expression in a concentration- and time-dependent manner. The results indicate that the COX-2-dependent induction of PGE(2) by P. intermedia in hPDLs is mediated by multiple signaling pathways.

  11. Rosiglitazone and 15-deoxy-Delta12,14-prostaglandin J2, PPARgamma agonists, differentially regulate cigarette smoke-mediated pro-inflammatory cytokine release in monocytes/macrophages.

    PubMed

    Caito, Samuel; Yang, Se-Ran; Kode, Aruna; Edirisinghe, Indika; Rajendrasozhan, Saravanan; Phipps, Richard P; Rahman, Irfan

    2008-02-01

    Peroxisome Proliferator-Activated Receptor gamma (PPARgamma) ligands have the potential for use as anti-inflammatory agents in chronic airway diseases. We hypothesized that cigarette smoke (CS)-mediated pro-inflammatory cytokine release would be downregulated in the monocyte-macrophage cell line (MonoMac6) by synthetic and natural PPARgamma ligands. Surprisingly, treatment of MonoMac6 cells with the natural PPARgamma ligand 15-deoxy-Delta12,14-prostaglandin J2 led to increased cytokine (IL-8) release in response to either TNF-alpha or CS extract (CSE). However, exposure to rosiglitazone, a synthetic agonist, led to decreased TNF-alpha, but not CSE, mediated cytokine release. Cytokine release correlated with nuclear PPARgamma localization; CSE reduced the amount of activated PPARgamma located in the nucleus and formed aldehyde adducts as PPARgamma protein carbonyls. Furthermore, it was shown that PPARgamma interacts with the RelA/p65 subunit of NF-kappaB under TNF-alpha exposure conditions, but this interaction was disrupted by CS exposure, suggesting that CS blocks this important anti-inflammatory pathway involving PPARgamma. Thus, these new data show that activation of PPARgamma with natural or synthetic ligands have differential inhibitory effects on CS-mediated pro-inflammatory mediator release. These data have implications in designing therapies for treatment of COPD and pulmonary fibrosis.

  12. [Prostaglandins in gynecology and obstetrics].

    PubMed

    Klausch, B; Kyank, H

    1972-06-03

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

  13. Role of the prostaglandins in labour and prostaglandin receptor inhibitors in the prevention of preterm labour.

    PubMed

    Olson, David M; Ammann, Christina

    2007-01-01

    Parturition is composed of five separate but integrated physiological events: fetal membrane rupture, cervical dilatation, myometrial contractility, placental separation, and uterine involution. Prostaglandins (PGs) have central roles in each of these events, but the most studied is myometrial contraction. Elevated uterine PGs or the enhanced sensitivity of the myometrium to PGs leads to contractions and labour. The primary regulator of PG synthesis is the mRNA expression of PG H Synthase (PGHS-2 or COX-2). Given the central role of PGs in labour, this enzyme becomes an obvious therapeutic target for the prevention of preterm labour, the major cause of perinatal mortality and morbidity. Unfortunately, even though the non-steroidal anti-inflammatory drugs (NSAIDs), which inhibit PGHS, are usually successful in suppressing preterm labour or prolonging pregnancy in animal and human studies, the NSAIDS have had adverse effects on fetal physiology and development. Therefore, other means to suppress PG synthesis or action to arrest preterm labour need to be investigated. The PGF2alpha receptor, FP, may prove to be a reasonable target for tocolysis. FP mRNA increases in the mouse uterus at preterm birth, whereas PGF2alpha concentrations do not increase, suggesting elevated uterine sensitivity to contractile agonists is one mechanism for preterm labour initiation. New data shows that administration of a specific FP antagonist, Theratechnologies (THG) 113.31, delays preterm birth in mice and sheep with no observable maternal or fetal side effects. Hence antagonizing PG action offers new hope for delaying preterm birth.

  14. 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

  15. 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.

  16. Synergistic enhancement of cytokine-induced human monocyte matrix metalloproteinase-1 by C-reactive protein and oxidized LDL through differential regulation of monocyte chemotactic protein-1 and prostaglandin E2.

    PubMed

    Zhang, Yahong; Wahl, Larry M

    2006-01-01

    C-reactive protein (CRP) and oxidized LDL (ox-LDL) are associated with inflammatory lesions, such as coronary artery disease, in which monocytes and matrix metalloproteinases (MMPs) may play a major role in the rupture of atherosclerotic plaques. Monocytes are recruited to inflammation sites by monocyte chemoattractant protein-1 (MCP-1), which may also participate in the activation of monocytes. The objective of this study was to compare the individual and combined effect of CRP and ox-LDL on human monocyte MMP-1 and the role of MCP-1 in this effect. Although CRP or ox-LDL failed to induce MMP-1 in control monocytes, these molecules enhanced MMP-1 production induced by tumor necrosis factor alpha (TNF-alpha) and granulocyte macrophage-colony stimulating factor (GM-CSF) with a synergistic increase in MMP-1 occurring in the presence of both mediators. Enhancement of MMP-1 by CRP and ox-LDL was attributable to a differential increase in MCP-1 and prostaglandin E2(PGE2). CRP, at physiological concentrations, induced high levels of MCP-1 and relatively low levels of PGE2, whereas ox-LDL caused a significant enhancement of PGE2 with little affect on MCP-1. Accordingly, CRP- and ox-LDL-induced MMP-1 production by monocytes was inhibited by anti-MCP-1 antibodies and indomethacin, respectively. Moreover, addition of exogenous MCP-1 or PGE2 enhanced MMP-1 production by TNF-alpha- and GM-CSF-stimulated monocytes. These results show that the combination of CRP and ox-LDL can cause a synergistic enhancement of the role of monocytes in inflammation, first, by increasing MCP-1, which attracts more monocytes and directly enhances MMP-1 production by activated monocytes, and second, by elevating PGE2 production, which also leads to higher levels of MMP-1.

  17. 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

  18. Prostaglandins and their receptors in insect biology

    USDA-ARS?s Scientific Manuscript database

    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...

  19. Prostaglandin Actions in Established Insect Cell Lines

    USDA-ARS?s Scientific Manuscript database

    Prostaglandins (PGs) are oxygenated metabolites of arachidonic acid (AA) and two other C20 polyunsaturated fatty acids that serve as biochemical signals that mediate a wide range of physiological functions in animal cells. For example, PGs influence protein expression in establish insect cell lines ...

  20. Review on prostaglandin and oxytocin activity in preterm labor.

    PubMed

    Ivanisević, M; Djelmis, J; Buković, D

    2001-12-01

    The principal difference between term and preterm labor is how they are activated. It has been proposed that term labor results from physiological activation of the common terminal pathway, whereas preterm labor is a pathological condition caused by multiple etiologies that activate one or more of the components of this pathway. Increased uterine contractility at preterm labor results from activation and stimulation of the myometrium. Myometrium is stimulated by increased concentrations ofprostaglandins and oxytocin. Increased production of stimulatory prostaglandins by intrauterine tissues is generally considered a central component of the cascade of events leading to preterm parturition. Prostaglandins act to mediate cervical ripening and to stimulate uterine contractions and indirectly to increase fundally dominant myometrial contractility by up regulation of gap junctions, oxytocin and arginine vasopressin receptors and synchronizations of contractions. The authors tried to explain the role and influence of oxytocin in human parturition, as well as the novel therapy in inhibiting the contractions in preterm labor. The selective oxytocin inhibitor was tested in vitro on human myometrium and decidua by the author of this article among the first in the world.

  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. cAMP-mediated beta-adrenergic signaling negatively regulates Gq-coupled receptor-mediated fetal gene response in cardiomyocytes.

    PubMed

    Patrizio, Mario; Vago, Valerio; Musumeci, Marco; Fecchi, Katia; Sposi, Nadia Maria; Mattei, Elisabetta; Catalano, Liviana; Stati, Tonino; Marano, Giuseppe

    2008-12-01

    The treatment with beta-blockers causes an enhancement of the norepinephrine-induced fetal gene response in cultured cardiomyocytes. Here, we tested whether the activation of cAMP-mediated beta-adrenergic signaling antagonizes alpha(1)-adrenergic receptor (AR)-mediated fetal gene response. To address this question, the fetal gene program, of which atrial natriuretic peptide (ANP) and the beta-isoform of myosin heavy chain are classical members, was induced by phenylephrine (PE), an alpha(1)-AR agonist. In cultured neonatal rat cardiomyocytes, we found that stimulation of beta-ARs with isoproterenol, a beta-AR agonist, inhibited the fetal gene expression induced by PE. Similar results were also observed when cardiomyocytes were treated with forskolin (FSK), a direct activator of adenylyl cyclase, or 8-CPT-6-Phe-cAMP, a selective activator of protein kinase A (PKA). Conversely, the PE-induced fetal gene expression was further upregulated by H89, a selective PKA inhibitor. To evaluate whether these results could be generalized to Gq-mediated signaling and not specifically to alpha(1)-ARs, cardiomyocytes were treated with prostaglandin F(2)alpha, another Gq-coupled receptor agonist, which is able to promote fetal gene expression. This treatment caused an increase of both ANP mRNA and protein levels, which was almost completely abolished by FSK treatment. The capability of beta-adrenergic signaling to regulate the fetal gene expression was also evaluated in vivo conditions by using beta1- and beta2-AR double knockout mice, in which the predominant cardiac beta-AR subtypes are lacking, or by administering isoproterenol (ISO), a beta-AR agonist, at a subpressor dose. A significant increase of the fetal gene expression was found in beta(1)- and beta(2)-AR gene deficient mice. Conversely, we found that ANP, beta-MHC and skACT mRNA levels were significantly decreased in ISO-treated hearts. Collectively, these data indicate that cAMP-mediated beta-adrenergic signaling

  3. Roles of prostaglandins and nitric oxide in the effect of endothelin-1 on renal hemodynamics.

    PubMed

    Lin, H; Smith, M J; Young, D B

    1996-09-01

    It is known that endothelin-1 stimulates the release of nitric oxide and prostaglandins in various vascular beds. We designed the present study to analyze the roles of prostaglandins and nitric oxide in the effect of endothelin-1 on the regulation of renal hemodynamics and renin release. We used N omega-nitro-L-arginine methyl ester (L-NAME) and meclofenamic acid to inhibit the production of nitric oxide and prostaglandins, respectively. With a nonfiltering kidney model, renal blood flow was reduced 21% in dogs treated with L-NAME and 18% in dogs treated with meclofenamic acid. Inhibition of nitric oxide and prostaglandins, however, produced opposite effects on estimated glomerular hydraulic pressure: L-NAME increased glomerular hydraulic pressure from 63.1 +/- 0.9 to 64.6 +/- 1.3 mm Hg (P < .01), and meclofenamic acid reduced glomerular hydraulic pressure from 63.3 +/- 1.4 to 59.8 +/- 1.6 mm Hg (P < .01). Endothelin-1 infusion produced a dose-dependent reduction in renal blood flow after blockade of nitric oxide and prostaglandins. The responses of glomerular hydraulic pressure were different in the two groups during endothelin-1 infusion. Endothelin-1 progressively reduced glomerular hydraulic pressure in a dose-dependent fashion in the meclofenamic acid group. However, endothelin-1 slightly increased glomerular hydraulic pressure until the infusion rate reached 5.0 ng/kg per minute. At that rate, endothelin-1 reduced glomerular hydraulic pressure from 63.3 +/- 1.4 to 47.0 +/- 1.4 mm Hg in the meclofenamic acid group (P < .01), a more than 25% reduction, whereas at the same dose, endothelin-1 reduced glomerular hydraulic pressure only less than 2% in the L-NAME group. In addition, blockade of nitric oxide and prostaglandins did not alter the inhibitory effect of endothelin-1 on renin release in the non-filtering kidney. Therefore, the present study demonstrates that the release of nitric oxide and prostaglandins might modulate the effects of endothelin-1 on the

  4. Intracervical prostaglandins for induction of labour.

    PubMed

    Boulvain, M; Kelly, A; Irion, O

    2008-01-23

    Prostaglandins have been used for cervical ripening and induction of labour since the 1970s. The goal of the administration of prostaglandins in the process of induction of labour is to achieve cervical ripening before the onset of contractions. One of the routes of administration that was proposed is intracervical. Using this route, prostaglandins are less easy to administer and the need for exposing the cervix may cause discomfort to the woman. To determine the effects of intracervical prostaglandins for third trimester cervical ripening or induction of labour compared with placebo/no treatment and with vaginal prostaglandins (except misoprostol). We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (August 2007) and bibliographies of relevant papers. Clinical trials comparing intracervical prostaglandins used for third trimester cervical ripening or labour induction with placebo/no treatment or other methods listed above it on a predefined list of labour induction methods (vaginal prostaglandins, except misoprostol). A strategy was developed to deal with the large volume and complexity of trial data relating to labour induction. This involved a two-stage method of data extraction. Fifty-six trials (7738 women) are included. INTRACERVICAL PGE2 WITH PLACEBO/NO TREATMENT: 28 TRIALS, 3764 WOMEN: Four studies reported the number of women who did not achieve vaginal delivery within 24 hours, showing a decreased risk with PGE2 (relative risk (RR) 0.61; 95% confidence interval (CI) 0.47 to 0.79). There was a small, and statistically non-significant, reduction of the risk of caesarean section when PGE2 was used (RR 0.88; 95% CI 0.77 to 1.00). The finding was statistically significant in a subgroup of women with intact membranes and unfavourable cervix only (RR 0.82; 95% CI 0.68 to 0.98). The risk of hyperstimulation with fetal heart rate (FHR) changes was not significantly increased (RR 1.21; 95% CI 0.72 to 2.05). However, the risk of

  5. Effects of prostaglandins and prostaglandin synthesis inhibitors on sexual behavior in boars.

    PubMed

    Estienne, Mark J; Harper, Allen F; Beal, Wilfred E; Crawford, Russell J

    2007-07-01

    Experiments were conducted investigating the effects of prostaglandins and prostaglandin synthesis inhibitors on libido in boars. In Experiment 1, two prostaglandin products were compared with regard to expediting the training of boars for semen collection. On each of five consecutive days, boars received i.m. treatment with saline, dinoprost tromethamine or cloprostenol sodium (n=12/group). On each of day 1 (p=0.06), day 2 (p<0.05), and day 3 (p<0.05), but not on day 4 or 5 (p>0.1), the percentage of boars collected after dinoprost tromethamine, but not cloprostenol sodium, was greater than controls. In Experiments 2 and 3, libido in boars that were trained previously for semen collection was assessed after treatment with prostaglandin synthesis inhibitors, testing the hypothesis that endogenous release of prostaglandin is necessary for expression of sexual behaviors. In Experiment 2, boars treated with flunixin meglumine (n=12) had suppressed (p<0.01) levels of 15-ketodihydro-prostaglandin-F(2) (PGFM) in serum but characteristics of libido were similar (p>0.1) to controls (n=12). In Experiment 3, boars were administered indomethacin orally (n=12) or served as untreated controls (n=12). Indomethacin decreased (p<0.01) serum levels of PGFM, increased (p<0.05) the number of false mounts (mounting artificial sow but dismounting before an ejaculate was collected), and tended (p=0.09) to lengthen the interval between entering the collection pen and the start of ejaculation. These results suggest that prostaglandin synthesis and release is necessary for the complete display of normal sexual behaviors in boars.

  6. 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. Copyright © 2014 Elsevier Inc. All rights reserved.

  7. Prostaglandins as negative regulators against lipopolysaccharide, lipoteichoic acid, and peptidoglycan-induced inducible nitric oxide synthase/nitric oxide production through reactive oxygen species-dependent heme oxygenase 1 expression in macrophages.

    PubMed

    Chien, Chih-Chiang; Shen, Shing-Chuan; Yang, Liang-Yo; Chen, Yen-Chou

    2012-11-01

    Although prostaglandins (PGs) were reported to exert proinflammatory and anti-inflammatory effects in macrophages, their action mechanisms remain unclear. The effects of PGs including PGJ2 (J2), Δ-PGJ2 (Δ), 15-deoxy-Δ PGJ2 (15d), PGE2 (E2), and PGF2α (F2α) on lipopolysaccharide (LPS)-, lipoteichoic acid (LTA)-, and peptidoglycan (PGN)-induced inducible nitric oxide (NO) synthase (iNOS)/NO production by RAW264.7 macrophages were investigated. First, we found that induction of cyclooxygenase 2 (COX-2) protein occurred at a time earlier than that of heme oxygenase 1 (HO-1) protein, and the addition of the COX-2 inhibitor NS398 reduced HO-1 protein expression in LPS-, LTA-, and PGN-treated RAW264.7 macrophages. Incubation of RAW264.7 macrophages with the indicated PGs showed that J2, Δ, and 15d significantly induced HO-1 protein expression; however, E2 and F2α did not. Heme oxygenase 1 protein induced by J2, Δ, and 15d was inhibited by the transcriptional inhibitor, actinomycin (Act) D; the translational inhibitor, cycloheximide; and the antioxidant, N-acetyl cysteine (NAC). Increases in intracellular peroxide levels by J2, Δ, and 15d were detected via a 2',7'™-dichlorofluorescein diacetate (DCFH-DA) analysis, and they were prevented by the addition of NAC. In addition, J2, Δ, and 15d produced significant inhibition of LPS-, LTA-, and PGN-induced iNOS protein and NO production by RAW264.7 cells, in accordance with increased HO-1 protein expression. Reductions of LPS-, LTA-, and PGN-induced phosphorylated c-Jun N-terminal kinase, c-Jun protein, and activator protein 1 luciferase activity by J2, Δ, and 15d were identified, and the addition of the HO-1 inhibitor, tin protoporphyrin, reversed the inhibitory effects of Δ and 15d on LPS- and LTA-induced iNOS/NO, phosphorylated c-Jun N-terminal kinase, and c-Jun protein expressions by macrophages. Knockdown of HO-1 protein expression by HO-1 small interfering RNA blocked Δ and 15d inhibition of LPS- and LTA

  8. Prostaglandin Pathway Gene Therapy for Sustained Reduction of Intraocular Pressure

    PubMed Central

    Barraza, Román A; McLaren, Jay W; Poeschla, Eric M

    2009-01-01

    Cyclooxygenase-2 (COX-2) is a rate-limiting enzyme in prostaglandin (PG) biosynthesis. In the eye, loss of COX-2 expression in aqueous humor–secreting cells has been associated with primary open-angle glaucoma (POAG). Reduction of intraocular pressure (IOP) is the main treatment goal in this disease. We used lentiviral vectors to stably express COX-2 and other PG biosynthesis and response transgenes in the ciliary body epithelium and trabecular meshwork (TM), the ocular suborgans that produce aqueous humor and regulate its outflow, respectively. We show that robust ectopic COX-2 expression and PG production require COX-2 complementary DNA (cDNA) sequence optimization. When COX-2 expression was coupled with a similarly optimized synthetic PGF2α receptor transgene to enable downstream signaling, gene therapy produced substantial and sustained reductions in IOP in a large animal model, the domestic cat. This study provides the first gene therapy for correcting the main cause of glaucoma. PMID:19953083

  9. Modulation of macrophage activation by prostaglandins

    PubMed Central

    Carnuccio, R.; D'Acquisto, F.; Rosa, M. Di

    1996-01-01

    The effect of prostaglandtn E2, iloprost and cAMP on both nitric oxide and tumour necrosis factor-α release in J774 macrophages has been studied. Both prostaglandin E2 and iloprost inhibited, in a concentration-dependent fashion, the lipopolysaccharide-induced generation of nitric oxide and tumour necrosis factor-α. The inhibitory effect of these prostanoids seems to be mediated by an increase of the second messenger cAMP since it was mimicked by dibutyryl cAMP and potentiated by the selective type IV phosphodiesterase inhibitor RO-20-1724. Our results suggest that the inhibition of nitric oxide release by prostaglandin E2 and iloprost in lipopolysaccharide-activated J774 macrophages may be secondary to the inhibition of tumour necrosis factor-α generation, which in turn is likely to be mediated by cAMP. PMID:18475691

  10. Prostaglandin synthesis inhibition and postprandial intestinal hyperemia.

    PubMed

    Gallavan, R H; Chou, C C

    1982-02-01

    The effect of prostaglandin synthesis inhibition on the postprandial intestinal hyperemia was examined in the jejunum of anesthetized dogs. Both intravenous and intra-arterial infusion of the cyclooxygenase inhibitors indomethacin and mefenamic acid reduced resting jejunal blood flow and markedly enhanced the food-induced jejunal hyperemia. The jejunal vascular response to food did not change after either intravenous or intra-arterial infusion of the carrier solutions or intra-arterial infusion of angiotensin II. The enhancement of the jejunal hyperemia was associated with an increase in the food-induced increase in jejunal oxygen consumption. Infusion of the cyclooxygenase inhibitors increased the mean amplitude of the monophasic intestinal contractions; however, this did not appear to play a role in the enhancement of the food-induced hyperemia. The study indicates that inhibition of prostaglandin synthesis has a marked effect on the postprandial intestinal hyperemia and that this may be due to its enhancement of the jejunal metabolic response to food. The prostaglandins involved and their mechanism of action are unknown.

  11. Animal-like prostaglandins in marine microalgae.

    PubMed

    Di Dato, Valeria; Orefice, Ida; Amato, Alberto; Fontanarosa, Carolina; Amoresano, Angela; Cutignano, Adele; Ianora, Adrianna; Romano, Giovanna

    2017-03-28

    Diatoms are among the most successful primary producers in ocean and freshwater environments. Deriving from a secondary endosymbiotic event, diatoms have a mixed genome containing bacterial, animal and plant genes encoding for metabolic pathways that may account for their evolutionary success. Studying the transcriptomes of two strains of the diatom Skeletonema marinoi, we report, for the first time in microalgae, an active animal-like prostaglandin pathway that is differentially expressed in the two strains. Prostaglandins are hormone-like mediators in many physiological and pathological processes in mammals, playing a pivotal role in inflammatory responses. They are also present in macroalgae and invertebrates, where they act as defense and communication mediators. The occurrence of animal-like prostaglandins in unicellular photosynthetic eukaryotes opens up new intriguing perspectives on the evolution and role of these molecules in the marine environment as possible mediators in cell-to-cell signaling, eventually influencing population dynamics in the plankton.The ISME Journal advance online publication, 28 March 2017; doi:10.1038/ismej.2017.27.

  12. Elevated plasma levels of F2 alpha isoprostane in cystic fibrosis.

    PubMed

    Collins, C E; Quaggiotto, P; Wood, L; O'Loughlin, E V; Henry, R L; Garg, M L

    1999-06-01

    Cystic fibrosis (CF) is associated with chronic lung infection, inflammation, and elevated indices of oxidative stress. Recently, isoprostanes were shown to be a reliable in vivo marker of oxidant injury with 8-iso-PGF2 alpha, shown to cause airflow obstruction and plasma exudation in guinea pig lung. The present study was designed to examine the relationship between 8-iso-PGF2 alpha levels, plasma antioxidants, and clinical status in CF. We hypothesized that plasma 8-iso-PGF2 alpha levels would be higher in subjects with CF compared to healthy controls. Plasma 8-iso-PGF2 alpha levels were prospectively measured in 22 subjects with CF and nine healthy controls using an 8-isoprostane enzyme immunoassay kit along with plasma vitamins A, E, and beta-carotene. Plasma 8-iso-PGF2 alpha levels were shown to be significantly elevated in the CF subjects compared to controls (319.6 +/- 52.6 vs. 145.0 +/- 21.0 pg/mL, P = 0.005). Plasma levels of antioxidants were significantly lower for the CF subjects compared to the controls (vitamin A, P < 0.003; vitamin E, P < 0.001; and beta-carotene, P < 0.01). This study confirms significantly elevated lipid peroxidation in CF using 8-iso-PGF2 alpha levels.

  13. The effects of some prostaglandins on respiration in anaesthetized cats

    PubMed Central

    McQueen, D.S.

    1974-01-01

    1 Some prostaglandins have been found to be capable of affecting respiration in anaesthetized cats. 2 Prostaglandins E1, E2, F2α, A1 and A2 all elicited increases in respiratory frequency when administered to cats anaesthetized with either pentobarbitone or α-chloralose. This effect was abolished by bilateral vagotomy. 3 Prostaglandins of the E and A series, but not prostaglandin F2α, elicited increases in tidal volume which were accompanied by falls in systemic blood pressure in cats anaesthetized with pentobarbitone. The changes in blood pressure were also obtained in cats anaesthetized with α-chloralose, but not the tidal volume changes. 4 It is unlikely that the prostaglandins influenced respiration by direct actions on arterial chemoreceptors or baroreceptors. 5 Mechanisms by which the prostaglandins may be acting to affect respiration are discussed. PMID:4447858

  14. Toxin-Induced Activation of Rat Hepatocyte Prostaglandin Synthesis and Phospholipid Metabolism

    DTIC Science & Technology

    1989-12-22

    SUBJECT TERMS (Continue on reverse if necesay and identify by block number) FIELD GROUP SUB-GROUP - microcystin -LR, arachidonic acid, phospholipid...pool was reduced to 47% (p ɘ.025) by l’ 3’ microcystin -LR. Changes in phospholipid classes indicated that prostaglandin formation induced by microcystin ... microcystin -LR has important effects on the regulation of inflammatory mediator synthesis in hepatocytes. 7.,1 ,- TOXIN-INDUCED ACTIVATION OF RAT HEPATOCYTE

  15. Improvement by ergonovine of sperm transport, fertilization and pregnancy rates in ewes in natural or prostaglandin-induced estrus.

    PubMed

    Hawk, H W; Cooper, B S

    1984-09-01

    Eight experiments were conducted with 451 ewes to test effects of ergonovine, prostaglandin F2 alpha (PGF2 alpha) and phenylephrine on sperm transport and fertility. In most experiments, ewes were mated at estrus and necropsied 2 or 3 h later. Sperm were flushed from the oviducts, uterus and anterior, middle and posterior thirds of the cervix and counted. Various doses of PGF2 alpha or phenylephrine given im at mating caused no significant increase in sperm numbers in any segment of the tract 2 h later. Three different dose levels of ergonovine were given im to ewes in natural estrus 1 h after mating and ewes were necropsied 3 h after mating. Doses of .2 and 1.0 mg were ineffective, but .5 mg increased sperm numbers about 10-fold in the oviducts and uterus. When given im at the time of artificial insemination, .6 mg of ergonovine increased the fertilization rate at 3 d from 5/25 in control ewes to 12/25 (P less than .05). In three experiments with ewes in PGF2 alpha-induced estrus, .6 mg of ergonovine increased sperm numbers in the cervix and uterus at 3 h after mating and in the uterus and oviducts at 23 h, near ovulation. Other ewes were artificially inseminated in the external cervical os and one-half of the ewes were given .6 mg of ergonovine im; ewes not returning to estrus were laparotomized at 22 to 26 d and embryos removed. After insemination during natural estrus with .2 ml of semen, pregnancy rates were 14/25 for control ewes and 15/25 for ergonovine-treated ewes; after insemination during natural estrus with .1 ml of semen, 6/35 and 18/35 (P less than .005); after insemination during PGF2 alpha-induced estrus with .2 ml of semen, 7/60 and 12/60. Fertilization and pregnancy rates combined were 32/145 (22%) for all control ewes and 57/145 (39%) for ergonovine-treated ewes (P less than .005).

  16. Estrus synchronization and pregnancy rates in beef cattle given CIDR-B, prostaglandin and estradiol, or GnRH.

    PubMed Central

    Martínez, M F; Kastelic, J P; Adams, G P; Janzen, E; McCartney, D H; Mapletoft, R J

    2000-01-01

    Two experiments were conducted to determine estrous response and pregnancy rate in beef cattle given a controlled internal drug release (CIDR-B) device plus prostaglandin F2 alpha (PGF) at CIDR-B removal, and estradiol or gonadotropin releasing hormone (GnRH). In Experiment I, crossbred beef heifers received a CIDR-B device and 1 mg estradiol benzoate (EB), plus 100 mg progesterone (E + P group; n = 41), 100 micrograms gonadotropin releasing hormone (GnRH group; n = 42), or no further treatment (Control group; n = 42), on Day 0. On Day 7, CIDR-B devices were removed and heifers were treated with PGF. Heifers in the E + P group were given 1 mg EB, 24 h after PGF, and then inseminated 30 h later. Heifers in the GnRH group were given 100 micrograms GnRH, 54 h after PGF, and concurrently inseminated. Control heifers were inseminated 12 h after onset of estrus. The estrous rate was lower (P < 0.01) in the GnRH group (55%) than in either the E + P (100%) or Control (83%) groups. The mean interval from CIDR-B removal to estrus was shorter (P < 0.01) and less variable (P < 0.01) in the E + P group than in the GnRH or Control groups. Pregnancy rate in the E + P group (76%) was higher (P < 0.01) than in the GnRH (48%) or Control (38%) groups. In Experiment II, 84 cows were treated similarly to the E + P group in Experiment I. Cows received 100 mg progesterone and either 1 mg EB or 5 mg estradiol-17 beta (E-17 beta) on Day 0 and either 1 mg of EB or 1 mg of E-17 beta on Day 8 (24 h after CIDR-B removal), in a 2 x 2 factorial design, and were inseminated 30 h later. There were no differences among groups for estrous rates or conception rates. The mean interval from CIDR-B removal to estrus was 44.2 h, s = 11.2. Conception rates were 67%, 62%, 52%, and 71% in Groups E-17 beta/E-17 beta, E-17 beta/EB, EB/E-17 beta, and EB/EB, respectively. In cattle given a CIDR-B device and estradiol plus progesterone, treatment with either EB or E-17 beta effectively synchronized estrus and

  17. 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.

  18. 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.

  19. Extra-amniotic prostaglandin E2 and the unfavourable cervix.

    PubMed

    Shepherd, J; Sims, C; Craft, I

    1976-10-02

    A small dose of prostaglandin E2 suspended in a viscous medium was instilled as a single application into the extra-amniotic space of patients with unfavourable induction features the day before planned induction in an attempt to improve the condition of the cervix. Two groups of 15 patients were studied, one receiving prostaglandin E2 250 mug suspended in methyl ethyl cellulose ('Tylose') 6% solution, and the other tylose alone. Cervical status did not change in those receiving tylose alone, whereas a significant improvement occurred in 14 out of 15 patients receiving the prostaglandin. Labour began before formal induction in 1 patient receiving tylose and in 8 receiving prostaglandin.

  20. Macrophages programmed by apoptotic cells promote angiogenesis via prostaglandin E2.

    PubMed

    Brecht, Kerstin; Weigert, Andreas; Hu, Jiong; Popp, Rüdiger; Fisslthaler, Beate; Korff, Thomas; Fleming, Ingrid; Geisslinger, Gerd; Brüne, Bernhard

    2011-07-01

    Macrophages contribute to tissue homeostasis in the developing as well as the adult organism. They promote tissue regeneration and remodeling after injury, which requires efficient neoangiogenesis. Signaling pathways activating an angiogenic program in macrophages are still poorly defined. We report that apoptotic cells (ACs), which originate from stressed or damaged tissues, can induce angiogenic properties in primary human macrophages. The signal originating from ACs is the lipid mediator sphingosine-1-phosphate (S1P), which activates S1P1/3 on macrophages to up-regulate cyclooxygenase-2. The formation and liberation of prostaglandin E(2) (PGE(2)) then stimulates migration of endothelial cells. This is demonstrated by using PGE(2) receptor antagonists or a neutralizing PGE(2) antibody in vitro, thereby attenuating endothelial cell migration using a Boyden chamber assay. In vivo, neutralization of PGE(2) from proangiogenic macrophage supernatants blocked vessel formation into Matrigel plugs. In particular, apoptotic cancer cells shifted prostanoid formation in macrophages selectively toward PGE(2) by up-regulating cyclooxygenase-2 and microsomal prostaglandin E synthase-1 (mPGES1), while down-regulating the PGE(2)-degrading enzyme 15-hydroxyprostaglandin dehydrogenase (15-PGDH) or prostaglandin-D synthase (PGDS). Angiogenic programming of macrophages by ACs, therefore, may control responses to tissue stress such as in tumors, where macrophages support cancer progression.

  1. Cytokine-induced prostaglandin E2 production and cyclooxygenase-2 expression in dental pulp cells: downstream calcium signalling via activation of prostaglandin EP receptor.

    PubMed

    Chang, M-C; Chen, Y-J; Tai, T-F; Tai, M-R; Li, M-Y; Tsai, Y-L; Lan, W-H; Wang, Y-L; Jeng, J-H

    2006-10-01

    To determine whether (i) proinflammatory cytokines stimulate prostaglandin E(2) (PGE(2)) production and cyclooxygenase (COX) gene expression in dental pulp cells, and (ii) pulp cells that express different prostaglandin E(2) receptor (EP) isoforms and their activation by PGE(2) leads to downstream Ca(2+) signalling. Cultured human dental pulp cells were exposed to interleukin (IL)-1beta and tumour necrotic factor-alpha (TNF-alpha). The expression of COX-1 and COX-2 was measured with reverse transcriptase-polymerase chain reaction (RT-PCR). The production of PGE(2) was measured using an enzyme-linked immunosorbent assay. Expression of prostaglandin EP receptor isoforms was studied by RT-PCR, whereas fura-2 fluorescence was used to measure calcium mobilization. The Kruskal-Wallis test and Wilcoxon sum rank test with Bonferroni correction were used for statistical analysis. Interleukin-1beta and TNF-alpha stimulate PGE(2) production of human dental pulp cells (P < 0.05). IL-1beta stimulated the COX-2 but not COX-1 mRNA expression. Pulp cells express mainly EP2, EP3 and EP1 receptors as analysed by RT-PCR. PGE(2) (0.25-2 micromol L(-1)) stimulated the Ca(2+) mobilization as indicated by increase in fura-2 fluorescence. Interleukin-1beta and TNF-alpha may stimulate PGE(2) production in dental pulp cells. Activation of prostaglandin EP receptors in dental pulp cells by PGE(2) may induce Ca(2+) signalling to regulate cellular biological activity during inflammation.

  2. 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

  3. Interplay between the prostaglandin transporter OATP2A1 and prostaglandin E2-mediated cellular effects.

    PubMed

    Bujok, Krystyna; Glaeser, Hartmut; Schuh, Wolfgang; Rau, Tilman T; Schmidt, Ingrid; Fromm, Martin F; Mandery, Kathrin

    2015-03-01

    Prostaglandins such as prostaglandin E2 (PGE2) play a pivotal role in physiological and pathophysiological pathways in gastric mucosa. Little is known about the interrelation of the prostaglandin E (EP) receptors with the prostaglandin transporter OATP2A1 in the gastric mucosa and gastric carcinoma. Therefore, we first investigated the expression of OATP2A1 and EP4 in normal and carcinoma gastric mucosa. Different PGE2-mediated cellular pathways and mechanisms were investigated using human embryonic kidney cells (HEK293) and the human gastric carcinoma cell line AGS stably transfected with OATP2A1. Colocalization and expression of OATP2A1 and EP4 were detected in mucosa of normal gastric tissue and of gastric carcinomas. OATP2A1 reduced the PGE2-mediated cAMP production in HEK293 and AGS cells overexpressing EP4 and OATP2A1. The expression of OATP2A1 in AGS cells resulted in a reduction of [(3)H]-thymidine incorporation which was in line with a higher accumulation of AGS-OATP2A1 cells in S-phase of the cell cycle compared to control cells. In contrast, the expression of OATP2A1 in HEK293 cells had no influence on the distribution in the S-phase compared to control cells. OATP2A1 also diminished the PGE2-mediated expression of interleukin-8 mRNA (IL-8) and hypoxia-inducible-factor 1α (HIF1α) protein in AGS-OATP2A1 cells. The expression of OATP2A1 increased the sensitivity of AGS cells against irinotecan which led to reduced cell viability. Taken together, these data show that OATP2A1 influences PGE2-mediated cellular pathways. Therefore, OATP2A1 needs to be considered as a key determinant for the understanding of the physiology and pathophysiology of prostaglandins in healthy and tumorous gastric mucosa.

  4. Effect of peroxisome proliferator activated receptor (PPAR)gamma agonists on prostaglandins cascade in joint cells.

    PubMed

    Moulin, David; Poleni, Paul-Emile; Kirchmeyer, Mélanie; Sebillaud, Sylvie; Koufany, Meriem; Netter, Patrick; Terlain, Bernard; Bianchi, Arnaud; Jouzeau, Jean-Yves

    2006-01-01

    In response to inflammatory cytokines, chondrocytes and synovial fibroblasts produce high amounts of prostaglandins (PG) which self-perpetuate locally the inflammatory reaction. Prostaglandins act primarily through membrane receptors coupled to G proteins but also bind to nuclear Peroxisome Proliferator-Activated Receptors (PPARs). Amongst fatty acids, the cyclopentenone metabolite of PGD2, 15-deoxy-Delta12,14PGJ2 (15d-PGJ2), was shown to be a potent ligand of the PPARgamma isotype prone to inhibit the production of inflammatory mediators. As the stimulated synthesis of PGE2 originates from the preferential coupling of inducible enzymes, cyclooxygenase-2 (COX-2) and membrane PGE synthase-1 (mPGES-1), we investigated the potency of 15d-PGJ2 to regulate prostaglandins synthesis in rat chondrocytes stimulated with interleukin-1beta (IL-1beta). We demonstrated that 15d-PGJ2, but not the high-affinity PPARgamma ligand rosiglitazone, decreased almost completely PGE2 synthesis and mPGES-1 expression. The inhibitory potency of 15d-PGJ2 was unaffected by changes in PPARgamma expression and resulted from inhibition of NF-kappaB nuclear binding and IkappaBalpha sparing, secondary to reduced phosphorylation of IKKbeta. Consistently with 15d-PGJ2 being a putative endogenous regulator of the inflammatory reaction if synthesized in sufficient amounts, the present data confirm the variable PPARgamma-dependency of its effects in joint cells while underlining possible species and cell types specificities.

  5. Immunosuppression and human cancer: role of prostaglandins.

    PubMed

    Harvey, H A; Allegra, J C; Demers, L M; Luderer, J R; Brenner, D E; Trautlein, J J; White, D S; Gillin, M A; Lipton, A

    1977-06-01

    Prostaglandins, unsaturated fatty acid derivatives with diversified pharmacologic activity, have been implicated in the pathophysiology of many diseases. Prostaglandin E (PGE) levels were measured by radioimmunoassay in the plasma of 41 normocalcemic patients with various stages of malignancies. Delayed hypersensitivity was assessed by a battery of six recall skin test antigens (ST) and by Dinitrochlorobenzene (DNCB) sensitization and challenge. Twenty-five patients with one or more positive skin tests had a mean PGE level of 87+/-8 pg/ml, whereas 16 patients with negative ST had a mean PGE level of 96+/-12 pg/ml. Twenty-one DNCB negative patients had a mean PGE level of 98+/-12 pg/ml and eight totally anergic patients had a mean PGE of 96+/-12 pg/ml. All PGE values were within the normal range and there was no statistical difference between the four groups. (p less than 0.1). We concluded that circulating PGE does not correlate with the non-specific immunosuppression seen in cancer patients.

  6. Acetylation of prostaglandin synthase by aspirin.

    PubMed Central

    Roth, G J; Stanford, N; Majerus, P W

    1975-01-01

    When microsomes of sheep or bovine seminal vesicles are incubated with [acetyl-3H]aspirin (acetyl salicylic acid), 200 Ci/mol, we observe acetylation of a single protein, as measured by sodium dodecyl sulfate/polyacrylamide gel electrophoresis. The protein has a molecular weight of 85,000 and corresponds to a similar acetylated protein found in the particulate fraction of aspirin-treated human platelets. The aspirin-mediated acetylation reaction proceeds with the same time course and at the same concentration as does the inhibition of prostaglandin synthase (cyclo-oxygenase) (EC 1.14.99.1; 8,11,14-eicosatrienoate, hydrogen-donor:oxygen oxidoreductase) by the drug. At 100 muM aspirin, 50% inhibition of prostaglandin synthase and 50% of maximal acetylation are observed after 15 min at 37 degrees. Furthermore, the substrate for cyclo-oxygenase, arachidonic acid, inhibits protein acetylation by aspirin at concentrations (50% inhibition at 10-30 muM) which correlate with the Michaelis constant of arachidonic acid as a substrate for cyclooxygenase. Arachidonic acid analogues and indomethacin inhibit the acetylation reaction in proportion to their effectiveness as cyclo-oxygenase inhibitors. The results suggest that aspirin acts as an active-site acetylating agent for the enzyme cyclo-oxygenase. This action of aspirin may account for its anti-inflammatory and anti-platelet action. PMID:810797

  7. [Prostaglandins, insulin secretion and diabetes mellitus].

    PubMed

    Giugliano, D; Torella, R; Scheen, A J; Lefebvre, P J; D'Onofrio, F

    1988-12-01

    The islets of Langerhans have the enzymatic equipment permitting the synthesis of the metabolites of arachidonic acid: cyclo-oxygenase and lipo-oxygenase. Numerous studies have shown that cyclo-oxygenase derivatives, mainly PGE2, reduce the insulin response to glucose whereas lipo-oxygenase derivatives, mainly 15-HPETE, stimulate insulin secretion. So, for instance, drugs that increase prostaglandins synthesis as colchicine or furosemide inhibit insulin secretion while non steroid anti-inflammator drugs, mainly salicylates, which inhibit cyclo-oxygenase, enhance the insulin response to various stimuli. In type-2 (non insulin-dependent) diabetes, an increased sensitivity to endogenous prostaglandins has been proposed as a possible cause for the insulin secretion defect which characterizes this disease. Play in favor of this hypothesis the fact that the administration of PGE inhibits the insulin response to arginine in type-2 diabetics but not in normal subject and the fact that the administration of salicylates could improve the insulin response to glucose in some of these patients.

  8. Prostaglandin levels in seminal plasma and sperm extracts of the domestic turkey, and the effects of cyclooxygenase inhibitors on sperm mobility

    PubMed Central

    Kennedy, Jessica H; Korn, Nancy; Thurston, Ronald J

    2003-01-01

    Background Turkey reproduction is by artificial insemination using pooled semen so there is interest in storing semen. Fertilizing capacity declines after six hours storage, possibly due to poor sperm mobility. Prostaglandins (PG) affect mammalian sperm motility, but avian sperm has not been widely studied. For this study, levels of PG E1, E2, and F2 alpha in turkey seminal plasma and sperm extract, and effects of cyclooxygenase (COX) inhibitors on sperm mobility were determined. Methods Seminal Plasma and sperm extract PG E1, E2, and F2 alpha, from 1.0 mL pooled semen, were measured by ELISA. In Trial 1, PG were determined from 122 wk old toms (n = 4). Trial 2 used 36 wk old toms (n = 7). For Trial 3, PGE2 only was measured from 48 wk (n = 6) and 154 wk old toms (n = 3). The effects of non-specific COX inhibitors indomethacin, diclofenac, tolmetin, or aspirin (n = 10), or specific COX-1 or COX-2 inhibitors (n = 3) on sperm mobility were measured (Accudenz swim-down test). Results Seminal plasma PG (pg/mL) in Trials 1 and 2, respectively, were 185.2 ± 88.4 and 187.2 ± 33.7 for PGE1; 141.4 ± 43.1 and 100.4 ± 14.6 for PGF2 alpha; and 431.0 ± 155.1 for PGE2 (Trial 1 only). Sperm extract PG (pg/10 billion cells) in Trials 1 and 2, respectively, were 215.1 ± 38.1 and 208.9 ± 41.5 for PGE1; 133.7 ± 51.7 and 49.8 ± 8.3 for PGF2 alpha; and 52.3 ± 8.6 for PGE2 (Trial 1 only). In Trial 3, seminal plasma PGE2 (pg/mL) in older versus younger males was 1097.9 ± 99.3 versus 853.2 ± 144.6 and sperm extract PGE2 (pg/10 billion cells) was 208.0 ± 56.1 versus 102.4 ± 14.8. Cyclooxygenase inhibitors (0.001 to 10 mM) decreased sperm mobility: indomethacin 15 to 100%; diclofenac 4 to 100%; tolmetin 27 to 74%; aspirin (tested at 0.01 to 15 mM) 22 to 42%; resveratrol (COX-1) and NS-398 (COX-2), both tested at 0.1 to 10 mM, 38 to 98% and 44 to 85%, respectively. Conclusion These results indicate that PG are present in turkey seminal plasma and sperm, and COX inhibitors

  9. 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.

  10. 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../.

  11. Prostaglandins for prelabour rupture of membranes at or near term.

    PubMed

    Tan, B P; Hannah, M E

    2000-01-01

    Induction of labour after prelabour rupture of membranes may reduce the risk of neonatal infection. However an expectant approach may be less likely to result in caesarean section. The objective of this review was to assess the effects of induction of labour with prostaglandins versus expectant management for prelabour rupture of membranes at or near term. We searched the Cochrane Pregnancy and Childbirth Group trials register. Randomised and quasi-randomised trials comparing early use of prostaglandins (with or without oxytocin) with no early use of prostaglandins in women with spontaneous rupture of membranes before labour, and 34 weeks or more of gestation. Trials were assessed for quality and data were abstracted. Fifteen trials were included. Most were of moderate to good quality. Different forms of prostaglandin preparations were used in these trials and it may be inappropriate to combine their results. Induction of labour by prostaglandins was associated with a decreased risk of chorioamnionitis (odds ratio 0.77, 95% confidence interval 0.61 to 0.97) based on eight trials and admission to neonatal intensive care (odds ratio 0.79, 95% confidence interval 0. 66 to 0.94) based on seven trials. No difference was detected for rate of caesarean section, although induction by prostaglandins was associated with a more frequent maternal diarrhoea and use of anaesthesia and/or analgesia. Based on one trial, women were more likely to view their care positively if labour was induced with prostaglandins,. Induction of labour with prostaglandins appears to decrease the risk of maternal infection (chorioamnionitis) and admission to neonatal intensive care. Induction of labour with prostaglandins does not appear to increase the rate of caesarean section, although it is associated with more frequent maternal diarrhoea and pain relief.

  12. 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.

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

    PubMed

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

    2014-03-14

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

  14. Biologic interaction of prostaglandin, thromboxane and prostacyclin: potential clinical applications.

    PubMed

    Bell, T G; Smith, W L; Oxender, W D

    1986-01-01

    Prostaglandins are vasoactive agents which have potent and varied effects depending on the species, conditions and organs tested. The clinician wishing to gain a significant overview of the field from current research literature has a demanding task for himself. A review of biologic interactions is exactly what is needed in a consideration of possible clinical applications of prostaglandins. Thus, it is necessary first to recount the last five years' advances in prostaglandin research. Only then will the listing and discussion of some diseases soon to benefit from the application of research be meaningful.

  15. Deletion of microsomal prostaglandin E synthase-1 increases sensitivity to salt loading and angiotensin II infusion.

    PubMed

    Jia, Zhanjun; Zhang, Aihua; Zhang, Hui; Dong, Zheng; Yang, Tianxin

    2006-11-24

    Microsomal prostaglandin E synthase-1 (mPGES-1), a membrane-associated protein, is critically involved in the inflammatory response and may be involved in physiological processes as well. The present study examined the role of mPGES-1 in regulation of sodium balance and blood pressure in the settings of salt loading and angiotensin II infusion. mPGES-1 -/- mice developed severe and progressive hypertension associated with an inappropriate increase in sodium balance when fed a high-salt diet. These mice exhibited a significantly impaired ability to excrete an acute enteral load of NaCl. Under these 2 settings of salt loading, urinary excretion of prostaglandin E(2) and nitrate/nitrite were remarkably increased in wild-type animals but not in mPGES-1 -/- mice. The changes of urinary cGMP paralleled that of urinary nitrate/nitrite. mPGES-1 -/- mice exhibited a remarkable inhibition of high salt-induced increase in gene expression of all 3 NO synthase isoforms, whereas these mice had upregulated expression of NO synthase III but not NO synthase I and NO synthase II at basal state. Chronic salt loading remarkably induced mPGES-1 protein expression exclusively in the distal nephron. In primary cultures of CD cells, mPGES-1 expression was significantly increased following exposure to hypertonic NaCl, in parallel with increased prostaglandin E(2) release. These findings have revealed a mPGES-1/prostaglandin E(2)/NO/cGMP pathway that appears to be critically important for salt adaptation. In addition, we provide evidence that mPGES-1 deficiency sensitized the hypertensive effect of angiotensin II. Overall, this study has characterized the natriuretic and antihypertensive role of mPGES-1 that likely contributes to blood pressure homeostasis.

  16. Immunolocalization of a microsomal prostaglandin E synthase in rabbit kidney.

    PubMed

    Fuson, Amanda L; Komlosi, Peter; Unlap, Tino M; Bell, P Darwin; Peti-Peterdi, János

    2003-09-01

    PGE2, the major cyclooxygenase (COX) metabolite of arachidonic acid, is an important paracrine regulator of numerous tubular and vascular functions in the kidney. To date, COX activity has been considered the key step in prostaglandin synthesis and is well characterized. However, much less is known about the recently cloned microsomal PGE2 synthase (mPGES), the terminal enzyme of PGE2 synthesis, which converts COX-derived PGH2 to the biologically important PGE2. Present studies provide the detailed localization of mPGES protein in the rabbit kidney using immunohistochemistry. In the cortex, strong mPGES labeling was found in the macula densa (MD) and principal cells of the connecting segment and cortical collecting tubule but not in intercalated cells. The medulla was abundant in mPGES-positive structures, with heavy labeling in the collecting duct system. In descending thin limbs and renal medullary interstitial cells, mPGES expression was less intense, and it was below the limits of detection in the vasa recta. Expression of MD mPGES, similarly to COX-2, was greatly increased in response to low-salt diet and angiotensin I-converting enzyme inhibition by captopril. These findings suggest autocrine regulation of renal salt and water transport by PGE2 in descending thin limb and collecting tubule and a paracrine effect of PGE2 on the glomerular and medullary vasculature. Similar to other organs, mPGES in the kidney is an inducible enzyme and may be similarly regulated and acts in concert with COX-2.

  17. Prostaglandin FP receptor inhibitor reduces ischemic brain damage and neurotoxicity

    PubMed Central

    Kim, Yun Tai; Moon, Sang Kwan; Maruyama, Takayuki; Narumiya, Shuh; Doré, Sylvain

    2012-01-01

    Bioactive lipids such as the prostaglandins have been reported to have various cytoprotective or toxic properties in acute and chronic neurological conditions. The roles of PGF2α and its receptor (FP) are not clear in the pathogenesis of ischemic brain injury. Considering that this G-protein coupled receptor has been linked to intracellular calcium regulation, we hypothesized that its blockade would be protective. We used FP antagonist (AL-8810) and FP receptor knockout (FP−/−) mice in in vivo and in vitro stroke models. Mice that were treated with AL-8810 had 35.7 ± 6.3% less neurologic dysfunction and 36.4 ± 6.0% smaller infarct volumes than did vehicle-treated mice after 48 hours of permanent middle cerebral artery occlusion (pMCAO); FP−/− mice also had improved outcomes after pMCAO. Blockade of the FP receptor also protected against oxygen-glucose deprivation (OGD)-induced cell death and reactive oxygen species formation in slice cultures. Finally, we found that an FP receptor agonist dose dependently increased intracellular Ca2+ levels in cultured neurons and established that FP-related Ca2+ signaling is related to ryanodine receptor signaling. These results indicate that the FP receptor is involved in cerebral ischemia-induced damage and could promote development of drugs for treatment of stroke and acute neurodegenerative disorders. PMID:22709986

  18. 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.

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

    PubMed

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

    2015-01-01

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

  20. Prostaglandin E2 As a Modulator of Viral Infections

    PubMed Central

    Sander, Willem J.; O'Neill, Hester G.; Pohl, Carolina H.

    2017-01-01

    Viral infections are a major cause of infectious diseases worldwide. Inflammation and the immune system are the major host defenses against these viral infection. Prostaglandin E2 (PGE2), an eicosanoid generated by cyclooxygenases, has been shown to modulate inflammation and the immune system by regulating the expression/concentration of cytokines. The effect of PGE2 on viral infection and replication is cell type- and virus-family-dependent. The host immune system can be modulated by PGE2, with regards to immunosuppression, inhibition of nitrogen oxide (NO) production, inhibition of interferon (IFN) and apoptotic pathways, and inhibition of viral receptor expression. Furthermore, PGE2 can play a role in viral infection directly by increasing the production and release of virions, inhibiting viral binding and replication, and/or stimulating viral gene expression. PGE2 may also have a regulatory role in the induction of autoimmunity and in signaling via Toll-like receptors. In this review the known effects of PGE2 on the pathogenesis of various infections caused by herpes simplex virus, rotavirus, influenza A virus and human immunodeficiency virus as well the therapeutic potential of PGE2 are discussed. PMID:28261111

  1. Activation of PPARγ by endogenous prostaglandin J2 mediates the antileukemic effect of selenium in murine leukemia.

    PubMed

    Finch, Emily R; Tukaramrao, Diwakar B; Goodfield, Laura L; Quickel, Michael D; Paulson, Robert F; Prabhu, K Sandeep

    2017-03-30

    Supplementation with nontoxic doses of micronutrient selenium has been shown to alleviate chronic myelogenous leukemia (CML) via the elimination of leukemia stem cells (LSCs) in mice. This treatment provides a new and novel method for eliminating the LSCs that are otherwise not targeted by existing therapies. The antileukemic effect of selenium was dependent on the production of endogenous cyclopentenone prostaglandins (CyPGs), Δ-12 prostaglandin J2 (Δ(12)-PGJ2), and 15-deoxy-Δ12,14-prostaglandin J2 (15d-PGJ2). Here, we show that these endogenous CyPGs, produced by mice maintained on selenium-supplemented diets, alleviate the symptoms of CML through their ability to activate the nuclear hormone receptor, peroxisome proliferator activated receptor γ (PPARγ). GW9662, a potent PPARγ antagonist, blocked the antileukemic effect of selenium supplementation by significantly reducing CyPGs. This effect was mediated by an increase in 15-prostaglandin dehydrogenase (15-Pgdh) activity, which oxidizes and inactivates Δ(12)-PGJ2 and 15d-PGJ2 In contrast, treatment with the PPARγ agonist pioglitazone mimicked selenium supplementation. This treatment led to decreased 15-Pgdh activity and increased CyPG levels, which inhibited CML progression. Selenium-dependent activation of PPARγ mediated by endogenous CyPGs decreased Stat5 expression leading to the downregulation of Cited2, a master regulator of LSC quiescence. These studies suggest a potential role for selenium supplementation as an adjuvant therapy in CML. © 2017 by The American Society of Hematology.

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

    PubMed Central

    Menter, David G.; DuBois, Raymond N.

    2012-01-01

    Prostaglandins exert a profound influence over the adhesive, migratory, and invasive behavior of cells during the development and progression of cancer. Cyclooxygenase-2 (COX-2) and microsomal prostaglandin E2 synthase-1 (mPGES-1) are upregulated in inflammation and cancer. This results in the production of prostaglandin E2 (PGE2), which binds to and activates G-protein-coupled prostaglandin E1–4 receptors (EP1–4). Selectively targeting the COX-2/mPGES-1/PGE2/EP1–4 axis of the prostaglandin pathway can reduce the adhesion, migration, invasion, and angiogenesis. Once stimulated by prostaglandins, cadherin adhesive connections between epithelial or endothelial cells are lost. This enables cells to invade through the underlying basement membrane and extracellular matrix (ECM). Interactions with the ECM are mediated by cell surface integrins by “outside-in signaling” through Src and focal adhesion kinase (FAK) and/or “inside-out signaling” through talins and kindlins. Combining the use of COX-2/mPGES-1/PGE2/EP1–4 axis-targeted molecules with those targeting cell surface adhesion receptors or their downstream signaling molecules may enhance cancer therapy. PMID:22505934

  3. Prosurvival effect of cumulus prostaglandin G/H synthase 2/prostaglandin2 signaling on bovine blastocyst: impact on in vivo posthatching development†.

    PubMed

    Nuttinck, Fabienne; Jouneau, Alice; Charpigny, Gilles; Hue, Isabelle; Richard, Christophe; Adenot, Pierre; Ruffini, Sylvie; Laffont, Ludivine; Chebrout, Martine; Duranthon, Véronique; Guienne, Brigitte Marquant-Le

    2017-03-07

    Apoptotic activity is a common physiological process which culminates at the blastocyst stage in the preimplantation embryo of many mammals. The degree of embryonic cell death can be influenced by the oocyte microenvironment. However, the prognostic significance of the incidence of apoptosis remains undefined. Prostaglandin E2 (PGE2) derived from prostaglandin G/H synthase-2 (PTGS2) activity is a well-known prosurvival factor that is mainly studied in oncology. PGE2 is the predominant PTGS2-derived prostaglandin present in the oocyte microenvironment during the periconceptional period. Using an in vitro model of bovine embryo production followed by transfer and collection procedures, we investigated the impact of periconceptional PGE2 on the occurrence of spontaneous apoptosis in embryos and on subsequent in vivo posthatching development. Different periconceptional PGE2 environments were obtained using NS-398, a specific inhibitor of PTGS2 activity, and exogenous PGE2. We assessed the level of embryonic cell death in blastocysts at day 8 postfertilization by counting total cell numbers, by the immunohistochemical staining of active caspase-3, and by quantifying terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling signals and apoptosis regulator (BCL-2/BAX) mRNA expression. Morphometric parameters were used to estimate the developmental stage of the embryonic disk and the extent of trophoblast elongation on day 15 conceptuses. Our findings indicate that periconceptional PGE2 signaling durably impacts oocytes, conferring increased resistance to spontaneous apoptosis in blastocysts and promoting embryonic disk development and the elongation process during preimplantation development.

  4. Role of seminal prostaglandins in male fertility. II. Effects of prostaglandin synthesis inhibition on spermatogenesis in man.

    PubMed

    Conte, D; Nordio, M; Romanelli, F; Manganelli, F; Giovenco, P; Dondero, F; Isidori, A

    1985-08-01

    The effect of prostaglandin biosynthesis inhibition has been studied in two groups of infertile oligozoospermic patients with high or normal-low seminal prostaglandin (PG) levels. PGE and 19-OH PGE were assayed by means of a gas chromatographic method and the most important seminal parameters (volume, concentration, motility and morphology of spermatozoa) were evaluated in basal conditions and at the end of indomethacin treatment, at a daily oral dose of 100 mg for thirty days. A drop in prostaglandin levels following indomethacin was observed in both groups of patients but only in the group with high concentrations of prostanoid derivates the prostaglandin inhibition was correlated with a significant improvement in sperm count and motility.

  5. Prostaglandin A1 inhibits replication of Mayaro virus in Aedes albopictus cells.

    PubMed

    Barbosa, J A; Rebello, M A

    1995-01-01

    Prostaglandin A1 (PGA1) reduced Mayaro virus replication in Aedes albopictus (mosquito) cells in culture. The highest nontoxic dose of PGA1, 7.5 microM, decreased virus production by 90%. In Mayaro virus-infected cells, PGA1 inhibited virus-specific protein synthesis. However, in mock-infected cells the presence of PGA1 stimulated the synthesis of several proteins with molecular masses of 70, 57 and 23 kDa, respectively. The data obtained from this study show that PGA1 plays a role in the metabolic regulation of Aedes albopictus cells, blocking the synthesis of Mayaro virus and inducing the synthesis of cellular polypeptides.

  6. The occurrence of 15-keto-prostaglandins in the red alga Gracilaria verrucosa.

    PubMed

    Dang, The Hung; Lee, Hye Ja; Yoo, Eun Sook; Hong, Jongki; Choi, Jae Sue; Jung, Jee H

    2010-09-01

    New 15-keto-prostaglandins (1-4) were isolated from the MeOH extract of the red alga, Gracilaria verrucosa. Their structures were determined to be prostaglandin B congeners (1-3) and a prostaglandin E congener (4) based on the NMR and MS data. Prostaglandins with a C-15 keto function are rare from natural sources. The presence of these metabolites in the alga is notable because 15-keto-prostaglandins (15-keto-PGs) are considered to be the metabolic products of regular prostaglandins in mammals. The occurrence of different prostaglandins in this alga might be due to the existence of different oxidative enzymes, as previously mentioned for oxygenated fatty acids of the red alga Gracilariopsis lemaneiformis. The antiinflammatory activity of these prostaglandins was examined by evaluating their inhibitory effects on nitric oxide production in lipopolysaccharide (LPS)-activated RAW264.7 murine macrophage cells. These prostaglandins showed weak activity on nitric oxide production.

  7. Prostaglandin content of tissue lining vascular prostheses

    SciTech Connect

    Greisler, H.P.; Kim, D.U.; Nussbaum, M.; Ellinger, J.; Schwarcz, T.H.

    1986-03-01

    This laboratory previously demonstrated arterial regeneration with a confluent endothelial-like flow surface 3-4 weeks after interposition of absorbable prostheses but not of dacron prostheses into the rabbit aorta. This study evaluates prostaglandin contents of inner capsular tissues within arterial prostheses. 6-keto-PGF/sub 1..cap alpha../ and TxB/sub 2/ were assayed (/sup 3/H-RIA) in supernatants of sonicated homogenates of tissues on the inner aspect of (a) absorbable polydioxanone (PDS), (b) absorbable polyglactin 910 (PG910), or (c) compound dacron-PG910 prostheses 3 or 6 months following implantation into rabbit aortas. Normal aortic controls from each rabbit were similarly treated. The 6-keto-PGF/sub 1..cap alpha../ values for all groups were lower than normal controls (p < .05). The ratio 6-keto-PGF/sub 1..cap alpha..//TxB/sub 2/ for PDS was nearly identical to normal aorta (1.69 +/- .54). This study shows that the quantity and ratio of eicosanoids in the inner capsular tissues is modified by the composition of the implanted arterial prosthesis.

  8. 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.

  9. Subcutaneous fat necrosis, hypercalcemia, and prostaglandin E.

    PubMed

    Sharata, H; Postellon, D C; Hashimoto, K

    1995-03-01

    We present two patients with subcutaneous fat necroses (SCFN) in whom endocrinologic studies revealed an association with elevated prostaglandin E (PGE) levels. A boy born after prolonged labor complicated by meconium aspiration developed erythematous, indurated plaques over the back, arms, buttocks, and cheeks at 4 days of age. A biopsy specimen of involved skin showed panniculitis with foci of necrotic adipocytes containing radially arranged, needle-shaped clefts and a granulomatous infiltrate in the septae. Laboratory studies revealed hypercalcemia of 13.6 mg/dl (normal 8.8-10.1 mg/dl), elevated 1.25-1.25(OH)2D3, and increased urinary excretion of PGE2. The child was hospitalized and treated with systemic steroids and diuretics, with resolution of SCFN and hypercalcemia. The second patient was a girl born with cyanotic heart disease. A diagnosis of Ebstein anomaly was made, and intravenous PGE1 was started to keep patent the ductus arteriosus. Four days later erythematous, indurated plaques were noted on the knee, back, and anterior chest. A skin biopsy specimen revealed SCFN. There was no associated laboratory abnormality. On discontinuing PGE1, no new lesions formed and the existing panniculitis resolved. These two cases demonstrate the association between SCFN and elevated PGE levels (endogenous in patient 1, exogenous in patient 2). No previous reports of SCFN after the administration of PGE1 have appeared in the literature.

  10. Prostaglandin analogs in the treatment of glaucoma.

    PubMed

    Hejkal, T W; Camras, C B

    1999-09-01

    Prostaglandin (PG) analogs are some of the most recent additions to the list of ocular hypotensive medications. Two analogs of naturally occurring PGs are available commercially, isopropyl unoprostone (Rescula [Ciba Vision, Atlanta, GA]) and latanoprost (Xalatan [Pharmacia & Upjohn, Bridgewater, NJ]). Presently, latanoprost 0. 005% is the only PG analog commercially available in the United States. These agents have been shown to be the most effective topical medications for reducing intraocular pressure. They have a different mechanism of action than other ocular hypotensives, and act primarily by increasing uveoscleral outflow. Because of this, PGs have a substantial additive effect when used with agents that reduce aqueous production (eg, beta blockers or carbonic anhydrase inhibitors) or that increase trabecular outflow facility (eg, pilocarpine). Local side effects include mild conjunctival hyperemia and local irritation, darkening of iris color, increased growth of eyelashes, and a possible association with cystoid macular edema or iritis in some patients with other risk factors. No systemic side effects have been proven to be caused by latanoprost. Recommended dosing is once daily at bedtime.

  11. 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

  12. 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.

  13. Prostaglandin synthesis is increased in selenium supplemented human mesangial cells despite suppression of phospholipase A2 - activity

    SciTech Connect

    Hampel, G.; Reinke, M.; Hren, J. )

    1991-01-01

    Antioxidants play an important role in the regulation of phospholipid hydrolysis and arachidonate metabolism. Supplementation of cultured human mesangial cells with selenium resulted in suppression of phospholipase A2 - activity and significantly increased production of three major prostaglandins. However, prostacyclin synthesis benefits most from selenium supplementation, suggesting that there is a specific action of selenium-dependent glutathione peroxidase on this pathway. Like in endothelial cells, production of platelet activating factor is significantly inhibited by selenium supplementation.

  14. 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

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

    PubMed Central

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

    2015-01-01

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

  16. 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.

  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. Responsivity to PGE2 labor induction involves concomitant differential prostaglandin E receptor gene expression in cervix and myometrium.

    PubMed

    Konopka, C K; Glanzner, W G; Rigo, M L; Rovani, M T; Comim, F V; Gonçalves, P B D; Morais, E N; Antoniazzi, A Q; Mello, C F; Cruz, I B M

    2015-09-10

    Prostaglandin E2 (dinoprostone) is largely used for labor induction. However, one-third of patients do not respond to treatment. One cause of this poor response may be associated with changes in regulation of prostaglandin E receptors (EP1-4). In this study, we investigated EP mRNA expression in the uterine cervix and lower uterine segment myometrium for term births. Biopsies were obtained from women with successful (responders) and failed (non-responders) dinoprostone labor induction, while women that underwent spontaneous labor were included as controls. EP1 mRNA was upregulated in the cervical tissue of women who did not respond to dinoprostone induction. In addition, in the myometrium, significantly higher levels of EP3 mRNA were observed in women treated with dinoprostone, independent of their responsiveness. Dinoprostone-responders presented 3.6-fold higher levels of EP3 mRNA expression than the spontaneous labor group. Significantly higher levels of EP3 mRNA in the myometrium of the dinoprostone-treated group indicated that dinoprostone may regulate the EP3 gene on the transcriptional level. These results highlight the relationship between EP gene expression and delivery and indicate that understanding the regulation of prostaglandin E receptors may lead to improved labor induction.

  19. CREB Mediates Prostaglandin F2α-Induced MUC5AC Overexpression

    PubMed Central

    Chung, Wen-Cheng; Ryu, Seung-Hee; Sun, Hongxia; Zeldin, Darryl C.; Koo, Ja Seok

    2009-01-01

    Mucus secretion is an important protective mechanism for the luminal lining of open tubular organs, but mucin overproduction in the respiratory tract can exacerbate the inflammatory process and cause airway obstruction. Production of MUC5AC, a predominant gel-forming mucin secreted by airway epithelia, can be induced by various inflammatory mediators such as prostaglandins. The two major prostaglandins involved in inflammation are prostaglandin (PG) E2 and F2α. PGE2-induced mucin production has been well studied, but the effect of PGF2α on mucin production remains poorly understood. To elucidate the effect and underlying mechanism of PGF2α on MUC5AC production, we investigated the signal transduction of PGF2α associated with this effect using normal human tracheobronchial epithelial cells. Our results demonstrated that PGF2α induces MUC5AC overproduction via a signaling cascade involving protein kinase C, extracellular signal-regulated kinase, p90 ribosomal S6 protein kinase, and cAMP response element binding protein (CREB). The regulation of PGF2α-induced MUC5AC expression by CREB was further confirmed by cAMP response element-dependent MUC5AC promoter activity and by interaction between CREB and MUC5AC promoter. The abrogation of all downstream signaling activities via suppression of each signaling molecule along the pathway indicates that a single pathway from PGF2α receptor to CREB is responsible for inducing MUC5AC overproduction. As CREB also mediates mucin overproduction induced by PGE2 and other inflammatory mediators, our findings have important clinical implication for the management of airway mucus hypersecretion. PMID:19201889

  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.

  1. Endocannabinoids and prostaglandins both contribute to GnRH neuron-GABAergic afferent local feedback circuits

    PubMed Central

    Glanowska, Katarzyna M.

    2011-01-01

    Gonadotropin-releasing hormone (GnRH) neurons form the final common pathway for central control of fertility. Regulation of GnRH neurons by long-loop gonadal steroid feedback through steroid receptor-expressing afferents such as GABAergic neurons is well studied. Recently, local central feedback circuits regulating GnRH neurons were identified. GnRH neuronal depolarization induces short-term inhibition of their GABAergic afferents via a mechanism dependent on metabotropic glutamate receptor (mGluR) activation. GnRH neurons are enveloped in astrocytes, which express mGluRs. GnRH neurons also produce endocannabinoids, which can be induced by mGluR activation. We hypothesized the local GnRH-GABA circuit utilizes glia-derived and/or cannabinoid mechanisms and is altered by steroid milieu. Whole cell voltage-clamp was used to record GABAergic postsynaptic currents (PSCs) from GnRH neurons before and after action potential-like depolarizations were mimicked. In GnRH neurons from ovariectomized (OVX) mice, this depolarization reduced PSC frequency. This suppression was blocked by inhibition of prostaglandin synthesis with indomethacin, by a prostaglandin receptor antagonist, or by a specific glial metabolic poison, together suggesting the postulate that prostaglandins, potentially glia-derived, play a role in this circuit. This circuit was also inhibited by a CB1 receptor antagonist or by blockade of endocannabinoid synthesis in GnRH neurons, suggesting an endocannabinoid element, as well. In females, local circuit inhibition persisted in androgen-treated mice but not in estradiol-treated mice or young ovary-intact mice. In contrast, local circuit inhibition was present in gonad-intact males. These data suggest GnRH neurons interact with their afferent neurons using multiple mechanisms and that these local circuits can be modified by both sex and steroid feedback. PMID:21917995

  2. 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.

  3. Prostaglandins and their receptors in insect biology.

    PubMed

    Stanley, David; Kim, Yonggyun

    2011-01-01

    We treat the biological significance of prostaglandins (PGs) and their known receptors in insect biology. PGs and related eicosanoids are oxygenated derivatives of arachidonic acid (AA) and two other C20 polyunsaturated fatty acids. PGs are mostly appreciated in the context of biomedicine, but a growing body of literature indicates the biological significance of these compounds extends throughout the animal kingdom, and possibly beyond. The actions of most PGs are mediated by specific receptors. Biomedical research has discovered a great deal of knowledge about PG receptors in mammals, including their structures, pharmacology, molecular biology and cellular locations. Studies of PG receptors in insects lag behind the biomedical background, however, recent results hold the promise of accelerated research in this area. A PG receptor has been identified in a class of lepidopteran hemocytes and experimentally linked to the release of prophenoloxidase. PGs act in several crucial areas of insect biology. In reproduction, a specific PG, PGE(2), releases oviposition behavior in most crickets and a few other insect species; PGs also mediate events in egg development in some species, which may represent all insects. PGs play major roles in modulating fluid secretion in Malpighian tubules, rectum and salivary glands, although, again, this has been studied in only a few insect species that may represent the Class. Insect immunity is a very complex defense system. PGs and other eicosanoids mediate a large number of immune reactions to infection and invasion. We conclude that research into PGs and their receptors in insects will lead to important advances in our understanding of insect biology.

  4. Prostaglandin analogues in the treatment of glaucoma.

    PubMed

    Lindén, C; Alm, A

    1999-05-01

    Prostaglandin (PG) analogues are a new class of ocular hypotensive drugs that have been developed for the treatment of open angle glaucoma. Two of these drugs, latanoprost and unoprostone, are presently commercially available. Latanoprost was introduced in 1996 in the US and Europe. Presently it enjoys the most widespread use and is the most well documented drug of this group. It reduces the intraocular pressure (IOP) by a mechanism of action different from other drugs; namely by increasing the uveoscleral outflow. The aqueous inflow is not affected. The optimal dose regimen is one drop of 50 microg/ml once daily, which reduces the IOP by approximately 30% in patients with glaucoma. A more pronounced ocular hypotensive effect is demonstrated when latanoprost is combined with other glaucoma therapies, including beta-blockers, adrenergic and cholinergic agonists or carbonic anhydrase inhibitors. Latanoprost is well tolerated. The drug reaches a plasma concentration below that needed for stimulation of the FP-receptor, which may explain its favourable systemic tolerability profile. The major ocular adverse effect is increased iris pigmentation, which is due to increased synthesis of melanin in the melanocytes of the iris stroma. It is most frequently seen in green-brown eyes and it is probably permanent. A low frequency of cystoid macular oedema has also been reported, predominantly in predisposed eyes. Unoprostone was launched in Japan in 1994, but there is little experience with this drug outside the Japanese market and the documentation is more limited. Its main mechanism of action is on outflow, but this is not yet fully elucidated. The recommended dosage regimen is 1 drop of 1.2 mg/ml twice daily. No comparative studies in humans between the 2 drugs have yet been published.

  5. The role of prostaglandins in reproductive physiology.

    PubMed

    Bardin, T P

    1970-10-01

    Research on the physiopathologic and biochemical nature of prostaglandins (PGs) suggest that PGs play a role in reproductive physiology. In vitro studies show that the PGE series decrease the motility of the human uterus, fallopian tubes, and ureter, and produce vasodilatation. PGFs cause vasoconstriction and increased motility of the uterus, fallopian tubes, ureter, and gastrointestinal muscle. PGs are also known to inhibit lipolysis, platelet aggregation, and gastric secretion. The exact mechanism of PGs are not fully understood, but evidence suggests that many responses can be attributed to interference with the enzyme adenyl cyclase, which catalyzes the formation of adenosine 3',5'-monophosphate (cyclic AMP) from adenosine triphosphate. The adenyl cyclase-cyclic AMP system mediates lipolysis, steroidogenesis, gastric secretion, certain smooth muscle motility responses, and increase in permeability due to vasopressin. Early studies of the myometrial effects of PGs showed that the PGE series inhibited the motility of the human myometrium in vitro while the PGF series produced mixed responses. The role of PGF2alpha in parturition has not been established but evidence suggests that it has a potential role as an oxytocic in cases of therapeutic abortion. In the area of human fertility, the physiologic role of PGs in seminal fluid is hypothesized to facilitate the migration of spermatozoa from the vagina into the uterine cavity. Karolinska Institute researchers have found that some infertile males have low PG levels in their ejaculates and are now working with methods of improving the PG levels to improve their fertility. Pickles et al. proposed a potential role for PGs in the etiology of dysmenorrhea, having found a significantly higher ratio of PGF to PGE in a series of patients with severe dysmenorrhea than in a comparable series of normal patients. The luteolytic and antinidatory effects of PGF2alpha are being investigated and studies appear encouraging. PGs have

  6. 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.

  7. Induction of abortion by different prostaglandin analogues.

    PubMed

    Bygdeman, M; Wiqvist, N

    1974-01-01

    The clinical advantages and disadvantages of intra amniotic administration of PGF2alpha in comparison with hypertonic saline has recently been summarized by the Prostaglandin Task Force within the World Health Organization Expanded program. The investigation comprised approximately 1,500 patients treated randomly with the two methods. The main advantage of the PG method was a significantly shorter induction-abortion interval and a lesser risk for serious complications and the significant disadvantage a slight increase in the mean frequency of minor complaints in terms of diarrhoea and vomiting. With PGF2alpha it seems difficult to obtain a "one shot" method to terminate second trimester pregnancy even with the intra-amniotic route of administration. The 15-methyl analogues seem more promising in this respect. The uterine response following administration of this compound is characterized by a more gradual initiation of uterine stimulation and a sustained effect, One intraamniotic injection of 2.5 mg 15-methyl-PGF2alpha induced abortion in nearly 100% of the cases and the incidence of side effects was low. Promising results with this compound have also been obtained following a single extra-amniotic instillation or by repeated intramuscular injections. Vaginal administration of 15-methyl PGF2alpha or its methyl ester can also be used for termination of pregnancy. Recently orally active PG analogues have become available for clinical testing. One of these compounds, 16,16-dimethyl-PGE2 may in some cases stimulate uterine contractility sufficiently to induce a second trimester abortion following repeated oral administration.

  8. Prostaglandins and Their Receptors in Insect Biology

    PubMed Central

    Stanley, David; Kim, Yonggyun

    2011-01-01

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

  9. Decreased RORC-dependent silencing of prostaglandin receptor EP2 induces autoimmune Th17 cells.

    PubMed

    Kofler, David M; Marson, Alexander; Dominguez-Villar, Margarita; Xiao, Sheng; Kuchroo, Vijay K; Hafler, David A

    2014-06-01

    Prostaglandin E2 (PGE2) promotes Th17 expansion while otherwise inhibiting other CD4+ T cell subsets. Here, we identified a PGE2-dependent pathway that induces pathogenic Th17 cells in autoimmune disease and is regulated by the transcription factor RORC. Compared with other CD4+ cell types from healthy subjects, there is a surprising lack of the prostaglandin receptor EP2 on Th17 cells; therefore, we examined the hypothesis that RORγt, which is highly expressed in Th17 cells, mediates EP2 downregulation. Chromatin immunoprecipitation followed by DNA sequencing revealed that RORγt binds directly to Ptger2 (the gene encoding EP2 receptor) in Th17 cells isolated from WT mice. In Th17 cells isolated from humans, RORC repressed EP2 by directly silencing PTGER2 transcription, and knock down of RORC restored EP2 expression in Th17 cells. Compared with Th17 cells from healthy individuals, Th17 cells from patients with MS exhibited reduced RORC binding to the PTGER2 promoter region, resulting in higher EP2 levels and increased expression of IFN-γ and GM-CSF. Finally, overexpression of EP2 in Th17 cells from healthy individuals induced a specific program of inflammatory gene transcription that produced a pathogenic Th17 cell phenotype. These findings reveal that RORC directly regulates the effects of PGE2 on Th17 cells, and dysfunction of this pathway induces a pathogenic Th17 cell phenotype.

  10. Decreased RORC-dependent silencing of prostaglandin receptor EP2 induces autoimmune Th17 cells

    PubMed Central

    Kofler, David M.; Marson, Alexander; Dominguez-Villar, Margarita; Xiao, Sheng; Kuchroo, Vijay K.; Hafler, David A.

    2014-01-01

    Prostaglandin E2 (PGE2) promotes Th17 expansion while otherwise inhibiting other CD4+ T cell subsets. Here, we identified a PGE2-dependent pathway that induces pathogenic Th17 cells in autoimmune disease and is regulated by the transcription factor RORC. Compared with other CD4+ cell types from healthy subjects, there is a surprising lack of the prostaglandin receptor EP2 on Th17 cells; therefore, we examined the hypothesis that RORγt, which is highly expressed in Th17 cells, mediates EP2 downregulation. Chromatin immunoprecipitation followed by DNA sequencing revealed that RORγt binds directly to Ptger2 (the gene encoding EP2 receptor) in Th17 cells isolated from WT mice. In Th17 cells isolated from humans, RORC repressed EP2 by directly silencing PTGER2 transcription, and knock down of RORC restored EP2 expression in Th17 cells. Compared with Th17 cells from healthy individuals, Th17 cells from patients with MS exhibited reduced RORC binding to the PTGER2 promoter region, resulting in higher EP2 levels and increased expression of IFN-γ and GM-CSF. Finally, overexpression of EP2 in Th17 cells from healthy individuals induced a specific program of inflammatory gene transcription that produced a pathogenic Th17 cell phenotype. These findings reveal that RORC directly regulates the effects of PGE2 on Th17 cells, and dysfunction of this pathway induces a pathogenic Th17 cell phenotype. PMID:24812667

  11. Pro-inflammatory prostaglandins and progression of colorectal cancer

    PubMed Central

    Wang, Dingzhi; DuBois, Raymond N.

    2008-01-01

    Chronic inflammation is a risk factor for several gastrointestinal malignancies, including esophageal, gastric, hepatic, pancreatic and colorectal cancer. It has long been known that long-term use of nonsteroidal anti-inflammatory drugs (NSAIDs) reduces the relative risk of developing colorectal cancer. NSAIDs exert their anti-inflammatory and anti-tumor effects primarily by inhibiting activity of cyclooxygenase (COX) enzymes. Cyclooxygenase enzymes catalyze the conversion of arachidonic acid into prostanoids, including prostaglandins (PGs) and thromboxanes (TXs). Emerging evidence demonstrates that prostaglandins play an important role in inflammation and cancer. In this review, we highlight recent breakthroughs in our understanding of the roles of the different prostaglandins in colorectal cancer (CRC) and inflammatory bowel disease (IBD). These findings may provide a rationale for the development of new anti-inflammatory therapeutic approaches to cancer prevention and/or treatment. PMID:18406516

  12. Prostaglandin EP2 and EP4 receptors modulate expression of the chemokine CCL2 (MCP-1) in response to LPS-induced renal glomerular inflammation.

    PubMed

    Zahner, Gunther; Schaper, Melanie; Panzer, Ulf; Kluger, Malte; Stahl, Rolf A K; Thaiss, Friedrich; Schneider, André

    2009-08-27

    The pro-inflammatory chemokine CCL2 [chemokine (Cys-Cys motif) ligand 2; also known as MCP-1 (monocyte chemotactic protein-1)] is up-regulated in the glomerular compartment during the early phase of LPS (lipopolysaccharide)-induced nephritis. This up-regulation also occurs in cultured MCs (mesangial cells) and is more pronounced in MCs lacking the PGE2 (prostaglandin E2) receptor EP2 or in MCs treated with a prostaglandin EP4 receptor antagonist. To examine a possible feedback mechanism of EP receptor stimulation on CCL2 expression, we used an in vitro model of MCs with down-regulated EP receptor expression. Selectively overexpressing the various EP receptors in these cells then allows the effects on the LPS-induced CCL2 expression to be examined. Cells were stimulated with LPS and CCL2 gene expression was examined and compared with LPS-stimulated, mock-transfected PTGS2 [prostaglandin-endoperoxide synthase 2, also known as COX-2 (cyclo-oxygenase-2)]-positive cells. Overexpression of EP1, as well as EP3, had no effect on LPS-induced Ccl2 mRNA expression. In contrast, overexpression of EP2, as well as EP4, significantly decreased LPS-induced CCL2 expression. These results support the hypothesis that PTGS2-derived prostaglandins, when strongly induced, counter-balance inflammatory processes through the EP2 and EP4 receptors in MCs.

  13. Intravaginal prostaglandin-E2 for cervical priming and induction of labour.

    PubMed

    Al-Taani, M I

    2007-01-01

    A prospective study examined the safety, efficacy and labour outcome in 436 women undergoing labour induction using intravaginal prostaglandin E2. Women with singleton pregnancies (235 nulliparas and 201 multiparas) were recruited if they had a clinically unfavourable cervix, and indications for induction. The mean (standard deviation) interval from initiation to delivery was statistically significantly shorter in multiparas than nulliparas: 13.5 hours (SD 1.8) versus 15.5 hours (SD 2.4). No more than 2 x 3 mg tablets were needed to achieve a clinically feasible cervix for amniotomy. The overall need for oxytocin augmentation of labour was 42%, significantly higher in nulliparas (47%) than multiparas (35%). Intrapartum complications, caesarean section and perinatal deaths showed no statistically significant differences between the groups.

  14. Appearance of Prostaglandin F2α in Human Blood during Labour*

    PubMed Central

    Karim, S. M. M.

    1968-01-01

    Blood samples from over 70 pregnant women have been examined for the presence of four prostaglandins. Samples obtained from women not in labour at different gestation periods and at term contained no detectable amounts of prostaglandins. Prostaglandin F2α was present in samples of blood obtained during normal spontaneous labour. The appearance of this substance in the blood preceded the uterine contraction. Whether prostaglandins play a part in the process of normal labour is still conjectural. PMID:5723366

  15. 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

  16. [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.

  17. Prostaglandin e and f receptor expression and myometrial sensitivity at labor onset in the sheep.

    PubMed

    Palliser, Hannah K; Hirst, Jonathan J; Ooi, Guck T; Rice, Gregory E; Dellios, Nicole L; Escalona, Ruth M; Parkington, Helena C; Young, I Ross

    2005-04-01

    Prostaglandins (PGs) play a pivotal role in the initiation and progression of term and preterm labor. Uterine activity is stimulated primarily by PGE(2) and PGF(2alpha) acting on prostaglandin E (EP) and prostaglandin F (FP) receptors, respectively. Activation of FP receptors strongly stimulates the myometrium, whereas stimulation of EP receptors may lead to contraction or relaxation, depending on the EP subtype (EP1-4) expression. Thus, the relative expression of FP and EP1-4 may determine the responsiveness to PGE(2) and PGF(2alpha). The aims of this study were to characterize the expression of EP1-4 and FP in intrauterine tissues and placentome, together with myometrial responsiveness to PG, following the onset of dexamethasone-induced preterm and spontaneous term labor. Receptor mRNA expression was measured using quantitative real-time polymerase chain reaction using species-specific primers. There was no increase in myometrial contractile receptor expression at labor onset, nor was there a change in sensitivity to PGE(2) and PGF(2alpha). This suggests expression of these receptors reaches maximal levels by late gestation in sheep. Placental tissue showed a marked increase in EP2 and EP3 receptor expression, the functions of which are unknown at this time. Consistent with previous reports, these results suggest that PG synthesis is the main factor in the regulation of uterine contractility at labor. This is the first study to simultaneously report PG E and F receptor expression in the key gestational tissues of the sheep using species-specific primers at induced-preterm and spontaneous labor onset.

  18. 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

  19. The cyclooxygenase-2-prostaglandin E2 pathway maintains senescence of chronic obstructive pulmonary disease fibroblasts.

    PubMed

    Dagouassat, Maylis; Gagliolo, Jean-Marie; Chrusciel, Sandra; Bourin, Marie-Claude; Duprez, Corinne; Caramelle, Philippe; Boyer, Laurent; Hue, Sophie; Stern, Jean-Baptiste; Validire, Pierre; Longrois, Dan; Norel, Xavier; Dubois-Randé, Jean-Luc; Le Gouvello, Sabine; Adnot, Serge; Boczkowski, Jorge

    2013-04-01

    Chronic obstructive pulmonary disease (COPD) is associated with lung fibroblast senescence, a process characterized by the irreversible loss of replicative capacity associated with the secretion of inflammatory mediators. However, the mechanisms of this phenomenon remain poorly defined. The aim of this study was to analyze the role of prostaglandin E2 (PGE2), a prostaglandin known to be increased in COPD lung fibroblasts, in inducing senescence and related inflammation in vitro in lung fibroblasts and in vivo in mice. Fibroblasts were isolated from patients with COPD and from smoker and nonsmoker control subjects. Senescence markers and inflammatory mediators were investigated in fibroblasts and in mice. Lung fibroblasts from patients with COPD exhibited higher expression of PGE2 receptors EP2 and EP4 as compared with nonsmoker and smoker control subjects. Compared with both nonsmoker and smoker control subjects, during long-term culture, COPD fibroblasts displayed increased senescent markers (increased senescence associated-β galactosidase activity, p16, and p53 expression and lower proliferative capacity), and an increased PGE2, IL-6, IL-8, growth-regulated oncogene (GRO), CX3CL1, and matrix metalloproteinase-2 protein and cyclooxygenase-2 and mPGES-1 mRNA expression. Using in vitro pharmacologic approaches and in vivo experiments in wild-type and p53(-/-) mice we demonstrated that PGE2 produced by senescent COPD fibroblasts is responsible for the increased senescence and related inflammation. PGE2 acts either in a paracrine or autocrine fashion by a pathway involving EP2 and EP4 prostaglandin receptors, cyclooxygenase-2-dependent reactive oxygen species production and signaling, and consecutive p53 activation. PGE2 is a critical component of an amplifying and self-perpetuating circle inducing senescence and inflammation in COPD fibroblasts. Modulating the described PGE2 signaling pathway could provide a new basis to dampen senescence and senescence

  20. 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.

  1. Plasma prostaglandin E(2) metabolite levels during labor induction with a sustained-release prostaglandin E(2) vaginal insert.

    PubMed

    Goharkhay, N; Stanczyk, F Z; Gentzschein, E; Wing, D A

    2000-01-01

    To measure prostaglandin E(2) levels during labor induction with a sustained-release vaginal polymer insert (prostaglandin E(2) insert) and to determine whether Bishop score change correlated with tachysystole. Twelve primiparas and 12 multiparas were treated with a 0.3 mg per hour sustained-release polymer vaginal prostaglandin E(2) insert for up to 24 hours. Bishop score was assessed at start and end of therapy, and serum samples were collected at 4-hour intervals. Prostaglandin E(2) metabolite (PGEM) levels were measured by specific enzyme immunoassay. Exposure averaged 13.5 +/- 7.2 hours. Four patients (16.7%, three nulliparas) had tachysystole. Mean PGEM levels increased from 187 +/- 42 pg/mL at baseline to 548 +/- 110 pg/mL at 12 hours (P <.05) and remained relatively stable thereafter. Nulliparas with Bishop score changes of four points or more had the highest increase, with average peak levels of 985 +/- 109 pg/mL, compared with 452 +/- 58 pg/mL for all others (P <.001). Patients with tachysystole had higher 4-hour (P <.01) and overall (P <.04) increases in PGEM level. Removal of the insert led to an average decrease of 335 pg/mL in PGEM levels (P <.01). The decrease correlated with the PGEM level measured before removal (r =.94, P <.0001) and the maximum PGEM increase from baseline (r =.94, P <.0001). The mean mixed venous cord PGEM level was 409 +/- 375 pg/mL. Administration of the prostaglandin E(2) insert led to a sustained increase in circulating PGEM levels in women who had labor induction. Peak PGEM levels correlated with Bishop score improvement. Rapid increases in prostaglandin E(2) levels might cause tachysystole.

  2. Prostaglandin E₂ receptor EP2 mediates Snail expression in hepatocellular carcinoma cells.

    PubMed

    Cheng, Shan-Yu; Zhang, Hai; Zhang, Min; Xia, Shu-Kai; Bai, Xiao-Ming; Zhang, Li; Ma, Juan; Rong, Rong; Wang, Yi-Pin; Du, Ming-Zhan; Wang, Jie; Chen, Meng; Shi, Feng; Yang, Qin-Yi; Leng, Jing

    2014-05-01

    Prostaglandin E2 (PGE2) has been shown to influence cell invasion and metastasis in several types of cancer, including hepatocellular carcinoma (HCC). however, the molecular mechanisms underlying it remain to be further elucidated. Snail, as one of key inducers of epithelial-mesenchymal transition (EMT), plays pivotal roles in HCC invasion and metastasis. The present study was designed to evaluate the possible signaling pathways through which PGE2 regulates Snail protein expression in HCC cell lines. PGE2 markedly enhanced Huh-7 cell invasion and migration ability by upregulating the expression level of Snail protein, and EP2 receptor played an important role in this process. Src, EGFR, Akt and mTOR were all activated and involved in the regulation of snail protein expression. Our findings suggest that PGE2 could upregulate the expression level of Snail protein through the EP2/Src/EGFR/Akt/mTOR pathway in Huh-7 cells, which promotes HCC cell invasion and migration.

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

    PubMed Central

    2010-01-01

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

  4. Primary structure of prostaglandin G/H synthase from sheep vesicular gland determined from the complementary DNA sequence.

    PubMed Central

    DeWitt, D L; Smith, W L

    1988-01-01

    Prostaglandin G/H synthase (8,11,14-icosatrienoate, hydrogen-donor:oxygen oxidoreductase, EC 1.14.99.1) catalyzes the first step in the formation of prostaglandins and thromboxanes, the conversion of arachidonic acid to prostaglandin endoperoxides G and H. This enzyme is the site of action of nonsteroidal anti-inflammatory drugs. We have isolated a 2.7-kilobase complementary DNA (cDNA) encompassing the entire coding region of prostaglandin G/H synthase from sheep vesicular glands. This cDNA, cloned from a lambda gt 10 library prepared from poly(A)+ RNA of vesicular glands, hybridizes with a single 2.75-kilobase mRNA species. The cDNA clone was selected using oligonucleotide probes modeled from amino acid sequences of tryptic peptides prepared from the purified enzyme. The full-length cDNA encodes a protein of 600 amino acids, including a signal sequence of 24 amino acids. Identification of the cDNA as coding for prostaglandin G/H synthase is based on comparison of amino acid sequences of seven peptides comprising 103 amino acids with the amino acid sequence deduced from the nucleotide sequence of the cDNA. The molecular weight of the unglycosylated enzyme lacking the signal peptide is 65,621. The synthase is a glycoprotein, and there are three potential sites for N-glycosylation, two of them in the amino-terminal half of the molecule. The serine reported to be acetylated by aspirin is at position 530, near the carboxyl terminus. There is no significant similarity between the sequence of the synthase and that of any other protein in amino acid or nucleotide sequence libraries, and a heme binding site(s) is not apparent from the amino acid sequence. The availability of a full-length cDNA clone coding for prostaglandin G/H synthase should facilitate studies of the regulation of expression of this enzyme and the structural features important for catalysis and for interaction with anti-inflammatory drugs. Images PMID:3125548

  5. Inhibition of Prostaglandin D Synthase Suppresses Muscular Necrosis

    PubMed Central

    Mohri, Ikuko; Aritake, Kosuke; Taniguchi, Hidetoshi; Sato, Yo; Kamauchi, Shinya; Nagata, Nanae; Maruyama, Toshihiko; Taniike, Masako; Urade, Yoshihiro

    2009-01-01

    Duchenne muscular dystrophy is a fatal muscle wasting disease that is characterized by a deficiency in the protein dystrophin. Previously, we reported that the expression of hematopoietic prostaglandin D synthase (HPGDS) appeared in necrotic muscle fibers from patients with either Duchenne muscular dystrophy or polymyositis. HPGDS is responsible for the production of the inflammatory mediator, prostaglandin D2. In this paper, we validated the hypothesis that HPGDS has a role in the etiology of muscular necrosis. We investigated the expression of HPGDS/ prostaglandin D2 signaling using two different mouse models of muscle necrosis, that is, bupivacaine-induced muscle necrosis and the mdx mouse, which has a genetic muscular dystrophy. We treated each mouse model with the HPGDS-specific inhibitor, HQL-79, and measured both necrotic muscle volume and selected cytokine mRNA levels. We confirmed that HPGDS expression was induced in necrotic muscle fibers in both bupivacaine-injected muscle and mdx mice. After administration of HQL-79, necrotic muscle volume was significantly decreased in both mouse models. Additionally, mRNA levels of both CD11b and transforming growth factor β1 were significantly lower in HQL-79-treated mdx mice than in vehicle-treated animals. We also demonstrated that HQL-79 suppressed prostaglandin D2 production and improved muscle strength in the mdx mouse. Our results show that HPGDS augments inflammation, which is followed by muscle injury. Furthermore, the inhibition of HPGDS ameliorates muscle necrosis even in cases of genetic muscular dystrophy. PMID:19359520

  6. Prostaglandin D2 inhibits wound-induced hair follicle neogenesis through the receptor, Gpr44.

    PubMed

    Nelson, Amanda M; Loy, Dorothy E; Lawson, John A; Katseff, Adiya S; Fitzgerald, Garret A; Garza, Luis A

    2013-04-01

    Prostaglandins (PGs) are key inflammatory mediators involved in wound healing and regulating hair growth; however, their role in skin regeneration after injury is unknown. Using wound-induced hair follicle neogenesis (WIHN) as a marker of skin regeneration, we hypothesized that PGD2 decreases follicle neogenesis. PGE2 and PGD2 were elevated early and late, respectively, during wound healing. The levels of WIHN, lipocalin-type prostaglandin D2 synthase (Ptgds), and its product PGD2 each varied significantly among background strains of mice after wounding, and all correlated such that the highest Ptgds and PGD2 levels were associated with the lowest amount of regeneration. In addition, an alternatively spliced transcript variant of Ptgds missing exon 3 correlated with high regeneration in mice. Exogenous application of PGD2 decreased WIHN in wild-type mice, and PGD2 receptor Gpr44-null mice showed increased WIHN compared with strain-matched control mice. Furthermore, Gpr44-null mice were resistant to PGD2-induced inhibition of follicle neogenesis. In all, these findings demonstrate that PGD2 inhibits hair follicle regeneration through the Gpr44 receptor and imply that inhibition of PGD2 production or Gpr44 signaling will promote skin regeneration.

  7. Prostaglandin D2 inhibits wound-induced hair follicle neogenesis through the receptor, Gpr44

    PubMed Central

    Nelson, Amanda M.; Loy, Dorothy E.; Lawson, John A.; Katseff, Adiya S.; FitzGerald, Garret A.; Garza, Luis A.

    2012-01-01

    Prostaglandins (PGs) are key inflammatory mediators involved in wound healing and regulating hair growth; however, their role in skin regeneration after injury is unknown. Using wound-induced hair follicle neogenesis (WIHN) as a marker of skin regeneration, we hypothesized that PGD2 decreases follicle neogenesis. PGE2 and PGD2 were elevated early and late respectively during wound healing. The levels of WIHN, lipocalin-type prostaglandin D2 synthase (Ptgds) and its product PGD2 each varied significantly among background strains of mice after wounding and all correlated such that the highest Ptgds and PGD2 levels were associated with the lowest amount of regeneration. Additionally, an alternatively spliced transcript variant of Ptgds missing exon 3 correlated with high regeneration in mice. Exogenous application of PGD2 decreased WIHN in wild type mice and PGD2 receptor Gpr44 null mice showed increased WIHN compared to strain-matched control mice. Furthermore, Gpr44 null mice were resistant to PGD2-induced inhibition of follicle neogenesis. In all, these findings demonstrate that PGD2 inhibits hair follicle regeneration through the Gpr44 receptor and imply that inhibition of PGD2 production or Gpr44 signaling will promote skin regeneration. PMID:23190891

  8. G-protein coupled receptor-evoked glutamate exocytosis from astrocytes: role of prostaglandins.

    PubMed

    Cali, Corrado; Lopatar, Jan; Petrelli, Francesco; Pucci, Luca; Bezzi, Paola

    2014-01-01

    Astrocytes are highly secretory cells, participating in rapid brain communication by releasing glutamate. Recent evidences have suggested that this process is largely mediated by Ca(2+)-dependent regulated exocytosis of VGLUT-positive vesicles. Here by taking advantage of VGLUT1-pHluorin and TIRF illumination, we characterized mechanisms of glutamate exocytosis evoked by endogenous transmitters (glutamate and ATP), which are known to stimulate Ca(2+) elevations in astrocytes. At first we characterized the VGLUT1-pHluorin expressing vesicles and found that VGLUT1-positive vesicles were a specific population of small synaptic-like microvesicles containing glutamate but which do not express VGLUT2. Endogenous mediators evoked a burst of exocytosis through activation of G-protein coupled receptors. Subsequent glutamate exocytosis was reduced by about 80% upon pharmacological blockade of the prostaglandin-forming enzyme, cyclooxygenase. On the other hand, receptor stimulation was accompanied by extracellular release of prostaglandin E2 (PGE2). Interestingly, administration of exogenous PGE2 produced per se rapid, store-dependent burst exocytosis of glutamatergic vesicles in astrocytes. Finally, when PGE2-neutralizing antibody was added to cell medium, transmitter-evoked exocytosis was again significantly reduced (by about 50%). Overall these data indicate that cyclooxygenase products are responsible for a major component of glutamate exocytosis in astrocytes and that large part of such component is sustained by autocrine/paracrine action of PGE2.

  9. Activation of the epithelial Na+ channel triggers prostaglandin E₂ release and production required for embryo implantation.

    PubMed

    Ruan, Ye Chun; Guo, Jing Hui; Liu, Xinmei; Zhang, Runju; Tsang, Lai Ling; Dong, Jian Da; Chen, Hui; Yu, Mei Kuen; Jiang, Xiaohua; Zhang, Xiao Hu; Fok, Kin Lam; Chung, Yiu Wa; Huang, Hefeng; Zhou, Wen Liang; Chan, Hsiao Chang

    2012-07-01

    Embryo implantation remains a poorly understood process. We demonstrate here that activation of the epithelial Na⁺ channel (ENaC) in mouse endometrial epithelial cells by an embryo-released serine protease, trypsin, triggers Ca²⁺ influx that leads to prostaglandin E₂ (PGE₂) release, phosphorylation of the transcription factor CREB and upregulation of cyclooxygenase 2, the enzyme required for prostaglandin production and implantation. We detected maximum ENaC activation, as indicated by ENaC cleavage, at the time of implantation in mice. Blocking or knocking down uterine ENaC in mice resulted in implantation failure. Furthermore, we found that uterine ENaC expression before in vitro fertilization (IVF) treatment is markedly lower in women with implantation failure as compared to those with successful pregnancy. These results indicate a previously undefined role of ENaC in regulating the PGE₂ production and release required for embryo implantation, defects that may be a cause of miscarriage and low success rates in IVF.

  10. 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.

  11. Effect of prostaglandins on human sperm function in vitro and seminal adenosine triphosphate content.

    PubMed

    Gottlieb, C; Svanborg, K; Eneroth, P; Bygdeman, M

    1988-02-01

    The aim of the present study was to evaluate the effect of addition of physiologic amounts of different prostaglandins normally present in semen, on sperm motility, on sperm penetration capacity in cervical mucus in vitro, and on the adenosine triphosphate (ATP) concentration in semen. Semen samples were obtained from volunteers who were attending the fertility outpatient clinic. Sperm motility was measured on a video recorder with a built-in timer, sperm penetration by the Kremer test, and ATP by bioluminescence assay. The addition of 19-hydroxy prostaglandin (PG) E to ejaculates positively stimulated sperm motility and sperm penetration capacity. The opposite effect was observed with 19-hydroxy PGF. PGE1, PGE2, and PGF2 alpha had no effect on either parameter, while PGF1 alpha reduced the sperm motility. The addition of 19-hydroxy PGE to ejaculates increased and the addition of 19-hydroxy PGF reduced semen concentrations of ATP. However, only the last-mentioned effect was statistically significant (P less than 0.05). It is suggested that, in particular, 19-hydroxy PGE and 19-hydroxy PGF are important regulators of sperm motility and that the effect may be mediated via effects on the ATP content in the spermatozoa.

  12. Prostaglandin E2 differentially modulates the central control of eupnoea, sighs and gasping in mice

    PubMed Central

    Koch, Henner; Caughie, Cali; Elsen, Frank P; Doi, Atsushi; Garcia, Alfredo J; Zanella, Sebastien; Ramirez, Jan-Marino

    2015-01-01

    Prostaglandins are important regulators of autonomic functions in the mammalian organism. Here we demonstrate in vivo that prostaglandin E2 (PGE2) can differentially increase the frequency of eupnoea (normal breathing) and sighs (augmented breaths) when injected into the preBötzinger complex (preBötC), a medullary area that is critical for breathing. Low concentrations of PGE2 (100–300 nm) increased the sigh frequency, while higher concentrations (1–2 μm) were required to increase the eupnoeic frequency. The concentration-dependent effects were similarly observed in the isolated preBötC. This in vitro preparation also revealed that riluzole, a blocker of the persistent sodium current (INap), abolished the modulatory effect on sighs, while flufenamic acid, an antagonist for the calcium-activated non-selective cation conductance (ICAN) abolished the effect of PGE2 on fictive eupnoea at higher concentrations. At the cellular level PGE2 significantly increased the amplitude and frequency of intrinsic bursting in inspiratory neurons. By contrast PGE2 affected neither excitatory nor inhibitory synaptic transmission. We conclude that PGE2 differentially modulates sigh, gasping and eupnoeic activity by differentially increasing INap and ICAN currents in preBötC neurons. PMID:25556802

  13. 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.

  14. 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

  15. [Problems of assessing the biological value of prostaglandin in vitro (author's transl)].

    PubMed

    Tullberg, K; Jacobi, H

    1978-01-01

    Isolated rat stomach strips were used to study the antagonism between psychotropic drugs and prostaglandin. It was found that the inhibited prostaglandin effect registered under the influence of psychotropic drugs in due not so much to the inhibition of synthetase action but rather to an inhibitory action on liberated prostaglandin. An atropine-like effect of the psychotropic drugs or an inhibition in the formation of endogenic prostaglandin in the walls are ruled out as possible explanations. The following possible explanations were discussed: a) the tested psychotropic drugs block prostaglandin receptors in the stomach; b) the test substances react with prostaglandin in the nutritive solution; c) the substances stimulate metabolic processes in the stomach wall that break down prostaglandin.

  16. Non-steroidal anti-inflammatory drugs and prostaglandin effects on pepsinogen secretion by dispersed human peptic cells.

    PubMed Central

    Lanas, A I; Nerín, J; Esteva, F; Sáinz, R

    1995-01-01

    The effects of aspirin and ibuprofen on pepsinogen secretion were studied in isolated human peptic cells prepared from endoscopically obtained biopsy specimens after collagenase digestion, mechanical disruption, and percoll gradient centrifugation. Pharmacological concentrations of aspirin and ibuprofen (10(-8)-10(-4) M), potentiated histamine (10(-6)-10(-4)M) and forskolin (10(-5)M) stimulated pepsinogen secretion without affecting basal secretion, acetylcholine (10(-6)M) stimulated pepsinogen secretion or cell vitality. Augmentation of secretagogue stimulated pepsinogen secretion was dependent on extracellular calcium because potentiation was abolished by calcium depletion of the medium. Cimetidine inhibited the potentiation effect on histamine but not on forskolin stimulated pepsinogen secretion, thus suggesting that this augmentation was independent of histamine H2 receptors. Of interest, potentiation was also independent of endogenous prostaglandin inhibition because exogenous addition of prostaglandin E2 and D2 increased both basal and acetylcholine stimulated pepsinogen secretion in a dose dependent way, but they did not modify histamine or histamine plus aspirin or ibuprofen stimulated pepsinogen secretion. In conclusion, aspirin and ibuprofen potentiate secretagogue stimulated pepsinogen secretion by dispersed human peptic cells and this might be an additional mechanism of non-steroidal anti-inflammatory drug (NSAID) induced gastric injury. This potentiation effect is regulated by calcium, independent of endogenous prostaglandin inhibition and seems to act on pepsinogen secretion at a post-receptor site. PMID:7797113

  17. Cellular mechanisms underlying prostaglandin-induced transient cAMP signals near the plasma membrane of HEK-293 cells

    PubMed Central

    Rich, Thomas; Xin, Wenkuan; Mehats, Céline; Hassell, Kathryn; Piggott, Leslie; Le, Xuan; Karpen, Jeffrey; Conti, Marco

    2007-01-01

    We have previously used cyclic nucleotide-gated (CNG) channels as sensors to measure cAMP signals in human embryonic kidney (HEK)-293 cells. We found that prostaglandin E1 (PGE1) triggered transient increases in cAMP concentration near the plasma membrane, whereas total cAMP levels rose to a steady plateau over the same time course. In addition, we presented evidence that the decline in the near-membrane cAMP levels was due primarily to a PGE1-induced stimulation of phosphodiesterase (PDE) activity, and that the differences between near-membrane and total cAMP levels were largely due to diffusional barriers and differential PDE activity. Here, we examine the mechanisms regulating transient, near-membrane cAMP signals. We observed that 5-min stimulation of HEK-293 cells with prostaglandins triggered a two- to threefold increase in PDE4 activity. Extracellular application of H89 (a PKA inhibitor) inhibited stimulation of PDE4 activity. Similarly, when we used CNG channels to monitor cAMP signals we found that both extracellular and intracellular (via the whole-cell patch pipette) application of H89, or the highly selective PKA inhibitor, PKI, prevented the decline in prostaglandin-induced responses. Following pretreatment with rolipram (a PDE4 inhibitor), H89 had little or no effect on near-membrane or total cAMP levels. Furthermore, disrupting the subcellular localization of PKA with the A-kinase anchoring protein (AKAP) disruptor Ht31 prevented the decline in the transient response. Based on these data we developed a plausible kinetic model that describes prostaglandin-induced cAMP signals. This model has allowed us to quantitatively demonstrate the importance of PKA-mediated stimulation of PDE4 activity in shaping near-membrane cAMP signals. PMID:16899551

  18. Feedback Control of the Arachidonate Cascade in Osteoblastic Cells by 15-deoxy-Δ12,14-Prostaglandin J2

    PubMed Central

    Ishino, Hidetaka; Kawahito, Yutaka; Tsubouchi, Yasunori; Kohno, Masataka; Wada, Makoto; Yamamoto, Aihiro; Hamaguchi, Masahide; Kadoya, Masatoshi; Tokunaga, Daisaku; Hojo, Tatsuya; Matsuyama, Masahide; Yoshimura, Rikio; Yoshikawa, Toshikazu

    2008-01-01

    15-deoxy-Δ12,14-prostaglandin J2 (15d-PGJ2) and an anti-diabetic thiazolidinedione, troglitazone (TRO) are peroxisome proliferator-activated receptor (PPAR)-γ ligands, which regulate immuno-inflammatory reactions as well as adipocyte differentiation. We previously reported that 15d-PGJ2 can suppress interleukin (IL)-1β-induced prostaglandin E2 (PGE2) synthesis in synoviocytes of rheumatoid arthritis (RA). IL-1 also stimulates PGE2 synthesis in osteoblasts by regulation of cyclooxygenase (COX)-2 and regulates osteoclastic bone resorption in various diseases such as RA and osteoporosis. In this study, we investigated the feedback mechanism of the arachidonate cascade in mouse osteoblastic cells, MC3T3-E1 cells, which differentiate into mature osteoblasts. Treatment with 15d-PGJ2 led to a significant increase in IL-1α-induced COX-2 expression and PGE2 production in a dose dependent manner. The effect of 15d-PGJ2 was stronger than that of TRO. However, it did not affect the expression of COX-1. In addition, cell viability of MC3T3-E1 cells was not changed in the condition we established. This means that 15d-PGJ2 exerts a positive feedback regulation of the arachidonate cascade of PGE2 in osteoblastic cells. These results may provide important information about the pathogenesis and treatment of bone resorption in a variety of diseases such as RA and osteoporosis. PMID:18231633

  19. Effects of centrally administered prostaglandin E(3) and thromboxane A(3) on plasma noradrenaline and adrenaline in rats: comparison with prostaglandin E(2) and thromboxane A(2).

    PubMed

    Shimizu, Takahiro; Yokotani, Kunihiko

    2009-06-02

    Previously, we reported the involvement of brain omega-6 prostanoids, especially prostaglandin E(2) and thromboxane A(2), in the activation of central sympatho-adrenomedullary outflow in rats. omega-3 Prostanoids, including prostaglandin E(3) and thromboxane A(3), are believed to be less bioactive than omega-6 prostanoids, although studies on the functions of omega-3 prostanoids in the central nervous system have not been reported. In the present study, therefore, we compared the effects of centrally administered omega-3 prostanoids, prostaglandin E(3) and thromboxane A(3), with those of omega-6 prostanoids, prostaglandin E(2) and thromboxane A(2), on the plasma catecholamines in anesthetized rats. Intracerebroventricularly (i.c.v.) administered prostaglandin E(2) (0.15, 0.3 and 1.5 nmol/animal) and prostaglandin E(3) (0.3 and 3 nmol/animal) predominantly elevated plasma noradrenaline but not adrenaline, but the latter was less efficient than the former. On the other hand, U-46619 (an analog of thromboxane A(2)) (30, 100 and 300 nmol/animal, i.c.v.) and Delta(17)-U-46619 (an analog of thromboxane A(3)) (100 and 300 nmol/animal, i.c.v.) both elevated plasma catecholamines (adrenaline>noradrenaline) to the same degree. These results suggest that centrally administered prostaglandin E(3) is less effective than prostaglandin E(2) to elevate plasma noradrenaline, and that thromboxane A(3) is almost as equipotent as thromboxane A(2) to elevate plasma catecholamines in rats.

  20. Induction of labor using prostaglandin vaginal gel: cost analysis comparing early amniotomy with repeat prostaglandin gel.

    PubMed

    Beckmann, Michael; Merollini, Katharina; Kumar, Sailesh; Flenady, Vicki

    2016-04-01

    In a randomized controlled trial of two policies for induction of labor (IOL) using Prostaglandin E2 (PGE2) vaginal gel, women who had an earlier amniotomy experienced a shorter IOL-to-birth time. To report the cost analysis of this trial and determine if there are differences in healthcare costs when an early amniotomy is performed as opposed to giving more PGE2 vaginal gel, for women undergoing IOL at term. Following an evening dose of PGE2 vaginal gel, 245 women with live singleton pregnancies, ≥37+0 weeks, were randomized into an amniotomy or repeat-PGE2 group. Healthcare costs were a secondary outcome measure, sourced from hospital finance systems and included staff costs, equipment and consumables, pharmacy, pathology, hotel services and business overheads. A decision analytic model, specifically a Markov chain, was developed to further investigate costs, and a Monte Carlo simulation was performed to confirm the robustness of these findings. Mean and median costs and cost differences between the two groups are reported, from the hospital perspective. The healthcare costs associated with IOL were available for all 245 trial participants. A 1000-patient cohort simulation demonstrated that performing an early amniotomy was associated with a cost-saving of $AUD289 ($AUD7094 vs $AUD7338) per woman induced, compared with administering more PGE2. Propagating the uncertainty through the model 10,000 times, early amniotomy was associated with a median cost savings of $AUD487 (IQR -$AUD573, +$AUD1498). After an initial dose of PGE2 vaginal gel, a policy of administering more PGE2 when the Modified Bishop's score is <7 was associated with increased healthcare costs compared with a policy of performing an amniotomy, if technically possible. Length of stay was the main driver of healthcare costs. Co