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Sample records for prostaglandin transporter slco2a1

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

    PubMed

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

    2015-01-01

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

  2. Identification of the Mutations in the Prostaglandin Transporter Gene, SLCO2A1 and Clinical Characterization in Korean Patients with Pachydermoperiostosis

    PubMed Central

    2016-01-01

    Pachydermoperiostosis (PDP), or primary hypertrophic osteoarthropathy, is a rare genetic disease affecting both skin and bones. Both autosomal dominant with incomplete penetrance and recessive inheritance of PDP have been previously confirmed. Recently, hydroxyprostaglandin dehydrogenase (HPGD) and solute carrier organic anion transporter family member 2A1 (SLCO2A1) were reported as pathogenic genes responsible for PDP. Both genes are involved in prostaglandin E2 (PGE2) degradation. We aimed to identify responsible genes for PDP and the clinical features in Korean patients with PDP. Six affected individuals and their available healthy family members from three unrelated Korean families with PDP were studied. All of the patients displayed complete phenotypes of PDP with finger clubbing, pachydermia, and periostosis. Mutation analysis revealed a novel heterozygous mutation in the SLCO2A1 gene at nucleotide 302 causing a substitution of the amino acid isoleucine to serine at codon 101 (p.IIe101Ser) in affected individuals. We also identified known SLCO2A1 mutations, one homozygous for c.940+1G>A, and another compound heterozygous for c.940+1G>A and c.1807C>T (p.Arg603*) from two PDP families. Genetic analyses of the PDP patients showed no abnormality in the HPGD gene. Our study further supports the role of mutations in the SLCO2A1 gene in the pathogenesis of PDP and could provide additional clues to the genotype-phenotype relations of PDP. PMID:27134495

  3. Influence of Genetic Polymorphisms in Prostaglandin E2 Pathway (COX-2/HPGD/SLCO2A1/ABCC4) on the Risk for Colorectal Adenoma Development and Recurrence after Polypectomy

    PubMed Central

    Pereira, Carina; Queirós, Sara; Galaghar, Ana; Sousa, Hugo; Marcos-Pinto, Ricardo; Pimentel-Nunes, Pedro; Brandão, Catarina; Medeiros, Rui; Dinis-Ribeiro, Mário

    2016-01-01

    Objectives: Deregulation of prostaglandin E2 (PGE2) levels reported in colorectal carcinogenesis contributes to key steps of cancer development. Our aim was to evaluate the influence of the genetic variability in COX-2/HPGD/SLCO2A1/ABCC4 PGE2 pathway genes on the development and recurrence of colorectal adenomas. Methods: A case-control study was conducted gathering 480 unscreened individuals and 195 patients with personal history of adenomas. A total of 43 tagSNPs were characterized using the Sequenom platform or real-time PCR. Results: Ten tagSNPs were identified as susceptibility biomarkers for the development of adenomas. The top three most meaningful tagSNPs include the rs689466 in COX-2 (odds ratio (OR)=3.23; 95% confidence interval (CI): 1.52–6.86), rs6439448 in SLCO2A1 (OR=0.38; 95% CI: 0.22–0.65) and rs1751051 in ABCC4 genes (OR=2.75; 95% CI: 1.58–4.80). The best four-locus gene–gene interaction model included the rs1346271, rs1863642 and rs12500316 single nucleotide polymorphisms in HPGD and rs1678405 in ABCC4 genes and was associated with a 13-fold increased susceptibility (95% CI: 3.84–46.3, P<0.0001, cross-validation (CV) accuracy: 0.78 and CV consistency: 8/10). Interesting, in low-risk patients the ABCC4 rs9524821AA genotype was associated not only with a higher hazard ratio (HR=2.93; 95% CI: 1.07–8.03), but half of these patients had adenoma recurrence at 60 months, considerably higher than the 21% noticed in low-risk patients. Conclusions: Genetic polymorphisms in COX-2/PGE2 pathway appear to contribute to the development of colorectal adenomas and influence the interval time to adenomas recurrence. The definition of risk models through the inclusion of genetic biomarkers might improve the adherence and optimization of current screening and surveillance guidelines for colorectal cancer prevention. PMID:27628421

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

    PubMed Central

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

    2015-01-01

    Peripheral ischemia, resulting from diminished arterial flow and defective local vascularization, is one of the main causes of impaired wound healing in diabetes. Vasodilatory prostaglandins (PGs), including PGE2 and PGI2, regulate blood flow in peripheral tissues. PGs also stimulate angiogenesis by inducing vascular endothelial growth factor. However, PG levels are reduced in diabetes mainly due to enhanced degradation. We hypothesized that inhibition of the prostaglandin transporter (PGT) (SLCO2A1), which mediates the degradation of PGs, would increase blood flow and stimulate vascularization, thereby mitigating peripheral ischemia and accelerating wound healing in diabetes. Here we report that inhibiting PGT with intravenously injected PGT inhibitor, T26A, increased blood flow in ischemic hind limbs created in non-diabetic rats and streptozotocin induced diabetic rats. Systemic, or combined with topical, T26A accelerated closure of cutaneous wounds. Immunohistochemical examination revealed that inhibition of PGT enhanced vascularization (marked by larger numbers of vessels formed by CD34+ cells), and accelerated re-epithelialization of cutaneous wounds. In cultured primary human bone marrow CD34+ cells and human epidermal keratinocytes (HEKs) either inhibiting or silencing PGT increased migration in both cell lines. Thus PGT directly regulates mobilization of endothelial progenitor cells (EPCs) and HEKs, which could contribute to PGT-mediated vascularization and re-epithelialization. At the molecular level, systemic inhibition of PGT raised circulating PGE2. Taken together, our data demonstrate that PGT modulates arterial blood flow, mobilization of EPCs and HEKs, and vascularization and epithelialization in wound healing by regulating vasodilatory and pro-angiogenic PGs. PMID:26230411

  5. 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.

  6. 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

  7. Ceramide 1-Phosphate Increases P-Glycoprotein Transport Activity at the Blood-Brain Barrier via Prostaglandin E2 Signaling.

    PubMed

    Mesev, Emily V; Miller, David S; Cannon, Ronald E

    2017-04-01

    P-glycoprotein, an ATP-driven efflux pump, regulates permeability of the blood-brain barrier (BBB). Sphingolipids, endogenous to brain tissue, influence inflammatory responses and cell survival in vitro. Our laboratory has previously shown that sphingolipid signaling by sphingosine 1-phosphate decreases basal P-glycoprotein transport activity. Here, we investigated the potential for another sphingolipid, ceramide 1-phosphate (C1P), to modulate efflux pumps at the BBB. Using confocal microscopy and measuring luminal accumulation of fluorescent substrates, we assessed the transport activity of several efflux pumps in isolated rat brain capillaries. C1P treatment induced P-glycoprotein transport activity in brain capillaries rapidly and reversibly. In contrast, C1P did not affect transport activity of two other major efflux transporters, multidrug resistance protein 2 and breast cancer resistance protein. C1P induced P-glycoprotein transport activity without changing transporter protein expression. Inhibition of the key signaling components in the cyclooxygenase-2 (COX-2)/prostaglandin E2 signaling cascade (phospholipase A2, COX-2, multidrug resistance protein 4, and G-protein-coupled prostaglandin E2 receptors 1 and 2), abolished P-glycoprotein induction by C1P. We show that COX-2 and prostaglandin E2 are required for C1P-mediated increases in P-glycoprotein activity independent of transporter protein expression. This work describes how C1P activates a signaling cascade to dynamically regulate P-glycoprotein transport at the BBB and offers potential clinical targets to modulate neuroprotection and drug delivery to the CNS.

  8. Ceramide 1-Phosphate Increases P-Glycoprotein Transport Activity at the Blood-Brain Barrier via Prostaglandin E2 Signaling

    PubMed Central

    Mesev, Emily V.; Miller, David S.

    2017-01-01

    P-glycoprotein, an ATP-driven efflux pump, regulates permeability of the blood-brain barrier (BBB). Sphingolipids, endogenous to brain tissue, influence inflammatory responses and cell survival in vitro. Our laboratory has previously shown that sphingolipid signaling by sphingosine 1-phosphate decreases basal P-glycoprotein transport activity. Here, we investigated the potential for another sphingolipid, ceramide 1-phosphate (C1P), to modulate efflux pumps at the BBB. Using confocal microscopy and measuring luminal accumulation of fluorescent substrates, we assessed the transport activity of several efflux pumps in isolated rat brain capillaries. C1P treatment induced P-glycoprotein transport activity in brain capillaries rapidly and reversibly. In contrast, C1P did not affect transport activity of two other major efflux transporters, multidrug resistance protein 2 and breast cancer resistance protein. C1P induced P-glycoprotein transport activity without changing transporter protein expression. Inhibition of the key signaling components in the cyclooxygenase-2 (COX-2)/prostaglandin E2 signaling cascade (phospholipase A2, COX-2, multidrug resistance protein 4, and G-protein–coupled prostaglandin E2 receptors 1 and 2), abolished P-glycoprotein induction by C1P. We show that COX-2 and prostaglandin E2 are required for C1P-mediated increases in P-glycoprotein activity independent of transporter protein expression. This work describes how C1P activates a signaling cascade to dynamically regulate P-glycoprotein transport at the BBB and offers potential clinical targets to modulate neuroprotection and drug delivery to the CNS. PMID:28119480

  9. Glucocorticoid mediates the transcription of OAT-PG, a kidney-specific prostaglandin transporter.

    PubMed

    Hatano, Ryo; Mukouchi, Hiroki; Matsumoto, Yosuke; Kawaguchi, Kotoku; Kazama, Itsuro; Endo, Yasuhiro; Toyama, Hiroaki; Ejima, Yutaka; Kurosawa, Shin; Kanai, Yoshikatsu; Matsubara, Mitsunobu; Asano, Shinji

    2014-05-01

    OAT-PG is a kidney-specific prostaglandin transporter and exclusively expressed at the basolateral membrane of proximal tubules in rodent kidneys. We previously reported that OAT-PG was dominantly expressed in the male kidney similar to the other SLC22 family proteins as organic anion transporter (OAT) 1 and OAT3. Recently, Wegner et al. revealed that a transcription factor, B-cell CLL/lymphoma 6 (BCL6), is associated with the male-dominant expressions of OAT1 and OAT3 in the rat kidney. Here, we performed the luciferase assay to investigate whether OAT-PG is also transcriptionally regulated by BCL6. However, the promoter activity of OAT-PG was not directly affected by BCL6 overexpression nor the testosterone treatment, suggesting that different regulatory mechanisms underlie the male-dominant transcriptional regulation of OAT-PG compared to those of OAT1 and OAT3. We newly found that adrenalectomy (Adx) of male rat caused a significant reduction of OAT-PG expression without any significant changes in the OAT1 and OAT3 expressions, and it was recovered by the dexamethasone administration. Furthermore, the renocortical PGE2 concentration was markedly increased in Adx male rat, concomitant with the downregulation of OAT-PG, and it was reduced to the basal level by dexamethasone treatment. In the luciferase assay, dexamethasone stimulated OAT-PG promoter activity but not OAT1. The luciferase activity responsiveness to dexamethasone was significantly reduced by the deletion of glucocorticoid response elements in the OAT-PG promoter region. These results suggest that glucocorticoid plays an important role in the regulation of the renocortical PGE2 concentration by the transcriptional regulation of OAT-PG in the rat kidney.

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

    PubMed Central

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

    2014-01-01

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

  11. Multispecific Organic Cation Transporter 1 (OCT1) from Bos taurus Has High Affinity and Slow Binding Kinetics towards Prostaglandin E2

    PubMed Central

    He, Xiao; Garza, Denisse; Nigam, Sanjay K.; Chang, Geoffrey

    2016-01-01

    Organic cation transporter 1 (OCT1, SLC22A1), like many solute carrier 22 (SLC22) family members, is important for the disposition of clinically important drugs, metabolites and signaling molecules. Several studies suggest that SLC22 family (eg. organic anion transporters or OATs and OCTs) bind and possibly transport prostaglandins with relatively high affinity (submicromolar). The affinities of OCT1 and OATs toward PGE2 and PGF2a reported in these cell-based transport studies are considerably greater than for xenobiotics and natural metabolite substrates—in many cases over 100-fold higher. This raises the possibility that prostaglandins are key endogenous substrates and/or that they act on the transporter in a manner different from other substrates such as xenobiotics and lower affinity metabolites. To further investigate OCT1—prostaglandin interactions, we designed biophysical studies using purified bovine OCT1 (Bos taurus, btOCT1/SLC22A1) with PGE2 analogs, in fluorescently labeled and label-free formats. Using fluorescence polarization (FP), we detected a binding of btOCT1 to the PGE2-Rhodamine conjugate at submicromolar affinity, consistent with affinity data for PGE2 from cells over-expressing the related human OCT1. Using purified native btOCT1 as analyte and biotinylated PGE2 analog as ligand, our data from surface plasmon resonance (SPR) revealed that btOCT1 specifically interacts to PGE2 with KD values in the hundred nanomolar range. BtOCT1 also demonstrated a slow association (ka) in the range of 103 M-1s-1 and an even slower dissociation rate (kd) in the range of 10−4 s-1 for PGE2, suggesting the possibility of a different mode of binding compared to other structurally unrelated transported substrates of low-affinity (eg. drugs, metabolites). Our results complement in vitro transport studies and provide direct evidence that OCT1—which is normally expressed in liver and other tissues—interacts with prostaglandin analogs. While it is not

  12. Multispecific Organic Cation Transporter 1 (OCT1) from Bos taurus Has High Affinity and Slow Binding Kinetics towards Prostaglandin E2.

    PubMed

    He, Xiao; Garza, Denisse; Nigam, Sanjay K; Chang, Geoffrey

    2016-01-01

    Organic cation transporter 1 (OCT1, SLC22A1), like many solute carrier 22 (SLC22) family members, is important for the disposition of clinically important drugs, metabolites and signaling molecules. Several studies suggest that SLC22 family (eg. organic anion transporters or OATs and OCTs) bind and possibly transport prostaglandins with relatively high affinity (submicromolar). The affinities of OCT1 and OATs toward PGE2 and PGF2a reported in these cell-based transport studies are considerably greater than for xenobiotics and natural metabolite substrates--in many cases over 100-fold higher. This raises the possibility that prostaglandins are key endogenous substrates and/or that they act on the transporter in a manner different from other substrates such as xenobiotics and lower affinity metabolites. To further investigate OCT1-prostaglandin interactions, we designed biophysical studies using purified bovine OCT1 (Bos taurus, btOCT1/SLC22A1) with PGE2 analogs, in fluorescently labeled and label-free formats. Using fluorescence polarization (FP), we detected a binding of btOCT1 to the PGE2-Rhodamine conjugate at submicromolar affinity, consistent with affinity data for PGE2 from cells over-expressing the related human OCT1. Using purified native btOCT1 as analyte and biotinylated PGE2 analog as ligand, our data from surface plasmon resonance (SPR) revealed that btOCT1 specifically interacts to PGE2 with KD values in the hundred nanomolar range. BtOCT1 also demonstrated a slow association (ka) in the range of 103 M(-1) s(-1) and an even slower dissociation rate (kd) in the range of 10-4 s(-1) for PGE2, suggesting the possibility of a different mode of binding compared to other structurally unrelated transported substrates of low-affinity (eg. drugs, metabolites). Our results complement in vitro transport studies and provide direct evidence that OCT1--which is normally expressed in liver and other tissues--interacts with prostaglandin analogs. While it is not

  13. N-linked glycans do not affect plasma membrane localization of multidrug resistance protein 4 (MRP4) but selectively alter its prostaglandin E2 transport activity.

    PubMed

    Miah, M Fahad; Conseil, Gwenaëlle; Cole, Susan P C

    2016-01-22

    Multidrug resistance protein 4 (MRP4) is a member of subfamily C of the ATP-binding cassette superfamily of membrane transport proteins. MRP4 mediates the ATP-dependent efflux of many endogenous and exogenous solutes across the plasma membrane, and in polarized cells, it localizes to the apical or basolateral plasma membrane depending on the tissue type. MRP4 is a 170 kDa glycoprotein and here we show that MRP4 is simultaneously N-glycosylated at Asn746 and Asn754. Furthermore, confocal immunofluorescence studies showed that N-glycans do not affect MRP4's apical membrane localization in polarized LLC-PK1 cells or basolateral membrane localization in polarized MDCKI cells. However, vesicular transport assays showed that N-glycans differentially affect MRP4's ability to transport prostaglandin E2, but not estradiol glucuronide. Together these data indicate that N-glycosylation at Asn746 and Asn754 is not essential for plasma membrane localization of MRP4 but cause substrate-selective effects on its transport activity.

  14. 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

  15. Sex hormones induce a gender-related difference in renal expression of a novel prostaglandin transporter, OAT-PG, influencing basal PGE2 concentration.

    PubMed

    Hatano, Ryo; Onoe, Kimitaka; Obara, Masaya; Matsubara, Mitsunobu; Kanai, Yoshikatsu; Muto, Shigeaki; Asano, Shinji

    2012-02-01

    Based on the nucleotide sequence of a mouse prostaglandin-specific transporter (mOAT-PG), we identified a rat homolog (rOAT-PG) which shares 80% identity with mOAT-PG in a deduced amino acid sequence. rOAT-PG transports PGE(2) and colocalizes with 15-hydroxyprostaglandin dehydrogenase (15-PGDH), a metabolic enzyme for PGs, in proximal tubules, suggesting that rOAT-PG is involved in PGE(2) clearance to regulate its physiological function in the renal cortex. We found that the expression level of rOAT-PG in the renal cortex was much higher in male rats than in female rats whereas there was no gender difference in the expression level of cyclooxygenase-2, a key enzyme producing PGE(2), and 15-PGDH in the renal cortex. Tissue PGE(2) concentration in the renal cortex was lower in male rats than in female rats, suggesting that renocortical PGE(2) concentration is primarily determined by the expression level of OAT-PG, which is regulated differently between male and female rats. Castration of male rat led to a remarkable reduction in OAT-PG expression and a significant increase in renocortical PGE(2) concentration. These alterations were recovered by testosterone supplementation. These results suggest that OAT-PG is involved in local PGE(2) clearance in the renal cortex. Although the physiological importance of the gender difference in local PGE(2) clearance is still unclear, these findings might be a key to clarifying the physiological roles of PGE(2) in the kidney.

  16. Role of the blood-cerebrospinal fluid barrier transporter as a cerebral clearance system for prostaglandin E₂ produced in the brain.

    PubMed

    Tachikawa, Masanori; Ozeki, Go; Higuchi, Takanori; Akanuma, Shin-Ichi; Tsuji, Kazuhiro; Hosoya, Ken-Ichi

    2012-12-01

    An increasing level of prostaglandin (PG) E(2) is involved in the progression of neuroinflammation induced by ischemia and bacterial infection. Although an imbalance in the rates of production and clearance of PGE(2) under these pathological conditions appears to affect the concentration of PGE(2) in the cerebrospinal fluid (CSF), the regulatory system remains incompletely understood. The purpose of this study was to investigate the cellular system of PGE(2) production via microsomal PGE synthetase-1 (mPGES-1), the inducible PGE(2) -generating enzyme, and PGE(2) elimination from the CSF via the blood-CSF barrier (BCSFB). Immunohistochemical analysis revealed that mPGES-1 was expressed in the soma and perivascular sheets of astrocytes, pia mater, and brain blood vessel endothelial cells, suggesting that these cells are local production sites of PGE(2) in the CSF. The in vivo PGE(2) elimination clearance from the CSF was eightfold greater than that of d-mannitol, which is considered to reflect CSF bulk flow. This process was inhibited by the simultaneous injection of unlabeled PGE(2) and β-lactam antibiotics, such as benzylpenicillin, cefazolin, and ceftriaxone, which are substrates and/or inhibitors of organic anion transporter 3 (OAT3). The characteristics of PGE(2) uptake by the isolated choroid plexus were at least partially consistent with those of OAT3. OAT3 was able to mediate PGE(2) transport with a Michaelis-Menten constant of 4.24 μM. These findings indicate that a system regulating the PGE(2) level in the CSF involves OAT3-mediated PGE(2) uptake by choroid plexus epithelial cells, acting as a cerebral clearance pathway via the BCSFB of locally produced PGE(2) .

  17. 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

  18. 8-iso-prostaglandin-F2α stimulates chloride transport in thick ascending limbs: role of cAMP and protein kinase A.

    PubMed

    Cabral, Pablo D; Silva, Guillermo B; Baigorria, Sandra T; Juncos, Luis A; Juncos, Luis I; García, Néstor H

    2010-12-01

    Salt reabsorption by the loop of Henle controls NaCl handling and blood pressure regulation. Increased oxidative stress stimulates NaCl transport in one specific segment of the loop of Henle called the thick ascending limb (TAL). The isoprostane 8-iso-prostaglandin-F2α (8-iso-PGF2α) is one of the most abundant nonenzymatic lipid oxidation products and has been implicated in the development of hypertension. However, it is not known whether 8-iso-PGF2α regulates transport or the mechanisms involved. Because protein kinase A (PKA) stimulates NaCl transport in several nephron segments, we hypothesized that 8-iso-PGF2α increases NaCl transport in the cortical TAL (cTAL) via a PKA-dependent mechanism. We examined the effect of luminal 8-iso-PGF2α on NaCl transport by measuring chloride absorption (J(Cl)) in isolated microperfused cTALs. Adding 8-iso-PGF2α to the lumen increased J(Cl) by 54% (from 288.7 ± 30.6 to 446.5 ± 44.3 pmol·min(-1)·mm(-1); P < 0.01), while adding it to the bath enhanced J(Cl) by 35% (from 236.3 ± 35.3 to 319.2 ± 39.8 pmol·min(-1)·mm(-1); P < 0.05). This stimulation was blocked by Na-K-2Cl cotransporter inhibition. Next, we tested the role of cAMP. Basal cAMP in the cTAL was 18.6 ± 1.6 fmol·min(-1)·mm(-1), and 8-iso-PGF2α raised it to 35.1 ± 1.4 fmol·min(-1)·mm(-1), an increase of 94% (P < 0.01). Because cAMP stimulates PKA, we measured J(Cl) using the PKA-selective inhibitor H89. In the presence of H89 (10 μM), 8-iso-PGF2α failed to increase transport regardless of whether it was added to the lumen (216.1 ± 16.7 vs. 209.7 ± 23.8 pmol·min(-1)·mm(-1); NS) or the bath (150.4 ± 32.9 vs. 127.1 ± 28.6 pmol·min(-1)·mm(-1); NS). We concluded that 8-iso-PGF2α stimulates cAMP and increases Cl transport in cTALs via a PKA-dependent mechanism.

  19. 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

  20. 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.

  1. 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

  2. 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.

  3. 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

  4. 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.

  5. 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.

  6. 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.

  7. Prostaglandins and their receptors in insect biology

    Technology Transfer Automated Retrieval System (TEKTRAN)

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

  8. 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.

  9. Protective effects of prostaglandins in the isolated gastric mucosa of the eel, Anguilla anguilla.

    PubMed

    Faggio, C; Denaro, M G; Lionetto, M G; Trischitta, F

    2000-09-01

    The protective effect of endogenous prostaglandins on the fish gastric mucosa was evaluated by studying the effect of indomethacin and aspirin, known cyclooxigenase inhibitors, on the mucosal ulceration in the isolated gastric sacs of Anguilla anguilla. Gastric sacs devoid of muscle layers were incubated in the presence of indomethacin (10(-4) mol x l(-1)) or aspirin (10(-4) mol x l(-1)) in different experimental conditions. Both the antiinflammatory drugs produced ulcers, but the effects were more severe in the presence of histamine and in the absence of HCO3- in the incubation bath. The effects of prostaglandin E2 (PGE2) on acid secretion rate (J(H)) and on alkaline secretion rate (J(OH)) were evaluated (with the aid of the pH stat method) in isolated gastric mucosa mounted in Ussing chambers. We found that PGE2 (10(-8)-10(-5) mol x l(-1)) increased JH in a dose-dependent manner. In tissues pretreated with luminal omeprazole (10(-4) mol x l(-1)), PGE2 stimulated gastric alkaline secretion. It was nullified by serosal removal of HCO3- or Na+ and by serosal ouabain (10(-4) mol x l(-1)). These results suggested that prostaglandins also exert their protective effects in fish gastric mucosa. This protection seems partially due to a stimulation of exogenous HCO3- transport from the serosal to the mucosal side. It is likely that this transport is an active transcellular mechanism coupled to Na+ transport.

  10. 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

  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. 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.

  13. 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

  14. 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.

  15. TRANSPORT

    EPA Science Inventory

    Presentation outline: transport principles, effective solubility; gasoline composition; and field examples (plume diving).
    Presentation conclusions: MTBE transport follows from - phyiscal and chemical properties and hydrology. Field examples show: MTBE plumes > benzene plu...

  16. 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.

  17. 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

  18. 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.

  19. 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.

  20. [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.

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

    PubMed

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

    2015-01-01

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

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

    PubMed Central

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

    2016-01-01

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

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

    PubMed

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

    2016-01-01

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

  4. Role of cytosolic phospholipase A2 in cytokine-stimulated prostaglandin release by human gallbladder cells.

    PubMed

    Grossmann, E M; Longo, W E; Mazuski, J E; Panesar, N; Kaminski, D L

    2000-01-01

    Eicosanoids are involved in gallbladder inflammation, epithelial water transport, and mucous secretion. Phospholipase Asubscript2 enzymes liberate arachidonic acid from membrane phospholipids for the synthesis of eicosanoids. The purpose of this study was to determine the effect of selective cytoplasmic and secretory phospholipase A2 inhibitors on basal and stimulated arachidonic acid and prostaglandin E2 release in gallbladder cells. Western immunoblotting was employed to evaluate both cytosolic and secretory phospholipase A2 enzymes in human gallbladder cells. Cells were incubated for 22 hours with (3)H-labeled arachidonic acid. Arachidonic acid and prostaglandin E2 release was then measured in the supernate after 2 hours of exposure to human interleukin-1beta, alone or after pretreatment for 1 hour with the inhibitors. Unstimulated gallbladder cells express both 85 kDa cytosolic and 14 kDa secretory phospholipase A2++. The 85 kDa phospholipase A2 was induced by interleukin-1beta, whereas there was no apparent change in secretory phospholipase A2 enzyme concentrations. Both the secretory phospholipase A2 inhibitor p-bromophenylacyl bromide and the cytosolic phospholipase A2 inhibitor arachidonyl trifluoromethyl ketone decreased basal and interleukin-1beta-stimulated arachidonic acid release. In contrast, only inhibition of cytosolic phospholipase A2 led to a decrease in interleukin-1beta-stimulated prostaglandin E2 release. Basal and interleukin-1beta-stimulated arachidonic acid release appears to be the result of the activity of both cytosolic and secretory phospholipase A2. Interleukin-1beta-stimulated prostaglandin E2 release appears to be dependent on the activity of cytosolic phospholipase A2.

  5. 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.

  6. 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

  7. 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.

  8. Rabbit blastocysts accumulate [3H]prostaglandins in vitro.

    PubMed

    Jones, M A; Harper, M J

    1984-08-01

    Rabbit blastocysts obtained on days 5, 6, and 6.8 of pregnancy were incubated in vitro in Tyrode's buffer with 3H-labeled prostaglandins (PGs). Accumulation of PGs was studied, using Whatman GF/F filters to separate bound and free ligands. The uptake and efflux of [3H]PGs were studied as a function of PG type, incubation time, temperature, and effect of metabolic inhibitors as well as age and number of blastocysts. Blastocysts of the same age accumulated approximately the same amount of [3H]PGE2 and [3H]PGF2 alpha from their environment; however, there was no apparent saturation over a PG concentration range of 1-1000 nM. Both the uptake and efflux of PG were age dependent, with older blastocysts accumulating more PGs. Approximately 90% of the [3H]PGs appear to be transported into the blastocoelic fluid, with little PG remaining in the blastomeres. PG accumulation was relatively insensitive to azide, ouabain, cyanide, or bromcresol green, but was affected by incubation at 0 C or the addition of indomethacin (10 micrograms/ml). No catabolism of the accumulated PGs was observed. The release of PGE2 in general did not differ from that of PGF2 alpha, except on day 6.8 of pregnancy when PGE2 was released more rapidly than on day 6. We conclude that rabbit blastocysts can accumulate PGs from their environment, which may imply a storage potential in the blastocyst and release before implantation.

  9. 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.

  10. 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.

  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. 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.

  13. 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.

  14. 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

  15. 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.

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

    PubMed Central

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

    2012-01-01

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

  17. Rabbit blastocysts accumulate (/sup 3/H)prostaglandins in vitro

    SciTech Connect

    Jones, M.A.; Harper, M.J.

    1984-08-01

    Rabbit blastocysts obtained on days 5, 6, and 6.8 of pregnancy were incubated in vitro in Tyrode's buffer with /sup 3/H-labeled prostaglandins (PGs). Accumulation of PGs was studied, using Whatman GF/F filters to separate bound and free ligands. The uptake and efflux of (/sup 3/H)PGs were studied as a function of PG type, incubation time, temperature, and effect of metabolic inhibitors as well as age and number of blastocysts. Blastocysts of the same age accumulated approximately the same amount of (/sup 3/H)PGE2 and (/sup 3/H)PGF2 alpha from their environment; however, there was no apparent saturation over a PG concentration range of 1-1000 nM. Both the uptake and efflux of PG were age dependent, with older blastocysts accumulating more PGs. Approximately 90% of the (/sup 3/H)PGs appear to be transported into the blastocoelic fluid, with little PG remaining in the blastomeres. PG accumulation was relatively insensitive to azide, ouabain, cyanide, or bromcresol green, but was affected by incubation at 0 C or the addition of indomethacin (10 micrograms/ml). No catabolism of the accumulated PGs was observed. The release of PGE2 in general did not differ from that of PGF2 alpha, except on day 6.8 of pregnancy when PGE2 was released more rapidly than on day 6. The authors conclude that rabbit blastocysts can accumulate PGs from their environment, which may imply a storage potential in the blastocyst and release before implantation.

  18. 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.

  19. 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.

  20. 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

  1. 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.

  2. 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

  3. R-Flurbiprofen Traps Prostaglandins within Cells by Inhibition of Multidrug Resistance-Associated Protein-4

    PubMed Central

    Wobst, Ivonne; Ebert, Lisa; Birod, Kerstin; Wegner, Marthe-Susanna; Hoffmann, Marika; Thomas, Dominique; Angioni, Carlo; Parnham, Michael J.; Steinhilber, Dieter; Tegeder, Irmgard; Geisslinger, Gerd; Grösch, Sabine

    2016-01-01

    R-flurbiprofen is the non-COX-inhibiting enantiomer of flurbiprofen and is not converted to S-flurbiprofen in human cells. Nevertheless, it reduces extracellular prostaglandin E2 (PGE2) in cancer or immune cell cultures and human extracellular fluid. Here, we show that R-flurbiprofen acts through a dual mechanism: (i) it inhibits the translocation of cPLA2α to the plasma membrane and thereby curtails the availability of arachidonic acid and (ii) R-flurbiprofen traps PGE2 inside of the cells by inhibiting multidrug resistance–associated protein 4 (MRP4, ABCC4), which acts as an outward transporter for prostaglandins. Consequently, the effects of R-flurbiprofen were mimicked by RNAi-mediated knockdown of MRP4. Our data show a novel mechanism by which R-flurbiprofen reduces extracellular PGs at physiological concentrations, particularly in cancers with high levels of MRP4, but the mechanism may also contribute to its anti-inflammatory and immune-modulating properties and suggests that it reduces PGs in a site- and context-dependent manner. PMID:28042832

  4. The influence of prostaglandin G2 on platelet ultrastructure and platelet secretion.

    PubMed Central

    Gerrard, J. M.; Townsend, D.; Stoddard, S.; Witkop, C. J.; White, J. G.

    1977-01-01

    Prostaglandin G2 (PGG2) is a labile endoperoxide produced physiologically following exposure of platelets to aggregating agents. We report here studies using isolated PGG2. This agent stimulates a concentration-dependent internal platelet contraction very similar to that produced by the calcium ionophore A23187. EDTA prevented platelet aggregation but did not prevent PGG2-stimulated internal contraction or secretion. In contrast, prostaglandin E1 and dibutyryl cyclic AMP inhich selectively labilizes platelet granules, was added to platelets together with PGG2 there was a superadditive effect on platelet secretion. Thus, granule labilization induced by PMA is a separable phenomenon and complementary to the effect of PGG2 on contraction. The ultimate degree of secretion is dependent on both processes. Studies using additional inhibitors supported the hypothesis that PGG2 activates platelets (either directly or following conversion to thromboxane A2) by transporting calcium from an intracellular store to the cytoplasmic site of the platelet contractile proteins. Images Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 Figure 7 Figure 8 PMID:188341

  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. 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

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

    SciTech Connect

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

    1985-10-25

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

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

    SciTech Connect

    Liston, T.E.

    1985-01-01

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

  9. 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.

  10. 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

  11. Prostaglandin E receptors as inflammatory therapeutic targets for atherosclerosis.

    PubMed

    Yang, Cui; Liu, Xiuxia; Cao, Qing; Liang, Qian; Qiu, Xiaohua

    2011-01-31

    Prostaglandin E receptors (EPs) are the G-protein-coupled receptors (GPCRs) that respond to type E(2) prostaglandin (PGE(2)). Data has shown that PGE(2) may function as an endogenous anti-inflammatory mediator by suppressing the production of cytokines. However, other studies have demonstrated that PGE(2), a pro-inflammatory mediator produced by various cell types within the wounded vascular wall, plays a crucial role in early atherosclerotic development. These contradictory results may be due to the versatility of EPs. Experimental data suggest an individual role for each PGE(2) receptor, such as EP(1), EP(2), EP(3) and EP(4), in atherosclerosis. In this review, the roles of EPs in atherosclerosis are summarized, and the value of EPs as new therapeutic targets for atherosclerosis is explored.

  12. Sex, drugs and sports: prostaglandins, epitestosterone and sexual development.

    PubMed

    Sanders, Bryan K

    2007-01-01

    Amateau and McCarthy's findings published in Nature Neuroscience (June 2004) are noteworthy for suggesting a role for prostaglandins in sexual development. However, evidence suggests that in manipulating PGE2, they unknowingly implicated 3alpha-hydroxysteroid dehydrogenase [E.C. 1.1.1.50], 3(or 17)alpha-hydroxysteroid dehydrogenase [E.C. 1.1.1.209] and their respective products, androsterone (ADT) and epitestosterone (EpiT), in the developmental masculinization of sex behavior. EpiT is generally regarded as a hormonally inactive 17alpha-epimer of testosterone (T). In rats, the kidney is the primary site of EpiT formation, whereas in humans it originates from the gonads, with only a small contribution secreted by the adrenals. Because the ratio of T to EpiT is nearly constant, it is presently used for assessing steroid abuse in competitive sports, where the World Anti-Doping Agency (WADA) considers a T/EpiT ratio >4 evidence of T doping. Despite its central role in the detection of illict anabolic steroid use, our knowledge of factors effecting EpiT production is poor. Clues in the literature, however, reveal that prostaglandin-mediated processes, such as LHRH release, may influence its production. Antimycotics, NSAIDs, and opioid analgesics used in sports medicine are all known to effect prostaglandin E2 synthesis. Primary PGs are potent inhibitors of ADT oxidation, while indomethacin, a prostaglandin blocker, powerfully inhibits 3alpha-HSD reduction and ADT oxidation. This is significant because ADT inhibits the oxidation of EpiT, and may modulate its antiandrogenic and neuroprotective effects. It is hypothesized that the T/EpiT ratio is increased by COX-2 inhibitors and opiod analgesics, and decreased by antimycotics that do not impair testosterone biosynthesis. Given the devastating personal and career consequences that may result from false positive drug tests, substantive research on the effects of PGE2 manipulations on EpiT is warranted.

  13. 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.

  14. 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

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

    SciTech Connect

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

    1988-03-01

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

  16. Mid trimester abortion by one shot administration of prostaglandin.

    PubMed

    Ganguli, A C; Krishna, U R; Mhatre, V S; Purandare, V N

    1977-10-01

    268 cases in which mid trimester abortion in the 2nd trimester of pregnancy was performed by injecting prostaglandins by intra-amniotic route were studied. Details are presented of 1 study in which 100 cases had prostaglandin injected intraamniotically in 1 shot. 50 cases received 50 mg of PGF2a and 40 received 2.5 mg of 15 Methyl PGF2a, an analogue more potent and longer acting. The majority of the patients were primigravida, most of these being unmarried mothers. The average gestation period in both groups was between 17-18 weeks. The average induction onset interval was considerably shorter in PGF2a group, but its abortion time was just about 1 hour less than that of the methyl analogue. The average incidence of vomiting is about 2-folds and that of loose motionsis almost 5 times in the 15 Methyl group. 81% of the patients were followed up, and 86% of this group stopped bleeding within 10 days and the remaining within 20 days. There has not been a single incidence of post abortal infection. The disadvantages associated with the original intravenous administration of prostaglandin have been overcome by using the intra-amniotic routes. 1 of the greatest advantages of 1 shot intra-amniotic PGF2a 50 mg was a low incidence of incomplete abortion. Only 12% of cases in this group had retained placenta compared to 40-50% in the other groups.

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

    DTIC Science & Technology

    2006-05-01

    al. 1996; Trancik et al. 1989). Thus, it is of vital importance to the field of dental implantology to investigate how prostaglandins mediate their...of Texas Graduate School of Biomedical Sciences at San Antonio Supervising Professor: David D. Dean, Ph.D. While the predictability of dental implants...control media lacking PGE2. Cells were incubated for an additional 3, 6, or 120 hrs to simulate the early response after dental implant placement, after

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

    NASA Technical Reports Server (NTRS)

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

    1994-01-01

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

  19. Role of endogenous prostaglandins in protection of rat gastric mucosa by tripotassium dicitrate bismuthate.

    PubMed

    Malandrino, S; Bestetti, A; Fumagalli, G; Borsa, M; Viganó, T; Tonon, G

    1987-10-01

    Gross and microscopic examination of rat gastric mucosa demonstrated that intragastric administration to rats of tripotassium dicitrate bismuthate (TDB), a colloidal bismuth compound, protects against gastric lesions induced by 85% ethanol. Indomethacin, a prostaglandin synthetase inhibitor, significantly blocked the gastric mucosal protective effect of TDB. The release of gastric mucosal prostaglandins was greater in animals treated with TDB than in control animals, both time- and dose-dependently. These results seem to indicate involvement of prostaglandins in the action of TDB.

  20. 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.

  1. Inflammation-induced anorexia and fever are elicited by distinct prostaglandin dependent mechanisms, whereas conditioned taste aversion is prostaglandin independent.

    PubMed

    Nilsson, Anna; Wilhelms, Daniel Björk; Mirrasekhian, Elahe; Jaarola, Maarit; Blomqvist, Anders; Engblom, David

    2017-03-01

    Systemic inflammation evokes an array of brain-mediated responses including fever, anorexia and taste aversion. Both fever and anorexia are prostaglandin dependent but it has been unclear if the cell-type that synthesizes the critical prostaglandins is the same. Here we show that pharmacological inhibition or genetic deletion of cyclooxygenase (COX)-2, but not of COX-1, attenuates inflammation-induced anorexia. Mice with deletions of COX-2 selectively in brain endothelial cells displayed attenuated fever, as demonstrated previously, but intact anorexia in response to peripherally injected lipopolysaccharide (10μg/kg). Whereas intracerebroventricular injection of a cyclooxygenase inhibitor markedly reduced anorexia, deletion of COX-2 selectively in neural cells, in myeloid cells or in both brain endothelial and neural cells had no effect on LPS-induced anorexia. In addition, COX-2 in myeloid and neural cells was dispensable for the fever response. Inflammation-induced conditioned taste aversion did not involve prostaglandin signaling at all. These findings collectively show that anorexia, fever and taste aversion are triggered by distinct routes of immune-to-brain signaling.

  2. Stimulation of electrogenic chloride secretion by prostaglandin E2 in guinea-pig isolated gastric mucosa.

    PubMed Central

    Bunce, K T; Spraggs, C F

    1988-01-01

    1. The effects of prostaglandin E2 (PGE2) on ion transport were investigated in guinea-pig isolated gastric mucosa. 2. Under resting conditions the mucosa produced a short-circuit current (SCC), the majority of which could be attributed to electrogenic chloride secretion. This interpretation was confirmed by the dependence of the basal SCC on extracellular chloride, and inhibition by the chloride channel blocker, diphenylamine-2-carboxylate. The mucosa also exhibited low rates of acid secretion and of sodium and rubidium absorption. 3. PGE2 stimulated an increase in net chloride secretion which was more than sufficient to account for the concomitant increase in SCC. As with the basal SCC, the SCC response to PGE2 was chloride dependent and inhibited by diphenylamine-2-carboxylate. PGE2 also significantly increased acid secretion and net rubidium absorption, but these changes were not sufficient to account for SCC. 4. The H+-K+-ATPase inhibitor, omeprazole, inhibited basal and PGE2-stimulated acid secretion, but did not modify the effects the PGE2 on net chloride secretion, SCC or conductance, suggesting that these effects of PGE2 were not related to changes in gastric acid secretion. 5. Both basal and PGE2-stimulated SCC were dependent on extracellular sodium and inhibited by ouabain, indicating the importance of a sodium gradient and the Na+-K+-ATPase in maintaining the electrogenic properties of the mucosa. 6. These results are consistent with the view that PGE2 stimulates electrogenic chloride secretion in guinea-pig gastric mucosa, and provide an ionic basis for the stimulation of secretion of sodium and chloride by prostaglandins observed in mammalian gastric mucosa in vivo. PMID:2458457

  3. 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

  4. Role of prostaglandins in development of porcine blastocysts.

    PubMed

    Geisert, R D; Rasby, R J; Minton, J E; Wetteman, R P

    1986-02-01

    Rapid elongation of porcine blastocysts between Days 11 to 12 of pregnancy coincides with an increase in uterine luminal content of prostaglandins. The present study evaluated the effect of two prostaglandin synthesis inhibitors (indomethacin and flunixin meglumine) on elongation of porcine blastocysts from spherical to filamentous forms between Day 11 to 12 of pregnancy. Gilts were hemi-hysterectomized on Day 11 of pregnancy. The excised uterine horn was flushed with 0.9% saline and diameter of blastocysts recovered were measured. Immediately following surgery, pregnant gilts were assigned to receive either: 1) vehicle every 4 h, 2) flunixin meglumine (banamine) every 4 h, or 3) indomethacin every 12 h. The remaining uterine horn was removed and flushed after the time of blastocyst elongation estimated for each gilt on basis of blastocyst development in the first horn. Uterine flushings were analyzed for total calcium, protein, acid phosphatase activity, estrone, estradiol-17 beta and prostaglandin F. Pretreatment blastocyst diameter was similar for all groups and ranged from 1 mm to 20 mm. Treatment of gilts with either banamine or indomethacin effectively inhibited (P less than 0.001) the increase in uterine luminal content of PGF. Total calcium, estrone and estradiol-17 beta were not influenced by treatment. Total uterine luminal protein and acid phosphatase activity were reduced (P less than 0.05) in banamine treated gilts compared to those receiving vehicle or indomethacin treatments. Although total PGF recovered in uterine flushings was reduced during the period of blastocyst elongation, treatment with PGF synthetase inhibitors failed to block rapid elongation of blastocysts from the spherical to filamentous forms.

  5. Screening of Zulu medicinal plants for prostaglandin-synthesis inhibitors.

    PubMed

    Jäger, A K; Hutchings, A; van Staden, J

    1996-06-01

    Aqueous and ethanolic extracts of 39 plants used in traditional Zulu medicine to treat headache or inflammatory diseases were screened for prostaglandin-synthesis inhibitors. Extracts were tested in an in vitro assay for cyclooxygenase inhibitors. In general, ethanolic extracts caused higher inhibition than aqueous extracts. Two-thirds of the plants screened had high inhibitory activity. The highest inhibition was obtained with ethanolic extracts of Bidens pilosa, Eucomis autumnalis, Harpephyllum caffrum, Helichrysum nudifolium, Leonotis intermedia, L. leonorus, Ocotea bullata, Rumex saggitatus, Solanum mauritianum, Synadenium cupulare and Trichilia dregeana.

  6. The effect of prostaglandin E1 analog misoprostol on chronic cyclosporin nephrotoxicity.

    PubMed

    John, E G; Fornell, L C; Radhakrishnan, J; Anutrakulchai, S; Jonasson, O

    1993-11-01

    Cyclosporin A has markedly improved graft survival in transplant patients but its side effects, such as renal toxicity and hypertension, pose management problems in transplant recipients. This toxicity has been attributed to prostaglandin inhibition. Concurrent administration of misoprostol (a prostaglandin E1 analog) prevents chronic cyclosporin A-induced nephrotoxicity but not hypertension in rats.

  7. Enteral feeding in prostaglandin-dependent neonates: is it a safe practice?

    PubMed

    Willis, Lisa; Thureen, Patti; Kaufman, Jonathan; Wymore, Erica; Skillman, Heather; da Cruz, Eduardo

    2008-12-01

    In many centers presurgical term neonates with prostaglandin-dependent cardiac lesions experience nutritional deficiency because of postponed enteral feeds. We recently adopted early enteral feeding in these infants. This retrospective study demonstrates feeding tolerance in 33 of 34 neonates fed enterally while receiving prostaglandin, suggesting the safety of this practice.

  8. Influence of different prostaglandin applications on cervical rheology.

    PubMed

    Spätling, L; Neuman, M R; Huch, R; Huch, A

    1985-10-01

    The softening effect of prostaglandin (PG) on cervical tissue prior to elective pregnancy termination is quantified by a new technique for the measurement of the elastance and relaxation of the cervix. The method is based on the pressure-volume relation of a compliant balloon placed in the cervical canal. These properties have been measured before and after different applications of prostaglandins in 58 patients electively terminating pregnancy. Application techniques used included high pressure jet application of PGE2 into the tissue of the portio uteri and the internal cervical os (120 micrograms), PGE2 and PGF2 alpha in Tylose gel (100 micrograms/0.5 ml); PGE2 as an intracervical tablet (150 micrograms) and PGE2 oral tablets placed into the posterior fornix of the vagina. Significant changes in cervical elastance were seen with the intracervically applied PGE2 in Tylose gel and the vaginally applied PGE2 tablets. The intracervically applied PGE2 gel also gave significant changes in cervical relaxation. No side effects other than mild cramping (2 patients) were seen with any of the applications in this study.

  9. 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.

  10. Role of prostaglandins in marihuana-induced bronchodilation.

    PubMed

    Laviolette, M; Bélanger, J

    1986-01-01

    In vitro evidence suggests that physiological effects of marihuana may be mediated by prostaglandins via the stimulation of phospholipase A2. To verify if marihuana could act by this route in vivo, we tested the effects of acetylsalicylic and mefenamic acids, inhibitors of cyclooxygenase, on marihuana-induced bronchodilation and tachycardia. In 11 healthy volunteers, marihuana smoking (7 mg/kg, 1.7% delta 9-tetrahydrocannabinol) produced a significant increase in specific airway conductance (from 0.262 +/- 0.033 to 0.360 +/- 0.050 s-1 X cm H2O-1, mean +/- SE, p less than 0.01), forced expiratory volume in 1 s (4.02 +/- 0.22-4.27 +/- 0.25 liter, p less than 0.05) and heart rate (73.2 +/- 2.0-108.5 +/- 5.2 beats/min, p less than 0.001). In a second session, acetylsalicylic or mefenamic acid was taken for 30 h before marihuana smoking. No inhibition of marihuana-induced increase of specific airway conductance, forced expiratory volume in 1 s and heart rate was found. These findings suggest that the bronchodilation and the tachycardia induced by marihuana smoking in humans are not mediated by prostaglandins.

  11. 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.

  12. Optimising daytime deliveries when inducing labour using prostaglandin vaginal inserts

    PubMed Central

    Miller, Hugh; Goetzl, Laura; Wing, Deborah A.; Powers, Barbara; Rugarn, Olof

    2016-01-01

    Abstract Objective: To determine induction start time(s) that would maximise daytime deliveries when using prostaglandin vaginal inserts. Methods: Women enrolled into the Phase III trial, EXPEDITE (clinical trial registration: NCT01127581), had labour induced with either a misoprostol or dinoprostone vaginal insert (MVI or DVI). A secondary analysis was conducted to determine the optimal start times for induction by identifying the 12-h period with the highest proportion of deliveries by parity and treatment. Results: Optimal start times for achieving daytime deliveries when using MVI appear to be 19:00 in nulliparae and 23:00 in multiparae. Applying these start times, the median time of onset of active labour would be approximately 08:30 for both parities and the median time of delivery would be the following day at approximately 16:30 for nulliparae and 12:00 (midday) for multiparae. Optimal start times when using DVI appear to be 07:00 for nulliparae and 23:00 for multiparae. Using these start times, the median time of onset of active labour would be the following day at approximately 04:00 and 11:50, and the median time of delivery would be approximately 13:40 and 16:10, respectively. Conclusions: When optimising daytime deliveries, different times to initiate induction of labour may be appropriate depending on parity and the type of retrievable prostaglandin vaginal insert used. PMID:25758619

  13. Role of prostaglandins in intrauterine migration of the equine conceptus.

    PubMed

    Stout, T A; Allen, W R

    2001-05-01

    Between at least day 9 and day 16 after ovulation the spherical equine conceptus migrates continuously throughout the uterine lumen, propelled by peristaltic myometrial contractions. This unusually long period of intrauterine movement ensures that the conceptus delivers its anti-luteolytic signal to the entire endometrium to achieve luteostasis. The present experiment tested the hypothesis that prostaglandins stimulate the myometrial contractions that result in the migration of the conceptus. Serial ultrasonographic examinations of the uteri of eight mares performed during 2 h periods between day 10 and day 18 of gestation recorded the pattern of conceptus migration before and after treatment with the cyclo-oxygenase inhibitor flunixin meglumine. Conceptus mobility was high between day 10 and day 14 after ovulation (4.3 +/- 0.8, 4.7 +/- 0.8 and 4.3 +/- 0.9 changes of location per h on day 10, day 12 and day 14, respectively), but was reduced immediately and markedly by an i.v. injection of flunixin meglumine (3.8 +/- 1.5, 1.8 +/- 0.8 and 0.7 +/- 0.2 location changes per h), thereby implicating prostaglandins as the primary stimulus for the myometrial contractions that drive migration of the conceptus.

  14. 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.

  15. Enhancement of neural and thermal vasoconstriction by prostaglandin B1.

    PubMed

    Engelbrecht, J A; Greenberg, S; Wilson, W R

    1975-03-01

    The vascular effects of prostaglandin B1 (PGB1) were studied during constant-flow perfusion of the canine hindpaw. The effects of PGB1 (50-200 ng/kg/min ia) on systemic and hindpaw perfusion pressures and on responses to local cooling (4 degrees C for 90 sec) and local heating (45 degrees C for 60 sec) were measured in 15 dogs. PGB1 (50-100 ng/kg/min) decreased perfusion pressure without any significant effect on systemic arterial pressure. Higher concentrations of PGB1 (200 ng/kg/min) elevated perfusion pressure to control values. The pressor responses to local cooling were increased from 11 to 32 mmHg while the dilator responses to local heating and nitroglycerin were reduced during infusions of PGB1. PGB1 also enhanced the pressor responses to norepinephrine or tyramine. These findings support the conclusions that (1) low concentrations of prostaglandin B1 enhance neurotransmitter release with minimal effects on vascular smooth muscle cells and (2) these effects are not secondary to increased perfusion pressures or vascular wall stresses since infusions of PGB1 resulted in vasodilation.

  16. 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.

  17. Multiple drug resistance-associated protein (MRP4) exports prostaglandin E2 (PGE2) and contributes to metastasis in basal/triple negative breast cancer.

    PubMed

    Kochel, Tyler J; Reader, Jocelyn C; Ma, Xinrong; Kundu, Namita; Fulton, Amy M

    2017-01-24

    Cyclooxygenase-2 (COX-2) and its primary enzymatic product, prostaglandin E2 (PGE2), are associated with a poor prognosis in breast cancer. In order to elucidate the factors contributing to intratumoral PGE2 levels, we evaluated the expression of COX-2/PGE2 pathway members MRP4, the prostaglandin transporter PGT, 15-PGDH (PGE2 metabolism), the prostaglandin E receptor EP4, COX-1, and COX-2 in normal, luminal, and basal breast cancer cell lines. The pattern of protein expression varied by cell line reflecting breast cancer heterogeneity. Overall, basal cell lines expressed higher COX-2, higher MRP4, lower PGT, and lower 15-PGDH than luminal cell lines resulting in higher PGE2 in the extracellular environment. Genetic or pharmacologic suppression of MRP4 expression or activity in basal cell lines led to less extracellular PGE2. The key finding is that xenografts derived from a basal breast cancer cell line with stably suppressed MRP4 expression showed a marked decrease in spontaneous metastasis compared to cells with unaltered MRP4 expression. Growth properties of primary tumors were not altered by MRP4 manipulation. In addition to the well-established role of high COX-2 in promoting metastasis, these data identify an additional mechanism to achieve high PGE2 in the tumor microenvironment; high MRP4, low PGT, and low 15-PGDH. MRP4 should be examined further as a potential therapeutic target in basal breast cancer.

  18. Multiple drug resistance-associated protein (MRP4) exports prostaglandin E2 (PGE2) and contributes to metastasis in basal/triple negative breast cancer

    PubMed Central

    Kochel, Tyler J; Reader, Jocelyn C; Ma, Xinrong; Kundu, Namita; Fulton, Amy M

    2017-01-01

    Cyclooxygenase-2 (COX-2) and its primary enzymatic product, prostaglandin E2 (PGE2), are associated with a poor prognosis in breast cancer. In order to elucidate the factors contributing to intratumoral PGE2 levels, we evaluated the expression of COX-2/PGE2 pathway members MRP4, the prostaglandin transporter PGT, 15-PGDH (PGE2 metabolism), the prostaglandin E receptor EP4, COX-1, and COX-2 in normal, luminal, and basal breast cancer cell lines. The pattern of protein expression varied by cell line reflecting breast cancer heterogeneity. Overall, basal cell lines expressed higher COX-2, higher MRP4, lower PGT, and lower 15-PGDH than luminal cell lines resulting in higher PGE2 in the extracellular environment. Genetic or pharmacologic suppression of MRP4 expression or activity in basal cell lines led to less extracellular PGE2. The key finding is that xenografts derived from a basal breast cancer cell line with stably suppressed MRP4 expression showed a marked decrease in spontaneous metastasis compared to cells with unaltered MRP4 expression. Growth properties of primary tumors were not altered by MRP4 manipulation. In addition to the well-established role of high COX-2 in promoting metastasis, these data identify an additional mechanism to achieve high PGE2 in the tumor microenvironment; high MRP4, low PGT, and low 15-PGDH. MRP4 should be examined further as a potential therapeutic target in basal breast cancer. PMID:28029661

  19. Long-Term Prostaglandin E1 Infusion for Newborns with Critical Congenital Heart Disease.

    PubMed

    Aykanat, Alper; Yavuz, Taner; Özalkaya, Elif; Topçuoğlu, Sevilay; Ovalı, Fahri; Karatekin, Güner

    2016-01-01

    Prostaglandin E1 is crucial for keeping the patent ductus arteriosus in critical congenital heart disease for the survival and palliation of particularly prematurely born babies until a cardiosurgical intervention is available. In this study, the side effects of prostaglandin E1 in newborns with critical congenital heart disease and clinical outcomes were evaluated. Thirty-five newborns diagnosed with critical congenital heart disease were treated with prostaglandin E1 between January 2012 and September 2014 at our hospital. Patient charts were examined for prostaglandin E1 side effects (metabolic, gastric outlet obstruction, apnea), clinical status, and prognosis. Acquired data were analyzed in the SPSS 20.0 program. Patients with birth weight under 2500 g needed more days of prostaglandin E1 infusion than ones with birthweight over 2500 g (P = 0.016). The ratio of patients with birth weight under 2500 g who received prostaglandin E1 longer than 7 days was higher than the patients with birth weight over 2500 g (P = 0.02). Eighteen side effects were encountered in 11 of 35 patients (31%). Of these side effects, 1 patient had 4, 4 patients had 2, and 6 patients had only 1 side effect. Discontinuation of the therapy was never needed. Prostaglandin E1 is an accepted therapy modality for survival and outcome in critical congenital heart disease in particularly low-birth-weight babies until a surgical intervention is available. Side effects are not less encountered but are almost always manageable, and discontinuation is not needed.

  20. Regional distribution of prostaglandin endoperoxide synthase studied by enzyme-linked immunoassay using monoclonal antibodies.

    PubMed

    Yoshimoto, T; Magata, K; Ehara, H; Mizuno, K; Yamamoto, S

    1986-06-11

    Prostaglandin endoperoxide synthase transforms arachidonic acid to prostaglandin H2 via prostaglandin G2. The enzyme purified from bovine vesicular gland was given to mice as antigen, and monoclonal antibodies were raised by the hybridoma technique. Two species of the monoclonal antibody recognizing different sites of the enzyme were utilized to establish a peroxidase-linked immunoassay of prostaglandin endoperoxide synthase. Fab' fragment of one of the antibodies was prepared and conjugated to horseradish peroxidase. The conjugate was then bound to prostaglandin endoperoxide synthase, and the labeled enzyme was precipitated by the addition of the other antibody. The peroxidase activity of the immunoprecipitate correlated linearly with the amount of prostaglandin endoperoxide synthase. This sensitive and convenient method to determine the enzyme amount rather than the enzyme activity was utilized to extensively screen the amount of prostaglandin endoperoxide synthase in various bovine tissues. In addition to vesicular gland, platelets and kidney medulla previously known as rich enzyme sources, the immunoenzymometric assay demonstrated a high content of the enzyme in various parts of alimentary tract and a low but significant amount of enzyme in some parts of brain.

  1. [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.

  2. Local prostaglandin administration for mid trimester abortion: a retrospective analysis.

    PubMed

    Cameron, I T; Baird, D T

    1987-01-01

    The hospital records of 548 consecutive patients undergoing midtrimester pregnancy termination by the local administration of prostaglandins (PGs) have been reviewed. Most women (352 or 64%) were single and 322 (59%) were pregnant for the 1st time. 2/3 of the patients (361 or 66%) were between 12-16 weeks pregnant, whereas 7 (1%) were considered to be more than 20 weeks pregnant. In 401 cases (92%), abortion was performed under Item 2 of the 1967 Abortion Act, although Item 4 was cited in 34 (81%) of those individuals with a pregnancy of greater than 17 weeks duration. Apart from 10 women (2%) in whom severe hemorrhage was documented, the major complication rate was less than 1%. The use of local PGs provides a safe, effective treatment method for therapeutic abortion in the 2nd trimester.

  3. 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

  4. High performance liquid chromotography of prostaglandins: biological applications.

    PubMed

    Carr, K; Sweetman, B J; Frölich, J C

    1976-01-01

    Two procedures are described for separation and purification of prostaglandins by high performance liquid chromatography. Both systems show excellent resolution of PGA2, PGE2 and PGF2a. Peak definition on the micro-particle silicic acid system is particularly good with the PGs appearing in 2-3 ml of organs effluent. Studies on reproducibility showed that PGE2 and PGE2a could be recovered with a retention volume of 54.2+/-0.76 ml and 64+/-0.6 ml, respectively (n=7, mean +/-50) with good recovery. The column can be run in about one hour and can be regenerated indefinitely (greater than 200 times). The degree of purification is compatible with analysis by gas chromatography-mass spectrometry. Examples showing the application of this chromatographic method to human seminal fluid, human renal tissue, platelet rich plasma and human urine samples indicate that it makes possible analysis of these samples even at low levels.

  5. Biosynthesis of prostaglandins in gingiva of patients with chronic periodontitis

    SciTech Connect

    Mendieta, C.F.; Reeve, C.M.; Romero, J.C.

    1985-01-01

    This study was undertaken to determine the ability of inflamed and normal gingival tissues to synthesize prostaglandins (PGs) from the precursor arachidonic acid. Thirteen samples of inflamed human gingival tissue and six samples of normal human gingival tissue were studied. The inflammation was characterized histologically. After incubation of the tissue with (/sup 14/C)arachidonate, PG metabolites were separated by thin-layer chromatography and identified by comparison with co-chromatographed standards. Inflamed gingival tissue synthesized significantly larger amounts, compared to normal tissue, of 6-keto-PGF1 alpha (P less than 0.05), thromboxane B2, PGD2, and PGA2. Some unidentified metabolites, possibly lipoxygenase products were detected in significantly larger amounts in inflamed than in normal tissue.

  6. 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.

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

    PubMed

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

    2007-06-22

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

  8. Fetal placental prostaglandin metabolism in the peripartum cow

    SciTech Connect

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

    1986-03-05

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

  9. 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

  10. Peroxidative oxidation of leuco-dichlorofluorescein by prostaglandin H synthase in prostaglandin biosynthesis from polyunsaturated fatty acids.

    PubMed

    Larsen, L N; Dahl, E; Bremer, J

    1996-01-05

    Prostaglandin H synthase can oxidize arachidonic acid with leuco-dichlorofluorescein as reducing cosubstrate. Addition of 0.5 mM phenol increases the oxidation of leuco-dichlorofluorescein to dichlorofluorescein 5-fold, probably by acting as a cyclic intermediate in the oxidation. Tetramethyl-p-phenylenediamine is also oxidized as cosubstrate. Its oxidation is not influenced by phenol. A stoichiometry of close to one mole of tetramethyl-p-phenylenediamine or leuco-dichlorofluorescein consumed per mole of arachidonic acid was found in the initial phase of the reaction. In the presence of phenol + leuco-dichlorofluorescein, the oxidation rate of arachidonic acid is about 40% lower than with phenol alone as cosubstrate. Since dichlorofluorescein has a molar extinction coefficient of 91 . 10(3) at 502 nm, the oxidation of less than 1 microM leuco-dichlorofluorescein can be detected spectrophotometrically. The rate of extinction change with leuco-dichlorofluorescein (at 502 nm) is about 4-fold more rapid than with tetramethyl-p-phenylenediamine (at 611 nm). With this spectrophotometric assay we have confirmed that arachidonic acid, linolenic acid, adrenic acid, gamma-linolenic acid, eicosapentaenoic acid, are substrates for prostaglandin H synthase with decreasing reaction rates in the mentioned order. The same order of reaction rates were found when oxygen consumption was measured. The assay also shows that docosahexaenoic acid is substrate for the enzyme. The reaction rate of the enzyme evidently is decreased both by a n-3 double bond and by deviation from a 20 carbon chain length of the fatty acid substrate.

  11. 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.

  12. Effects of advancing gestation and non-Caucasian race on ductus arteriosus gene expression

    PubMed Central

    Waleh, Nahid; Barrette, Anne Marie; Dagle, John M.; Momany, Allison; Jin, Chengshi; Hills, Nancy K.; Shelton, Elaine L.; Reese, Jeff; Clyman, Ronald I.

    2015-01-01

    Objective To identify genes affected by advancing gestation and racial/ethnic origin in human ductus arteriosus (DA). Study design We collected three sets of DA tissue (n=93, n=89, n=91; total = 273 fetuses) from second trimester pregnancies. We examined four genes, with DNA polymorphisms that distribute along racial lines, to identify "Caucasian" and "Non-Caucasian" DA. We used RT-PCR to measure RNA expression of 48 candidate genes involved in functional closure of the DA, and used multivariable regression analyses to examine the relationships between advancing gestation, "Non-Caucasian" race, and gene expression. Results Mature gestation and Non-Caucasian race are significant predictors for identifying infants who will close their patent DA when treated with indomethacin. Advancing gestation consistently altered gene expression in pathways involved with oxygen-induced constriction (e.g., calcium-channels, potassium-channels, and endothelin signaling), contractile protein maturation, tissue remodeling, and prostaglandin and nitric oxide signaling in all three tissue sets. None of the pathways involved with oxygen-induced constriction appeared to be altered in "Non-Caucasian" DA. Two genes, SLCO2A1 and NOS3, (involved with prostaglandin reuptake/metabolism and nitric oxide production, respectively) were consistently decreased in "Non-Caucasian" DA. Conclusions Prostaglandins and nitric oxide are the most important vasodilators opposing DA closure. Indomethacin inhibits prostaglandin production, but not nitric oxide production. Because decreased SLCO2A1 and NOS3 expression can lead to increased prostaglandin and decreased nitric oxide concentrations, we speculate that prostaglandin-mediated vasodilation may play a more dominant role in maintaining the "Non-Caucasian" PDA, making it more likely to close when inhibited by indomethacin. PMID:26265282

  13. Role of mucosal prostaglandins and DNA synthesis in gastric cytoprotection by luminal epidermal growth factor.

    PubMed Central

    Konturek, S J; Brzozowski, T; Piastucki, I; Dembinski, A; Radecki, T; Dembinska-Kiec, A; Zmuda, A; Gregory, H

    1981-01-01

    This study compares the effect of epidermal growth factor and prostaglandins (PGE2 or PGI2), applied topically to gastric mucosa, on gastric secretion and formation of ASA-induced gastric ulcerations in rats. Epidermal growth factor given topically in non-antisecretory doses prevented dose-dependently the formation of ASA-induced ulcers without affecting prostaglandin generation but with a significant rise in DNA synthesis in the oxyntic mucosa. The anti-ulcer effect of topical prostaglandins was also accompanied by an increase in DNA synthesis. This study indicates that topical epidermal growth factor, like PGE2 or PGI2, is cytoprotective and that this cytoprotection is not mediated by the inhibition of gastric secretion or prostaglandin formation but related to the increase in DNA synthesis in oxyntic mucosa. PMID:7030877

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

    PubMed

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

    2014-09-12

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

  15. [Prostaglandin E1 in the treatment of chronic ischemia of the extremities].

    PubMed

    Kowal-Gierczak, B; Kurzawska-Mielecka, M; Czarnacki, M

    1990-11-01

    The authors observed the effect of prostaglandin E1 (Prostavasine) on the blood flow in the lower extremities in 25 patients with chronic ischemia caused by thrombo-angitis obliterans and arteriosclerosis obliterans (clinical stage III and IV). The blood flow in the lower extremities and the effects of prostaglandin E1 were assessed by means of rheo-angiographic and Doppler-testing investigations. The parameters A (amplitude), S (area) and WOT (index) of rheo-angiographic curves showed significant increased. No significant changes were found in the determined Doppler's indexes. The observed differences of values the parameters of rheo-angiographic curves suggests that prostaglandin E1 evident improvement the tissue blood flow in patients with critical ischemia of the lower extremities. The authors found that prostaglandin E1 was without any significant effect dilating the great vessels, but an evident improvement was observed in rheo-angiographic records which reflect rather the blood flow values in the small vessels.

  16. Plasma prostaglandins across the tumor bed of patients with gynecologic malignancy.

    PubMed

    Mortel, R; Allegra, J C; Demers, L M; Harvey, H A; Trautlein, J; Nahhas, W; White, D; Gillin, M A; Lipton, A

    1977-05-01

    Prostaglandin E produced by tumors has recently been implicated as a mechanism by which tumors may subvert the immune system and grow despite their antigenicity. Arterial and venous determinations of prostaglandin E were performed in eleven patients with gynecologic malignancy. No significant difference was found when arterial and venous levels were compared and there was no difference in venous PGE levels when subjects with cancer were compared to patients with benign gynecologic disease.

  17. Signal pathways mediating oxytocin stimulation of prostaglandin synthesis in select target cells.

    PubMed

    Soloff, M S; Jeng, Y J; Copland, J A; Strakova, Z; Hoare, S

    2000-03-01

    A major action of oxytocin is to stimulate prostaglandin production in reproductive tissues. The two major enzyme systems involved are cytosolic phospholipase A2 (cPLA2), which catalyses the formation of arachidonic acid from membrane glycerophospholipids, and prostaglandin endoperoxide-H synthases-1 and -2, which allow conversion of arachidonic acid to prostaglandins. During gestation, the concentrations of all three enzymes rise in the rabbit amnion. Agonists, including oxytocin, increase cPLA2 activity, in part, by elevating intracellular Ca2+ concentration, which causes cPLA2 to be translocated from the cytosol to intracellular membrane binding sites. Cytosolic PLA2 is then activated by a mitogen-activated protein kinase (MAPK)-dependent step. Our studies have elucidated signal pathways involved in oxytocin-stimulated prostaglandin output in both rabbit amnion cells and Chinese hamster ovary cells stably transfected with the rat oxytocin receptor. The two cell types are alike with respect to oxytocin-stimulated intracellular Ca2+ transients, mediation via Gq, and the specific MAPK that catalyses the phosphorylation of cPLA2. However, they differ with respect to the mechanisms of upregulation of key enzymes involved in prostaglandin E2 synthesis. These findings illustrate the tiers of complementary mechanisms involved in oxytocin stimulation of prostaglandin E2, and the extent of the diversity in the cellular signalling pathways involved.

  18. 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.

  19. 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

  20. 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.

  1. [Morphologic and biochemical aspects of prostaglandin-induced cervix ripening].

    PubMed

    Rath, W; Adelmann-Grill, B C; Schauer, A; Kuhn, W

    1987-01-01

    For examination by electron microscopy tissue samples were taken from the posterior lip of the cervix of 8 patients having a termination of pregnancy at 9-12th week gestation and 16 patients of comparable gestational age who had an intracervical application of either 2 ml 5% tylose or 50 micrograms sulprostone-tylose gel 8 hours before biopsy. The efficacy of cervical priming was demonstrated objectively by tonometric studies. In addition, collagenase and protease activities were determined in the cervical tissue extracts of the different treatment groups. For identification of typical collagen fragments SDS-polyacrylamide-gel-electrophoresis were carried out on the acetic acid soluble extracts. The local application of sulprostone gel induced a marked multifocal loosening of the collagenous framework; there was no evidence for leucocyte infiltration or necrosis caused by the prostaglandin (PG) pretreatment. In the areas of disorganized collagen fibres cervical fibroblasts seemed to be activated characterized by fine granular loosening of the cytoplasma, dilated cisternae of rough endoplasmatic reticulum, vacuolized enlarged mitochondria and an increased number of cytoplasmatic vesicles close to the cell surface. Collagenase and protease activities were found in all extracts of the different treatment groups, however, PG-application led to no significant increase in enzymatic activities. There was no evidence for the presence of typical collagen cleavage products in the SDS-electrophoresis. Contradictory to the hitherto published literature enzymatic collagen degradation does not play an essential role in PG-induced cervical ripening.

  2. Prostaglandin E2 Mediates Immunosuppression in Acutely Decompensated Cirrhosis

    PubMed Central

    O’Brien, Alastair J.; Fullerton, James N.; Massey, Karen A.; Auld, Grace; Sewell, Gavin; James, Sarah; Newson, Justine; Karra, Effie; Winstanley, Alison; Alazawi, William; Garcia-Marquez, Rita; Cordoba, Juan; Nicolaou, Anna; Gilroy, Derek W.

    2017-01-01

    Patients with advanced cirrhosis experience frequent infections leading to sepsis, which carries high mortality. While innate immune dysfunction underlies this vulnerability, the precise cause remains elusive. We found prostaglandin (PGE2) elevated in acutely decompensated (AD) patients at immunosuppressive levels. Plasma from AD and end-stage liver disease (ESLD) patients suppressed macrophage cytokine secretion and bacteria killing in a PGE2 receptor-dependent manner, effects not seen in stable cirrhosis. Mouse models (bile duct ligation and CCL4-liver injury) also demonstrated elevated PGE2, which when inhibited completely restored immune competence and survival following infection. Importantly, albumin binds/inactivates PGE2 resulting in greater PGE2 bioavailability. This results in enhanced immunosuppressive effects of AD plasma in patients with low albumin levels. Administering albumin to AD patients reversed immunosuppressive properties of their plasma; protective effects recapitulated in rodent survival studies. Thus, elevated PGE2 combined with hypoalbuminemia mediates immunosuppression in AD and ESLD patients, which can be reversed with albumin. PMID:24728410

  3. Prostaglandin concentrations in uterine fluid of cows with pyometra.

    PubMed Central

    Manns, J G; Nkuuhe, J R; Bristol, F

    1985-01-01

    Uterine fluid was obtained from eight clinical cases of pyometra with retained corpus luteum and nine additional samples of fluid were collected from animals slaughtered at an abattoir. These samples, along with uterine flushes from normal cows in their luteal phase were analyzed for prostaglandin of the F (PGF) and E (PGE) groups. Blood samples were also obtained from the clinical cases for analysis of 13,14-dihydro-15-keto PGF (PGFM) the major metabolite of PGF. Pyometrial exudate from clinical cases of abattoir samples had high concentrations of PGF (17.9 ng/mL) and PGE (33.2 ng/mL) and the total amount of PGF and PGE in the uterus was calculated to be several hundred times as great as in normal cows. Furthermore, clinical cases had elevated PGFM in their blood compared to that of controls, which suggests that at least some of the PGF was being absorbed from the uterus. These results are discussed in light of our current understanding of the maternal recognition of pregnancy in cattle. PMID:4075244

  4. 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.

  5. Possible role of prostaglandin F in blastocyst implantation

    SciTech Connect

    Kasamo, M.; Ishikawa, M.; Yamashita, K.; Sengoku, K.; Shimizu, T.

    1986-02-01

    The synthesis and release of Prostaglandin F (PGF) by the rabbit blastocyst and endometrium were investigated on Day 6 and Day 7, using radioimmunoassay, autoradiography and conversion experiments. The following results were obtained: The content of PGF in the blastocyst increased significantly (P less than 0.01) from Day 6 to Day 7. The content of PGF in the endometrium was significantly higher (P less than 0.05) on Day 7 implantation sites compared to the other areas. The in vitro synthesis and release of PGF by Day 6 blastocysts sharply increased after one and two hours of culture, respectively. Thereafter both values declined with time. The in vitro synthesis and release of PGF by Day 6 endometria increased continuously with time. /sup 14/C-arachidonic acid (/sup 14/C-AA) was incorporated into Day 6 blastocysts in vitro and converted to PGF2 alpha. These results suggest that both the endometrium and the blastocyst are the sources of the PGs involved in implantation, and that PGF derived from the blastocysts may act as the trigger of implantation.

  6. 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.

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

    SciTech Connect

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

    2005-09-30

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

  8. Discovery of anti-inflammatory role of prostaglandin D2

    PubMed Central

    MURATA, Takahisa; MAEHARA, Toko

    2016-01-01

    Nonsteroidal anti-inflammatory drugs (NSAIDs) including aspirin are one of the most frequently used classes of drug worldwide and inhibit prostaglandin (PG) production by inhibiting cyclooxygenase activity. Although NSAIDs are broadly used against inflammatory diseases, they have side effects including alimentary canal disorders, kidney damage, infection and cardiovascular disorders. Thus, it is necessary to elucidate the pathophysiological role of each PG in various diseases to develop better therapies with fewer and milder side effects. PGD2 is a PG that was identified in 1973 by Hamberg and is produced by the activities of cyclooxygenase and either hematopoietic or lipocalin-type PGD synthase. PGD2 exerts its physiological effects by stimulating two distinct G protein-coupled receptors, namely D prostanoid receptor (DP) and chemoattractant receptor-homologous molecule expressed on Th2 cells (CRTH2). The physiological role of PGD2 remains controversial. Some studies have reported that PGD2 has bronchoconstrictory and pro-inflammatory effects inducing immune cell accumulation. In contrast, other groups have reported that PGD2 has anti-inflammatory effects by inhibiting the recruitment of dendritic cells and neutrophils. We have investigated the pathophysiological role of PGD2 using various disease models and reported on its anti-inflammatory actions. Here, we review the anti-inflammatory roles of PGD2 and the underlying mechanisms. PMID:27498997

  9. Anti-inflammatory prostaglandins for the prevention of preterm labour.

    PubMed

    Sykes, Lynne; MacIntyre, David A; Teoh, Tiong Ghee; Bennett, Phillip R

    2014-08-01

    Preterm birth occurs in 10-12% of pregnancies and is the primary cause of neonatal mortality and morbidity. Tocolytic therapies have long been the focus for the prevention of preterm labour, yet they do not significantly improve neonatal outcome. A direct causal link exists between infection-induced inflammation and preterm labour. As inflammation and infection are independent risk factors for poor neonatal outcome, recent research focus has been shifted towards exploring the potential for anti-inflammatory strategies. Nuclear factor kappa B (NFκB) is a transcription factor that controls the expression of many labour-associated genes including PTGS2 (COX2), prostaglandins (PGs) and the oxytocin receptor (OXTR) as well as key inflammatory genes. Targeting the inhibition of NFκB is therefore an attractive therapeutic approach for both the prevention of preterm labour and for reducing neonatal exposure to inflammation. While PGs are considered to be pro-labour and pro-inflammatory, the cyclopentenone PG 15-deoxy-Δ(12,14)PGJ2 (15d-PGJ2) exhibits anti-inflammatory properties via the inhibition of NFκB in human amniocytes, myocytes and peripheral blood mononuclear cells in vitro. 15d-PGJ2 also delays inflammation-induced preterm labour in the mouse and significantly increases pup survival. This review examines the current understanding of inflammation in the context of labour and discusses how anti-inflammatory PGs may hold promise for the prevention of preterm labour and improved neonatal outcome.

  10. Prostaglandin E2 Prevents Disuse-Induced Cortical Bone Loss

    NASA Technical Reports Server (NTRS)

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

    1992-01-01

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

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

    PubMed Central

    Bockman, R S

    1980-01-01

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

  12. [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.

  13. Prostaglandin E production and hypercalcaemia in rats bearing the Walker carcinosarcoma.

    PubMed

    Seyberth, H W; Bonsch, G; Müller, H; Minne, H W; Erlenmaier, T; Strein, K; Imbeck, H; Mrongovius, R

    1980-09-01

    The hypothesis that there is prostaglandin-mediated hypercalcaemia associated with the Walker carcinosarcoma in the rat was tested by measuring PGE production during the development of the hypercalcaemia, and determining the effects of inhibition of prostaglandin synthesis on serum calcium concentration. Parathyroid hormone (PTH) activity was estimated by the determination of the serum concentration of immunoreactive PTH. There was a 3-fold increase in the urinary excretion of 7α-hydroxy-5,11-diketotetranor-prostane-1,16-dioic acid (PGE-M), a major urinary metabolite of the E prostaglandins from basal levels. Treatment with indomethacin, a potent inhibitor of prostaglandin synthesis, did not lower serum calcium concentrations with two different doses (1·6 mg/kg/day orally and 5 mg/kg/day i.m.); effective inhibition of prostaglandin synthesis was demonstrated by the suppression of PGE-M excretion rates below basal levels. Serum concentrations of immunoreactive PTH were not significantly altered by either tumour growth or indomethacin. Dexamethasone (0·5 mg/kg/day i.m.) attenuated both the increased urinary excretion of PGE-M and the rise in serum calcium concentration, suggesting that one or several lipoxygenase products might be the actual mediators of the hypercalcaemia. We conclude that the hypercalcaemia in the rat with Walker carcinosarcoma is probably not mediated by E-prostaglandins and probably not by any other product of the cyclo-oxygenase pathway. The increased PGE turnover may be considered as a biochemical marker of tumour load, but not as an indicator of a prostaglandin-mediated hypercalcaemia.

  14. Prostaglandin E production and hypercalcaemia in rats bearing the Walker carcinosarcoma

    PubMed Central

    Seyberth, H. W.; Bonsch, G.; Müller, H.; Minne, H. W.; Erlenmaier, T.; Strein, K.; Imbeck, H.; Mrongovius, R.

    1980-01-01

    The hypothesis that there is prostaglandin-mediated hypercalcaemia associated with the Walker carcinosarcoma in the rat was tested by measuring PGE production during the development of the hypercalcaemia, and determining the effects of inhibition of prostaglandin synthesis on serum calcium concentration. Parathyroid hormone (PTH) activity was estimated by the determination of the serum concentration of immunoreactive PTH. There was a 3-fold increase in the urinary excretion of 7α-hydroxy-5,11-diketotetranor-prostane-1,16-dioic acid (PGE-M), a major urinary metabolite of the E prostaglandins from basal levels. Treatment with indomethacin, a potent inhibitor of prostaglandin synthesis, did not lower serum calcium concentrations with two different doses (1·6 mg/kg/day orally and 5 mg/kg/day i.m.); effective inhibition of prostaglandin synthesis was demonstrated by the suppression of PGE-M excretion rates below basal levels. Serum concentrations of immunoreactive PTH were not significantly altered by either tumour growth or indomethacin. Dexamethasone (0·5 mg/kg/day i.m.) attenuated both the increased urinary excretion of PGE-M and the rise in serum calcium concentration, suggesting that one or several lipoxygenase products might be the actual mediators of the hypercalcaemia. We conclude that the hypercalcaemia in the rat with Walker carcinosarcoma is probably not mediated by E-prostaglandins and probably not by any other product of the cyclo-oxygenase pathway. The increased PGE turnover may be considered as a biochemical marker of tumour load, but not as an indicator of a prostaglandin-mediated hypercalcaemia. PMID:7426347

  15. 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.

  16. Circadian and estral changes in the hypothalamic prostaglandin e content and [h]prostaglandin e binding in female rats.

    PubMed

    Bommelaer-Bayet, M C; Wisner, A; Renard, C A; Levi, F A; Dray, F

    1990-04-01

    Abstract Prostaglandin E(2), (PGE(2)) is involved in the luteinizing hormone-releasing hormone-stimulated luteinizing hormone surge in female rats and may act via specific membrane receptors. The following studies were performed to determine whether there were any changes in the hypothalamic PGE(2) binding and/or PGE(2) content which were specific to proestrus and not to the rest of the estrous cycle. Groups of female Wistar rats were sacrificed at 3-h intervals throughout the estrous cycle to determine both the circadian and circaestral changes in the hypothalamic PGE(2) content and [(3)H]PGE(2) binding. The hypothalamic PGE(2) content was maximal at 1700 h on each of the 4 consecutive days of the estrous cycle but was independent of the stage of the cycle. [(3)H]PGE(2) binding also displayed a circadian rhythm; the lowest binding occurred near the circadian peak of PGE(2), suggesting that the PGE(2) binding sites were occupied by endogenous PGE(2). Since such circadian rhythms were not observed in the hypothalamus of male rats, they may be under the control of ovarian steroids. Also, since PGE(2) binding and the PGE(2) content both exhibit a diurnal pattern independent of the day of the cycle, there may be changes in the PGE(2) receptor-mediated process coupled to an adenylyl cyclase which could explain the luteinizing hormone surge in proestrus.

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

    NASA Technical Reports Server (NTRS)

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

    1991-01-01

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

  19. Prostaglandin protection of human isolated gastric glands against indomethacin and ethanol injury. Evidence for direct cellular action of prostaglandin.

    PubMed Central

    Tarnawski, A; Brzozowski, T; Sarfeh, I J; Krause, W J; Ulich, T R; Gergely, H; Hollander, D

    1988-01-01

    Isolated human gastric glands from surgical specimens were preincubated in an oxygenated medium with placebo or 16,16 dimethyl prostaglandin E2 (dmPGE2) and incubated at 37 degrees C in either medium alone, medium containing 4.43 mM indomethacin or medium containing 8% ethanol. We assessed the viability of gland cells with fast green exclusion, release of lactate dehydrogenase (LDH) into the medium, and ultrastructural damage by scanning and transmission electron microscopy. Both indomethacin and ethanol significantly reduced the viability of placebo-pretreated glands, increased LDH release into the medium, and produced prominent ultrastructural damage. DmPGE2 significantly reduced both indomethacin and ethanol-induced injury, increased the number of viable cells, reduced LDH release, and diminished the extent of ultrastructural damage. These studies indicate that PG protection of gastric mucosal cells has a direct cellular action that is not limited to replacement of depleted endogenous PGs. PG protection in our experiments did not depend on PG's previously described systemic actions, such as protection of the microvessels, preservation of the mucosal blood flow, or stimulation of bicarbonate and mucus secretion. Images PMID:3350966

  20. Further evidence implicating prostaglandin E sub 2 in the genesis of pyrogen fever

    SciTech Connect

    Coceani, F.; Lees, J.; Bishai, I. )

    1988-03-01

    Conscious cats were used to study the effects of endotoxin and interleukin 1 (IL 1) on levels of prostaglandin (PG) E{sub 2} and thromboxane (TX) B{sub 2} (the stable TXA{sub 2} byproduct) in cerebrospinal fluid (CSF) from the third ventricle. Pyrogens were given intravenously or intraventricularly and prostanoids were measured by radioimmunoassay. PGE{sub 2} was normally less abundant than TXB{sub 2}, and its level increased severalfold during the sustained fever following intravenous endotoxin (bolus) or IL 1 (bolus plus infusion). PGE{sub 2} elevation preceded the fever and was maintained thereafter. Likewise, intraventricular pyrogens promoted PGE{sub 2} formation, and their effect was also manifest during the latent period of the fever. The PGE{sub 2} metabolite, 13,14-dihydro-15-keto-PGE{sub 2}, was not measurable in CSF from either afebrile or febrile animals. Basal content of PGE{sub 2}, on the other hand, was higher in animals pretreated with probenecid, confirming the importance of transport processes in removing prostanoids from brain. Unlike PGE{sub 2}, TXB{sub 2} levels did not change during the fever to intravenous endotoxin. TXB{sub 2} rose instead in response to intraventricular endotoxin, although the elevation did not extend beyond fever uprise. Furthermore, a TXA{sub 2} analog had inconsistent effects on body temperature, while a TXA{sub 2} antagonist did not interfere with endotoxin fever. These findings strongly support a causative role for PGE{sub 2} in the onset and progression of pyrogen fever. No evidence of a similar role was obtained for TXA{sub 2}.

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

    PubMed

    Yuan, Chong; Smith, William L

    2015-02-27

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

  2. Prostaglandin A2 Enhances Cellular Insulin Sensitivity via a Mechanism that Involves the Orphan Nuclear Receptor NR4A3

    PubMed Central

    Zhu, X.; Walton, R. G.; Tian, L.; Luo, N.; Ho, S-R.; Fu, Y.; Garvey, W. T.

    2014-01-01

    We have previously reported that members of the NR4A family of orphan nuclear receptors can augment insulin’s ability to stimulate glucose transport in adipocytes. In the current study, we endeavored to test for an insulin-sensitizing effect in muscle cells and to identify a potential transactivator. Lentiviral constructs were used to engineer both hyperexpression and shRNA silencing of NR4A3 in C2C12 myocytes. The NR4A3 hyper-expression construct led to a significant increase in glucose transport rates in the presence of maximal insulin while the NR4A3 knock-down exhibited a significant reduction in insulin-stimulated glucose transport rates. Consistently, insulin-mediated AKT phosphorylation was increased by NR4A3 hyperexpression and decreased following shRNA NR4A3 suppression. Then, we examined effects of prostaglandin A2 (PGA2) on insulin action and NR4A3 transactivation. PGA2 augmented insulin-stimulated glucose uptake in C2C12 myocytes and AKT phosphorylation after 12-h treatment, without significant effects on basal transport or basal AKT phosphorylation. More importantly, we demonstrated that PGA2 led to a greater improvement in insulin-stimulated glucose rates in NR4A3 overexpressing C2C12 myocytes, when compared with Lac-Z controls stimulated with insulin and PGA2. Moreover, the sensitizing effect of PGA2 was significantly diminished in NR4A3 knockdown myocytes compared to scramble controls. These results show for the first time that: (i) PGA2 augments insulin action in myocytes as manifested by enhanced stimulation of glucose transport and AKT phosphorylation; and (ii) the insulin sensitizing effect is dependent upon the orphan nuclear receptor NR4A3. PMID:23104421

  3. Prostaglandin J2: a potential target for halting inflammation-induced neurodegeneration

    PubMed Central

    Figueiredo-Pereira, Maria E.; Corwin, Chuhyon; Babich, John

    2015-01-01

    Prostaglandins are produced via cyclooxygenases, which are enzymes that play a major role in neuroinflammation. Epidemiological studies show that chronic treatment with low levels of cyclooxygenase inhibitors (NSAIDs) lowers the risk for Alzheimer's (AD) and Parkinson's (PD) diseases by as much as 50%. Unfortunately, inhibiting cyclooxygenases with NSAIDs blocks the synthesis of downstream neuroprotective and neurotoxic prostaglandins, thus producing adverse side effects. We focus on prostaglandin J2 (PGJ2) because it is highly neurotoxic compared to PGA1, D2, and E2. Unlike other prostaglandins, PGJ2 and its metabolites have a cyclopentenone ring with reactive α,β-unsaturated carbonyl groups that form covalent Michael adducts with key cysteines in proteins and GSH. Cysteine-binding electrophiles such as PGJ2 are considered to play an important role in determining whether neurons will live or die. We discuss in vitro and in vivo studies showing that PGJ2 induces pathological processes relevant to neurodegenerative disorders such as AD and PD. Furthermore, we found that increasing intracellular cAMP with the lipophilic peptide PACAP27 counteracts some of the PGJ2-induced detrimental effects. In conclusion, new therapeutic strategies that neutralize the effects of specific neurotoxic prostaglandins downstream from cyclooxygenases could have a significant impact on the treatment of chronic neurodegenerative disorders with fewer adverse side effects. PMID:26748744

  4. Prostaglandin E2 increases the skeletal response to mechanical loading

    NASA Technical Reports Server (NTRS)

    Tang, L. Y.; Cullen, D. M.; Yee, J. A.; Jee, W. S.; Kimmel, D. B.

    1997-01-01

    The study tested the influence of prostaglandin E2 (PGE2) on the skeletal response to increased in vivo mechanical loading through a four-point bending device. One hundred and twenty Sprague-Dawley female rats (6 months old, 354 +/- 34 g) were divided into 12 groups to accommodate all possible combinations of doses of loads (25, 30, or 35 N) and PGE2 (0, 0.1, 0.3, or 1 mg/kg). Rats received subcutaneous injections of PGE2 daily and in vivo loading of the right tibia every Monday, Wednesday, and Friday for four weeks. Histomorphometric analysis of the periosteal and endocortical surfaces following in vivo dual fluorochrome labeling was performed on both the loaded region of the right tibial diaphysis and a similar region of the left tibial diaphysis. Without PGE2, the threshold for loading to stimulate bone formation was 30 N (peak strain 1360 mu epsilon) at the periosteal surface and 25 N (peak strain 580 mu epsilon) at the endocortical surface. Without loading, the minimum dose of PGE2 to stimulate bone formation at all surfaces was 1 mg/kg/day. When 1 mg/kg/day PGE2 was combined with the minimum effective load, an additive effect of PGE2 and loading on bone formation was observed at the endocortical surface, but a synergistic effect was noted at the periosteal surface. No combined effect of ineffective doses of loading and PGE2 was found. A synergistic effect at peak strains of approximately 1625 mu epsilon on the periosteal surface could suggest either the involvement of locally produced growth factors or autoregulation of endogenous synthesis of PGE2 by exogenously administered PGE2.

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

    PubMed

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

    2015-10-12

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

  6. Unidirectional transfer of prostaglandin endoperoxides between platelets and endothelial cells.

    PubMed Central

    Schafer, A I; Crawford, D D; Gimbrone, M A

    1984-01-01

    An important determinant of platelet-vessel wall interactions is the local balance of production of endothelial prostacyclin (PGI2) and platelet thromboxane (TX) A2, labile eicosanoids with opposing effects on hemostasis. Disputed evidence suggests that platelet-derived prostaglandin endoperoxide intermediates may be utilized as substrates for vascular PGI2 synthesis. Using several different approaches, we have found that platelets can transfer endoperoxides to cultured endothelial cells for efficient conversion to PGI2, but a reciprocal transfer of endothelial endoperoxides for utilization by platelet thromboxane synthetase does not occur under the same experimental conditions. However, platelets can utilize arachidonic acid released by endothelial cells for lipoxygenase metabolism. We have directly demonstrated the production of [3H]6-keto-PGF1 alpha (the breakdown product of [3H]PGI2) by aspirin-treated endothelial cells in the presence of platelets stimulated with [3H]arachidonic acid. In coincubation experiments using either arachidonate or ionophore A23187 as a stimulus, radioimmunoassay of the net production of arachidonic acid metabolites showed that 6-keto-PGF1 alpha generation by aspirin-treated endothelial cells in the presence of platelets may actually exceed its generation by uninhibited endothelial cells alone. In functional assays, platelet aggregation was inhibited in the presence of aspirin-treated endothelial cells after stimulation with either arachidonate or ionophore A23187. In contrast, the inverse experiments, using aspirin-treated platelets and uninhibited endothelial cells, failed to demonstrate platelet utilization of endothelial endoperoxides for TXA2 production by any of the above methods. These studies thus provide evidence that efficient unidirectional transfer and utilization of platelet-derived endoperoxides for endothelial PGI2 production can occur. This process may serve to amplify PGI2 generation adjacent to areas of vascular

  7. Protease-activated receptors and prostaglandins in inflammatory lung disease

    PubMed Central

    Peters, Terence; Henry, Peter J

    2009-01-01

    Protease-activated receptors (PARs) are a novel family of G protein-coupled receptors. Signalling through PARs typically involves the cleavage of an extracellular region of the receptor by endogenous or exogenous proteases, which reveals a tethered ligand sequence capable of auto-activating the receptor. A considerable body of evidence has emerged over the past 20 years supporting a prominent role for PARs in a variety of human physiological and pathophysiological processes, and thus substantial attention has been directed towards developing drug-like molecules that activate or block PARs via non-proteolytic pathways. PARs are widely expressed within the respiratory tract, and their activation appears to exert significant modulatory influences on the level of bronchomotor tone, as well as on the inflammatory processes associated with a range of respiratory tract disorders. Nevertheless, there is debate as to whether the principal response to PAR activation is an augmentation or attenuation of airways inflammation. In this context, an important action of PAR activators may be to promote the generation and release of prostanoids, such as prostglandin E2, which have well-established anti-inflammatory effects in the lung. In this review, we primarily focus on the relationship between PARs, prostaglandins and inflammatory processes in the lung, and highlight their potential role in selected respiratory tract disorders, including pulmonary fibrosis, asthma and chronic obstructive pulmonary disease. This article is part of a themed issue on Mediators and Receptors in the Resolution of Inflammation. To view this issue visit http://www3.interscience.wiley.com/journal/121548564/issueyear?year=2009 PMID:19845685

  8. Modulation of prostaglandin biosynthesis in murine mammary adenocarcinoma tumor cells

    SciTech Connect

    Shalinsky, D.R.

    1988-01-01

    In efforts to exploit the differential oxygen levels within the subcompartments of solid neoplasms, this project has focused on modulating prostaglandin (PG) biosynthesis under aerobic and hypoxic conditions. Mammary adenocarcinoma tumor cells (Line 4526), either intact or sonicated, were incubated with either 2.0 uM {sup 14}C-arachidonic acid (AA) or 20.0 uM {sup 14}C-PGH{sub 2}, respectively. Following metabolism, products were extracted, separated by thin layer chromatography and analyzed by radiochromatographic scan. PGE{sub 2} was predominantly formed with minimal amounts of PGF{sub 2a} or PGD{sub 2}. Indomethacin and ibuprofen inhibited the PGE{sub 2} formation from AA with an IC{sub 50} value of 6.3 {times} 10{sup {minus}8} and 9.6 {times} 10{sup {minus}5}M, respectively. Suspended cells in glass vials were made hypoxic by flushing with N{sub 2} for varying time intervals to study AA metabolism. A time-dependent inhibition of PG biosynthesis was observed under hypoxia, and by 30 min, the PGE{sub 2} synthesis was reduced by 50% which was further inhibited by indomethacin. Misonidazole, a 2-nitroimidazole analogue, partially reversed the inhibition of PGE{sub 2} synthesis under hypoxia by 49% at 100 uM. However, misonidazole did not affect PG biosynthesis under aerobic conditions. The stimulation of PGE{sub 2} biosynthesis by misonidazole under hypoxia was blocked by indomethacin, suggesting that misonidazole can not act independently of the cyclooxygenase.

  9. Interleukin-2 deficit in hemodialysis patients. Role of prostaglandins.

    PubMed

    Glez-Gutiérrez, M; de Francisco, A L; Sanz de Castro, S; Ruiz, J C; Prieto, M; García Fuentes, M; Arias, M

    1992-01-01

    Uremic patients suffer from various immunological alterations, whose pathogenesis is still unknown. Here, we studied 37 hemodialysis patients in order to investigate the role of prostaglandins (PGs) in uremic immunological deficiency, specifically in relation to interleukin-2 (IL-2) synthesis. We confirmed previous published data on deficient response to PHA in chronic renal failure patients (cpm, mean +/- SEM: 15,400 +/- 2,100 in uremics vs. 29,500 +/- 3,380 in controls, p < 0.04) and established a correlation between this deficiency and diminished IL-2 synthesis (r = 0.619, p < 0.05). The direct measurement of PGs in lymphocyte cultures showed greatly increased concentrations in the presence of uremic serum (US). We found that PGs synthesis can be inhibited by up to 80% if cultures are supplemented with indomethacin (IND--a cyclooxigenase inhibitor) or by removal of monocytes (producers of PGs). Both methods situated the uremic proliferative response within the normal range in cultures with FCS, and close to the normal range in cultures with US. We observed a deficit of IL-2 in hemodialysis patients (means +/- SD: 8,940 +/- 6,420 in uremics vs. 16,900 +/- 3,890 in controls). Addition of exogenous IL-2 normalized lymphocyte response even in US cultures, with no additive effect between PGs inhibition and exogenous IL-2 except in US cultures. It is suggested that IL-2 deficit of uremics depends, at least in part, on an increase in PGs synthesis induced by US.(ABSTRACT TRUNCATED AT 250 WORDS)

  10. Role of prostaglandins in the renal response to calcium infusion.

    PubMed

    Lahera, V; Fiksen-Olsen, M J; Romero, J C

    1990-04-01

    The effects of intrarenal infusions of calcium gluconate (10 and 100 micrograms Ca.kg-1.min-1) on renal hemodynamics and on renal excretory function were studied in anesthetized mongrel dogs. In one group, the two doses of calcium were infused for 30 min each (1 ml/min). In a second group, the same doses were administered 30 min after the start of an infusion of prostaglandin (PG) inhibitors (intrarenal indomethacin, 10 micrograms.kg-1.min-1, or intravenous bolus injection of meclofenamate, 5 mg/kg). No change with physiological significance was observed during the infusion of 10 micrograms Ca.kg-1.min-1. However, the infusion of 100 micrograms Ca.kg-1.min-1 induced increases (P less than 0.05) in glomerular filtration rate (50%), sodium excretion rate (180%), and fractional excretion of sodium (160%), with respect to control precalcium values. All these changes were prevented by the concurrent administration of PG synthesis inhibitors. Urinary PGE2 and 6-keto-PGF1 alpha increased 220 and 85%, respectively, during the infusion of 100 micrograms Ca.kg-1.min-1, but both decreased (P less than 0.05) below basal levels during the concurrent administration of PG synthesis inhibitors. The infusion of 100 micrograms Ca.kg-1.min-1 decreased (P less than 0.05) renal blood flow by 16% during the administration of PG synthesis inhibitors. These results suggest that PGs are mediating the increase in hemodynamic and excretory factors induced by the intrarenal infusion of 100 micrograms Ca.kg-1.min-1.

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

    SciTech Connect

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

    1985-12-15

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

  12. 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.

  13. 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.

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

    NASA Technical Reports Server (NTRS)

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

    1990-01-01

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

  15. [Evaluation of the use of prostaglandins E2 in cervical maturation].

    PubMed

    Loria Casanova, M; Lemus Maichel, M; Kably Ambe, A

    1989-07-01

    This is a prospective study in order to know the efficacy of prostaglandin E2 gel in the induction of labor by intravaginal administration at the Instituto Nacional de Perinatología. All pregnancies had between 16 and 34 weeks of gestation. There were two groups: Group A (n = 40) patients in whom the induction was made with prostaglandin plus oxitocin, and Group B (n = 40) when just oxitocin was employed. In the first group it was shown a shortening in the length of time of induction, hospitalization days and resolution of the pregnancy by vaginal route in the 100% of the cases. We did not observed side effects in relation to the use of the prostaglandin.

  16. TISSUE REGENERATION. Inhibition of the prostaglandin-degrading enzyme 15-PGDH potentiates tissue regeneration.

    PubMed

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

    2015-06-12

    Agents that promote tissue regeneration could be beneficial in a variety of clinical settings, such as stimulating recovery of the hematopoietic system after bone marrow transplantation. Prostaglandin PGE2, a lipid signaling molecule that supports expansion of several types of tissue stem cells, is a candidate therapeutic target for promoting tissue regeneration in vivo. Here, we show that inhibition of 15-hydroxyprostaglandin dehydrogenase (15-PGDH), a prostaglandin-degrading enzyme, potentiates tissue regeneration in multiple organs in mice. In a chemical screen, we identify a small-molecule inhibitor of 15-PGDH (SW033291) that increases prostaglandin PGE2 levels in bone marrow and other tissues. SW033291 accelerates hematopoietic recovery in mice receiving a bone marrow transplant. The same compound also promotes tissue regeneration in mouse models of colon and liver injury. Tissues from 15-PGDH knockout mice demonstrate similar increased regenerative capacity. Thus, 15-PGDH inhibition may be a valuable therapeutic strategy for tissue regeneration in diverse clinical contexts.

  17. The effect of prostaglandin inhibition on the development of pulmonary pathology associated with dead Dirofilaria immitis.

    PubMed

    Tarish, J H; Atwell, R B

    1993-09-01

    Flunixin meglumine was used to examine the effect of prostaglandin inhibition on the pathogenesis of Dirofilaria immitis in the pulmonary arteries of dogs. Immunopathological reactions to dead filariae were monitored by light and transmission electron microscopy and serology. Lung lesions in prostaglandin-inhibited dogs exposed to dead filariae were enhanced compared to control dogs. This was associated with the persistence of parasitic antigen in lung tissue and in the blood. Serology demonstrated that after insertion of D. immitis in treated dogs, antibody levels did not change, while immune complex and antigen levels increased. These results indicate that prostaglandin may have a protective effect on the way the lung reacts to dead D. immitis, and that altered dynamics of the antigen processing may well contribute to the associated lung lesions.

  18. High-Throughput Quantification of Bioactive Lipids by MALDI Mass Spectrometry: Application to Prostaglandins

    PubMed Central

    Manna, Joseph D.; Reyzer, Michelle L.; Latham, Joey C.; Weaver, C. David; Marnett, Lawrence J.; Caprioli, Richard M.

    2011-01-01

    Analysis and quantification of analytes in biological systems is a critical component of metabolomic investigations of cell function. The most widely used methods employ chromatographic separation followed by mass spectrometric analysis, which requires significant time for sample preparation and sequential chromatography. We introduce a novel high-throughput, separation-free methodology based on MALDI mass spectrometry that allows for the parallel analysis of targeted metabolomes. Proof-of-concept is demonstrated by analysis of prostaglandins and glyceryl prostaglandins. Derivatization to incorporate a charged moiety into ketone-containing prostaglandins dramatically increases the signal-to-noise ratio relative to underivatized samples. This resulted in an increased dynamic range (15 fmol – 2000 fmol on plate) and improved linearity (r2= 0.99). The method was adapted for high-throughput screening methods for enzymology and drug discovery. Application to cellular metabolomics was also demonstrated. PMID:21770391

  19. 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.

  20. Effect of exogenous ovarian steroids on the uterine luminal prostaglandins in ovariectomised mares with experimental endometritis.

    PubMed

    Watson, E D; Stokes, C R; Bourne, F J

    1988-05-01

    Prostaglandins (PGs) F and E2 were measured in lavage fluid from the uterus of ovariectomised mares after experimental induction of uterine inflammation. Treatment with progesterone alone, or progesterone followed by oestradiol, significantly increased the concentrations of these PGs in the lavage compared with mares treated with oestradiol or control mares. Ovarian steroids, therefore, influenced uterine PG synthesis in response to an inflammatory stimulus. To determine whether the uterine lavage procedure might contribute to the concentrations of prostaglandins in the lavage, the procedure was also performed on six intact mares. With the exception of washings obtained at luteolysis, uterine concentrations of PGF (measured as the plasma metabolite 15-keto-13,14-dihydro PGF2 alpha) had returned to prewashing levels within 30 minutes of the start of uterine lavage. Lavage was therefore unlikely to have influenced the concentrations of prostaglandins in the lavage fluid.

  1. Prostaglandin receptor EP2 is responsible for cyclooxygenase-2 induction by prostaglandin E2 in mouse skin.

    PubMed

    Ansari, Kausar M; Sung, You Me; He, Guobin; Fischer, Susan M

    2007-10-01

    The EP2 prostanoid receptor is one of the four subtypes of receptors for prostaglandin E2 (PGE2). We previously reported that deletion of EP2 led to resistance to chemically induced mouse skin carcinogenesis, whereas overexpression of EP2 resulted in enhanced tumor development. The purpose of this study was to investigate the underlying molecular mechanisms. We found that EP2 knockout mice had reduced cyclooxygenase-2 (COX-2) expression after 12-O-tetradecanoylphorbol-13-acetate (TPA) treatment compared with wild-type (WT) mice. Further, primary keratinocytes from EP2 transgenic mice had increased COX-2 expression after either TPA or PGE2 treatment and COX-2 expression was blocked by 10 microM SQ 22,536, an adenylate cyclase inhibitor. EP2 knockout mice had significantly decreased, whereas EP2 transgenic mice had significantly increased PGE2 production in response to a single treatment of TPA. Cyclic AMP response element-binding protein (CREB) phosphorylation was elevated to a greater extent in keratinocytes from EP2 transgenic mice compared with those of WT mice following PGE2 treatment. A protein kinase A (PKA) inhibitor reduced PGE2-mediated CREB phosphorylation in keratinocytes from EP2 transgenic mice. Furthermore, we found that there was no CREB phosphorylation in EP2 knockout mice following PGE2 treatment. PGE2-induced DNA synthesis (cell proliferation) was significantly decreased in keratinocytes from EP2 knockout mice following pretreatment with 10 microM SQ 22,536. Taken together, EP2 activation of the PKA/CREB-signaling pathway is responsible for keratinocyte proliferation and our findings reveal a positive feedback loop between COX-2 and PGE2 that is mediated by the EP2 receptor.

  2. Skin graft hypertrichosis associated with prostaglandin analog in the treatment of glaucoma.

    PubMed

    Shafi, Fariha; Madge, Simon N

    2014-01-01

    Prostaglandin analogs are commonly used in the treatment of glaucoma. They are a safe and effective treatment associated with few side effects. Common local side effects include conjunctival hyperemia, iris pigmentation, and eyelash hypertrichosis. The authors present a case of a patient using travoprost treatment for primary open-angle glaucoma, who underwent excision of a lower eyelid basal cell carcinoma and reconstruction with an upper eyelid tarsoconjunctival flap and overlying skin graft. The patient developed hypertrichosis of the skin graft attributable to prostaglandin analog use.

  3. Theophylline prevents the inhibitory effect of prostaglandin E2 on glucose-induced insulin secretion in man.

    PubMed

    Giugliano, D; Cozzolino, D; Salvatore, T; Giunta, R; Torella, R

    1988-06-01

    This study was undertaken to assess the mechanism by which prostaglandins of the E series inhibit glucose-induced insulin secretion in man. Acute insulin response (mean change 3-10 min) to iv glucose (0.33 g/kg) was decreased by 40% during the infusion of prostaglandin E2 (10 micrograms/min) and glucose disappearance rates were reduced (P less than 0.05). Insulin response to arginine (5 g iv) and tolbutamide (1 g iv) were not affected by the same rate of prostaglandin E2 infusion. The inhibitory effect of prostaglandin E2 on glucose-induced insulin secretion was prevented by theophylline (100 mg as a loading dose followed by a 5 mg/min infusion), a drug that increases the intracellular cAMP concentrations by inhibiting phosphodiesterase activity. Our data suggest the involvement of the adenylate cyclase system in the inhibitory action of prostaglandin E2 on glucose-induced insulin secretion in man.

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

    PubMed

    Ganesh, Thota

    2015-07-01

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

  5. 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

  6. 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.

  7. Inhibition of the prostaglandin receptor EP2 following status epilepticus reduces delayed mortality and brain inflammation.

    PubMed

    Jiang, Jianxiong; Quan, Yi; Ganesh, Thota; Pouliot, Wendy A; Dudek, F Edward; Dingledine, Raymond

    2013-02-26

    Prostaglandin E2 is now widely recognized to play critical roles in brain inflammation and injury, although the responsible prostaglandin receptors have not been fully identified. We developed a potent and selective antagonist for the prostaglandin E2 receptor subtype EP2, TG6-10-1, with a sufficient pharmacokinetic profile to be used in vivo. We found that in the mouse pilocarpine model of status epilepticus (SE), systemic administration of TG6-10-1 completely recapitulates the effects of conditional ablation of cyclooxygenase-2 from principal forebrain neurons, namely reduced delayed mortality, accelerated recovery from weight loss, reduced brain inflammation, prevention of blood-brain barrier opening, and neuroprotection in the hippocampus, without modifying seizures acutely. Prolonged SE in humans causes high mortality and morbidity that are associated with brain inflammation and injury, but currently the only effective treatment is to stop the seizures quickly enough with anticonvulsants to prevent brain damage. Our results suggest that the prostaglandin receptor EP2 is critically involved in neuroinflammation and neurodegeneration, and point to EP2 receptor antagonism as an adjunctive therapeutic strategy to treat SE.

  8. Inhibition of the prostaglandin receptor EP2 following status epilepticus reduces delayed mortality and brain inflammation

    PubMed Central

    Jiang, Jianxiong; Quan, Yi; Ganesh, Thota; Pouliot, Wendy A.; Dudek, F. Edward; Dingledine, Raymond

    2013-01-01

    Prostaglandin E2 is now widely recognized to play critical roles in brain inflammation and injury, although the responsible prostaglandin receptors have not been fully identified. We developed a potent and selective antagonist for the prostaglandin E2 receptor subtype EP2, TG6-10-1, with a sufficient pharmacokinetic profile to be used in vivo. We found that in the mouse pilocarpine model of status epilepticus (SE), systemic administration of TG6-10-1 completely recapitulates the effects of conditional ablation of cyclooxygenase-2 from principal forebrain neurons, namely reduced delayed mortality, accelerated recovery from weight loss, reduced brain inflammation, prevention of blood–brain barrier opening, and neuroprotection in the hippocampus, without modifying seizures acutely. Prolonged SE in humans causes high mortality and morbidity that are associated with brain inflammation and injury, but currently the only effective treatment is to stop the seizures quickly enough with anticonvulsants to prevent brain damage. Our results suggest that the prostaglandin receptor EP2 is critically involved in neuroinflammation and neurodegeneration, and point to EP2 receptor antagonism as an adjunctive therapeutic strategy to treat SE. PMID:23401547

  9. 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.

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

    Technology Transfer Automated Retrieval System (TEKTRAN)

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

  11. 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.

  12. Neutrophil activation: an alternative to prostaglandin inhibition as the mechanism of action for NSAIDs.

    PubMed

    Altman, R D

    1990-02-01

    Experimental findings suggest that inhibition of neutrophil activation rather than suppression of prostaglandin formation may represent the principal mechanism of action of antiinflammatory drugs. This theory would account for the effectiveness of prostaglandin preserving agents, such as the nonacetylated salicylate salsalate, in the treatment of rheumatic disease. Results of the controlled clinical trials described in other papers contained in this supplement indicate that salsalate is equally effective as aspirin and the newer NSAID naproxen in relieving the signs and symptoms of rheumatoid arthritis. The damage to the gastric mucosa associated with NSAID use is believed to be attributable to impairment of mucosal defense mechanisms resulting from the inhibition of gastroprotective prostaglandins. Confirmation of neutrophil activation as the mechanism of action of NSAIDs would explain the efficacy of salsalate in light of its lower incidence of gastrointestinal side effects in controlled clinical trials with aspirin and naproxen. Establishment of such a mechanism would also suggest that the other adverse effects related to prostaglandin inhibition, such as hypersensitivity reactions, platelet dysfunction, and a reduction in renal function, are not necessary correlates of effective antiinflammatory therapy.

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

    PubMed

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

    2015-01-02

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

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

    PubMed

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

    2013-06-01

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

  16. Role of nitric oxide and prostaglandins in the bone formation response to mechanical loading.

    PubMed

    Chow, J W

    2000-10-01

    Nitric oxide and prostaglandins are crucial early mediators in mechanically induced bone formation. They are also responsible for the associated induction of gene expression of c-fos and IGF-1 in osteocytes, key mechanosensory cells in bone. Insight into the cellular and molecular mechanisms underlying bone formation has important implications for the maintenance of structural competence of bone.

  17. 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

  18. Different effects of growth hormone-releasing hormone (GRH) and somatostatin on growth hormone and stable metabolite of prostaglandin E2, 13, 14-dihydro-15-keto-prostaglandin E2 (PGE2-M) in normal subjects.

    PubMed

    Zacharieva, S; Muchá, I; Popova, J; Andonova, K

    1992-01-01

    Twenty four healthy subjects were placed in two treatment groups: 1. The first group consisted of twelve subjects in whom growth releasing hormone (GRH) (1 microgram/kg.BW) resulted in a marked and sustained elevation of serum growth hormone (GH) and a slight and delayed increase in plasma prostaglandin E2-M. In the second group, consisting also of twelve subjects, somatostatin infusion (500 micrograms/250 ml) was initiated and maintained for 60 min. Serum GH significantly decreased at 30 and 60 min during infusion and 15 min thereafter. We did not observe any changes in plasma prostaglandin E2-M during or after somatostatin infusion. The results obtained confirm previous in vitro studies and suggest a possible link between growth releasing hormone and prostaglandin E2 in their action on growth hormone secretion. It seems that somatostatin does not play a role in the control of prostaglandin E2 release.

  19. 15-deoxy prostaglandin J2, the nonenzymatic metabolite of prostaglandin D2, induces apoptosis in keratinocytes of human hair follicles: a possible explanation for prostaglandin D2-mediated inhibition of hair growth.

    PubMed

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

    2016-07-01

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

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

    PubMed

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

    2015-12-01

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

  1. 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.

  2. 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.

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

    PubMed Central

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

    2013-01-01

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

  4. A cross-sectional survey of the association between bilateral topical prostaglandin analogue use and ocular adnexal features.

    PubMed

    Shah, Mamta; Lee, Grace; Lefebvre, Daniel R; Kronberg, Benjamin; Loomis, Stephanie; Brauner, Stacey C; Turalba, Angela; Rhee, Douglas J; Freitag, Suzanne K; Pasquale, Louis R

    2013-01-01

    We studied the relation between prostaglandin analogue use and ocular adnexal features. We used a prospective, cross-sectional study involving 157 current, 15 past, and 171 never users of prostaglandin analogues. Patients 50 years of age or older and without conditions affecting ocular adnexal anatomy underwent glaucoma medication use history, external digital photography and systematic external adnexal exam. Two masked readers assessed the digital photos for upper lid dermatochalasis and lower lid steatoblepharon using a validated grading scheme. Another masked clinical examiner also assessed upper lid ptosis, levator muscle function, and inferior scleral show. We performed ordinal logistic regression analysis accounting for multiple covariates to assess the relation between prostaglandin analogue use and adnexal features. Multivariable analyses indicated there was a 230-fold increased risk of incremental involution of dermatochalasis (odds ratio (OR) = 2.30; 95% confidence interval (CI) 1.43-3.69; p = 5.44E-04) and a 249-fold increased risk of incremental loss of lower lid steatoblepharon (OR = 2.49; 95% CI, 1.54-4.03; p= 1.98E-04) associated with current prostaglandin analogue use (bimatoprost 0.03%, travoprost 0.005%, or latanoprost 0.004%) versus prostaglandin analogue never or past users. Upper lid ptosis (OR = 4.04; 95% CI, 2.43-6.72; p = 7.37E-08), levator dysfunction (OR = 7.51; 95% CI, 3.39-16.65; p = 6.74E-07) and lower lid retraction (OR = 2.60; 95% CI, 1.58-4.28; p = 1.72E-04) were highly associated with current prostaglandin analogue use versus prostaglandin analogue never or past users. The associations between prostaglandin analogue use and deepening of the upper lid sulci and between prostaglandin analogue use and loss of inferior periorbital fat are confirmed in this multivariable analysis. The associations between prostaglandin analogue use and levator muscle dysfunction and between prostaglandin analogue use and upper lid ptosis represent

  5. 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.

  6. Implication of Prostaglandins and Histamine H1 and H2 Receptors in Radiation-Induced Temperature Responses of Rats

    DTIC Science & Technology

    1988-05-01

    1988) S Implication of Prostaglandins and Histamine H1 and H 2 Receptors in Radiation-Induced Temperature Responses of Rats SATHASIVA B. KANDASAMY ... KANDASAMY , S. B., HUNT. W. A., AND MICKLEY, G. A. Implications of Prostaglandins and Histamine H I and H2 Receptors in Radiation-Induced Temperature...lateral ventricle according to coordinates derived from the atlas of Pelligrino et al. (31): 0.8 mm posterior to bregma. 2.5 mm lateral. 44 KANDASAMY , HUNT

  7. Exaggerated human vascular cell prostaglandin biosynthesis mediated by monocytes: role of monokines and interleukin 1.

    PubMed

    Albrightson, C R; Baenziger, N L; Needleman, P

    1985-09-01

    Incubation of cultured human umbilical vein endothelial cells with factors derived from human peripheral blood mononuclear cells (MNCF) or adherent monocytes (AMF) resulted in concentration-and time-dependent increases in prostacyclin and prostaglandin E2 (PGE2) production. MNCF and AMF also stimulated prostacyclin and PGE2 biosynthesis in cultured human arterial smooth muscle cells and human dermal fibroblasts. The effect of these monokines on endothelial cells and fibroblasts was mimicked by treatment with purified human interleukin 1 (IL 1). Mononuclear cell-conditioned medium subjected to gel filtration yielded fractions (Mr 12,000 to 18,000 daltons) which simultaneously contained endothelial cell and fibroblast prostaglandin-stimulating activity and IL 1 activity. Therefore, monokines, specifically IL 1, appear to serve as chemical mediators of the interaction between monocytes and vascular cells as would occur in blood vessel injury, inflammation, and atherosclerosis.

  8. Molecular cloning and expression of rat prostaglandin E receptor EP2 subtype.

    PubMed

    Sando, T; Usui, T; Tanaka, I; Mori, K; Sasaki, Y; Fukuda, Y; Namba, T; Sugimoto, Y; Ichikawa, A; Narumiya, S

    1994-05-16

    A cDNA clone encoding the rat prostaglandin (PG) E receptor EP2 subtype was cloned from a rat lung cDNA library. It encodes 488 amino acid residues with putative seven-transmembrane domains. Specific binding of [3H]PGE2 was found in COS-7 cells transfected with the cDNA and was displaced with unlabeled prostaglandins in the order of PGE2 = PGE1 > iloprost > or = PGF2 alpha > or = PGD2. The binding was also inhibited by misoprostol, an EP2 and EP3 agonist, but not by sulprostone, an EP1 and EP3 agonist. Northern blot analysis demonstrated that the EP2 mRNA is widely expressed in various tissues, the significant expression being observed in the thymus, lung, spleen, heart stomach, and pancreas.

  9. 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

  10. 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.

  11. Inhibition of Mayaro virus replication by prostaglandin A(1) in Vero cells.

    PubMed

    Burlandy, F M; Rebello, M A

    2001-01-01

    Prostaglandins exhibit antiviral activity against a wide variety of RNA and DNA viruses. In the present report, we describe the effect of cyclopentenone prostaglandin A(1) (PGA(1)) on Mayaro virus replication in Vero cells. Virus yield was significantly reduced at nontoxic concentrations which did not suppress DNA, RNA or protein synthesis in uninfected or infected cells. Antiviral action decreased if PGA(1) was added at later times after infection. In Mayaro virus-infected cells, PGA(1) inhibited the synthesis of virus proteins. This effect is accompanied by the induction of heat shock proteins (HSPs). Actinomycin D treatment not only inhibited the induction of HSPs but also partially prevented PGA(1) antiviral activity.

  12. Cafeteria diet increases prostaglandin E2 levels in rat prostate, kidney and testis.

    PubMed

    Brunetti, L; Leone, S; Chiavaroli, A; Orlando, G; Recinella, L; Ferrante, C; Di Nisio, C; Verratti, V; Vacca, M

    2010-01-01

    Nutrient composition, particularly the omega-6/omega-3 polyunsaturated fatty acids ratio, may differently affect inflammatory mediators production in tissues, which could be causally related to increased cancer incidence in obesity. We evaluated prostaglandin E(2) levels in male Wistar rat prostate, kidney and testicle tissues after 15 days of either a high fat, cafeteria-style diet (5.50 Kcal/g, 30 percent calories from fat, omega-6/omega-3 ratio 2.33) or a standard laboratory chow diet (3.35 Kcal/g, 3 percent calories from fat, omega-6/omega-3 ratio 0.56). In the cafeteria diet compared to standard laboratory diet rats, we found both an increase in weight gain and increased prostaglandin E(2) (PGE(2)) levels in prostate, kidney and testicle tissues. The increased levels of PGE(2) induced by the cafeteria diet could drive an inflammatory process leading to increased incidence of prostate, kidney and testicular cancer in overweight patients.

  13. Does prostaglandin D2 hold the cure to male pattern baldness?

    PubMed

    Nieves, Ashley; Garza, Luis A

    2014-04-01

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

  14. Gas-liquid chromotography of trimethylsilyl and alkyl oxime-trimethylsilyl derivatives of some prostaglandins.

    PubMed

    Middleditch, B S; Desiderio, D M

    1972-08-01

    TMS (trimethylsilyl), MO-TMS (methyl oxime-TMS), and EO-TMS (ethyl oxime-TMS) derivatives of several prostaglandins (A, B1, B2, E1, 8-iso-E1, E2 and 8-iso-E2) were prepared and their gas chromatographic properties examined on a moderately polar (OV-17) and a relatively non-polar (SE-30) stationary phase. Combined gas chromatography-mass spectrometry (GC-MS) using an LKB 9000 instrument was used to identify the different derivatives. Although the TMS derivatives are more easily prepared, the TMS derivatives of the PgE series are thermally somewhat unstable. Thus, MO-TMS and EO-TMS derivatives which exhibit more regular retention increments are more useful for analytical work. The EO-TMS derivatives may be useful in determining mass spectral fragmentation modes of the prostaglandin derivatives.

  15. 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

  16. Oxygen resuscitation after hypoxia ischemia stimulates prostaglandin pathway in rat cortex

    PubMed Central

    Perez-Polo, J. Regino; Reilly, Conor B.; Rea, Harriet C.

    2011-01-01

    Exposure to hypoxia and hyperoxia in a rodent model of perinatal ischemia results in delayed cell death and and inflammation. Hyperoxia increases oxidative stress that can trigger inflammatory cascades, neutrophil activation, and brain microvascular injury. Here we show that 100% oxygen resuscitation in our rodent model of perinatal ischemia increases cortical COX-2 protein levels, S-nitrosylated COX-2cys526, PGE2, iNOS and 5-LOX, all components of the prostaglandin and leukotriene inflammatory pathway. PMID:21514373

  17. Discovery of AAT-008, a novel, potent, and selective prostaglandin EP4 receptor antagonist.

    PubMed

    Okumura, Yoshiyuki; Yamagishi, Tatsuya; Nukui, Seiji; Nakao, Kazunari

    2017-03-01

    Starting from acylsufonamide HTS hit 2, a novel series of para-N-acylaminomethylbenzoic acids was identified and developed as selective prostaglandin EP4 receptor antagonists. Structural modifications on lead compound 4a were explored with the aim of improving potency, physicochemical properties, and animal PK predictive of QD (once a day) dosing regimen in human. These efforts led to the discovery of the clinical candidate AAT-008 (4j), which exhibited significantly improved pharmacological profiles over grapiprant (1).

  18. 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

  19. 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.

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

    NASA Technical Reports Server (NTRS)

    Chromiak, Joseph A.; Vandenburgh, Herman H.

    1993-01-01

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

  1. Migraine: possible role of platelet insensitivity to prostaglandin E1 (PGE1).

    PubMed

    Cerneca, F; de Luyk, S; Radillo, O; Simeone, R; Mangiarotti, M

    1993-01-01

    Platelet aggregation inhibition, induced by prostaglandin E1 (PGE1), was evaluated in 38 patients affected by migraine. Our data indicate a complete insensitivity to PGE1 in these subjects. The insensitivity to PGE1 leads to decreased cyclic-AMP (cAMP) levels, determining an imbalance in the inhibitory mechanism. From this observation we can suppose that the decreased affinity of PGE1-receptors, causing decreased cAMP levels, may be involved in pathogenesis of migraine.

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

    PubMed Central

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

    2010-01-01

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

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

    PubMed

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

    2013-09-01

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

  4. Identification and characterization of the ocular hypotensive efficacy of travoprost, a potent and selective FP prostaglandin receptor agonist, and AL-6598, a DP prostaglandin receptor agonist.

    PubMed

    Hellberg, Mark R; McLaughlin, Marsha A; Sharif, Naj A; DeSantis, Louis; Dean, Tom R; Kyba, Evan P; Bishop, John E; Klimko, Peter G; Zinke, Paul W; Selliah, Robert D; Barnes, George; DeFaller, Joseph; Kothe, Angela; Landry, Theresa; Sullivan, E Kenneth; Andrew, Russell; Davis, Alberta A; Silver, Lewis; Bergamini, Michael V W; Robertson, Stella; Weiner, Alan L; Sallee, Verney L

    2002-08-01

    The structure-activity studies that led to the identification of travoprost, a highly selective and potent FP prostaglandin analog, and AL-6598, a DP prostaglandin analog, are detailed. In both series, the 1-alcohol analogs are very effective and are thought to be acting as prodrugs for the biologically active carboxylic acids. The efficacy of amide prodrugs depends on the degree of substitution and the size of the substituents. Selected compounds are profiled in vitro and in vivo preclinically. Clinical studies show that travoprost 0.004% (isopropyl ester) provided intraocular pressure control superior to timolol 0.5% when used as monotherapy in patients with open-angle glaucoma or ocular hypertension. In clinical studies, AL-6598 0.01% provided a sustained intraocular pressure reduction with q.d. application; b.i.d. provided greater intraocular pressure control. The acute and, apparently, conjunctival hyperemia associated with topical ocular AL-6598 can be attenuated while maintaining intraocular pressure-lowering efficacy by formulating with brimonidine.

  5. 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

  6. Inflammatory mediators and nociception in the joint: excitation and sensitization of slowly conducting afferent fibers of cat's knee by prostaglandin I2.

    PubMed

    Schepelmann, K; Messlinger, K; Schaible, H G; Schmidt, R F

    1992-09-01

    The effects of prostaglandin I2 on the discharge properties of fine articular afferents (group III and group IV fibers) in the cat were examined by extracellular recordings from single units dissected from the medial articular nerve of the knee joint. Prostaglandin I2 was applied intra-arterially close to the joint in doses of 0.3-30 micrograms per 0.3 ml bolus injection, and its effects on the spontaneous activity as well as on discharges evoked by mechanical and chemical stimulation (bradykinin) were monitored. Prostaglandin E2 was also applied and the effects of prostaglandins I2 and E2 on particular units were compared. An excitatory effect of prostaglandin I2 was observed in 49% of 37 group III and in 37% of 27 group IV units. A sensitization to passive movements of the joint occurred in 71% of 31 group III and 48% of 21 group IV units. Sixty-seven per cent of 32 units (groups III and IV) were both excited and sensitized by prostaglandin I2 to movements of 27% were sensitized but not excited. In 64% of 11 group III and 63% of eight group IV units studied the responses to bradykinin were enhanced by prostaglandin I2. Prostaglandin E2 had qualitatively similar effects as prostaglandin I2 but excited and sensitized a lower proportion of articular afferents. Forty-one per cent of the units were sensitive to both prostaglandins but 26% of the fibers were only sensitive to prostaglandin I2. None of the units was exclusively sensitive to prostaglandin E2. In general, the excitatory and sensitizing effects of prostaglandin E2 had a longer duration than those exerted by prostaglandin I2. We conclude that prostaglandin I2 increases the sensitivity to mechanical stimuli as well as to chemical stimulation by bradykinin in the majority of articular group III and group IV fibers. Moreover, in a large proportion of articular afferents, prostaglandin I2 had an excitatory effect. Thus, prostaglandin I2 may be an inflammatory mediator which is important for inflammation

  7. Comparison of effects of aspirin and indomethacin on human platelet prostaglandin synthetase.

    PubMed Central

    Crook, D; Collins, A J

    1977-01-01

    Human platelets were incubated in vitro with either aspirin or indomethacin and the prostaglandin synthetase activity of the resultant microsomal fraction from each incubation measured using a radiometric technique. Whereas aspirin produced a dose-related inhibition of the enzyme, indomethacin produced little or no inhibition over the same concentration range (10(-6) mol/l--10(-3) mol/l). Furthermore, administration of aspirin (600 mg) to volunteers produced a highly significant, prolonged inhibition of platelet microsomal prostaglandin synthetase whereas no inhibition was found with indomethacin (50 mg). As indomethacin is considerably more potent than aspirin as an inhibitor of human platelet prostaglandin synthetase in vitro, the results suggest a fundamental difference in the nature of the inhibition produced by each drug, aspirin being an essentially irreversible inhibitor whereas the inhibition produced by indomethacin is reversible. Studies with [3H-acetyl] aspirin have confirmed previous findings (Roth and Majerus, 1975) that aspirin produces an irreversible acetylation of a particulate fraction protein from human platelets. PMID:411427

  8. Molecular cloning and characterization of the canine prostaglandin E receptor EP2 subtype.

    PubMed

    Hibbs, T A; Lu, B; Smock, S L; Vestergaard, P; Pan, L C; Owen, T A

    1999-05-01

    Prostaglandin E2 (PGE2) binds to four G-protein coupled cell surface receptors (EP1-EP4) and has been implicated as a local mediator of bone anabolism via a cyclic AMP mediated pathway following activation of the EP2 and/or EP4 receptor subtype. A canine kidney cDNA library was screened using a human EP2 probe, and a clone with an open reading frame of 1083 bp, potentially encoding a protein of 361 amino acids, was characterized. This open reading frame has 89% identity to the human EP2 cDNA at the nucleotide level and 87% identity at the predicted protein level. Scatchard analysis of a CHO cell line stably transfected with canine EP2 yielded a dissociation constant of 22 nM for PGE2. Competition binding studies, using 3H-PGE2 as ligand, demonstrated specific displacement by PGE2, Prostaglandin E1, Prostaglandin A3, and butaprost (an EP2 selective ligand), but not by ligands with selectivity for the related DP, FP, IP, or TP receptors. Specific ligand binding also resulted in increased levels of cAMP in EP2 transfected cells with no evidence of short-term, ligand-induced desensitization. Northern blot analysis revealed two transcripts of 3300 and 2400 bp in canine lung, and reverse-transcription polymerase chain reaction showed expression in all tissues examined. Southern blot analysis suggests the presence of a single-copy gene for EP2 in the dog.

  9. Chronic stimulation of uterine prostaglandin synthesis during cervical ripening before the onset of labor.

    PubMed

    Keirse, M J; Thiery, M; Parewijck, W; Mitchell, M D

    1983-05-01

    Concentrations of 13,14-dihydro-15-keto-PGF2 alpha (PGFM) were measured in plasma of six carefully selected primigravid women with an unripe cervix at term before and at various intervals after extra-amniotic insertion of a Foley catheter with or without methylhydroxyethylcellulose (Tylose) gel. The procedure caused an acute elevation of PGFM levels within 5 min (P less than 0.025), which was maintained for at least 6 hours in the absence of uterine activation at 179 +/- 32% of the initial values (P less than 0.01). Extra-amniotic administration of Tylose gel caused an increase in PGFM levels which was both higher and more prolonged (greater than 12 hours) than insertion of a Foley catheter alone. The observations indicate that cervical ripening without concomitant uterine activation is associated with an increase in PGFM levels. They also demonstrate that prolonged activation of (intra) uterine prostaglandin synthesis may occur several hours before the onset of labor-like uterine activity. A chance finding further suggests that spontaneous rupture of the membranes too may be preceeded by an increase in (intra) uterine prostaglandin synthesis. In their totality these observations lend strong support to the proposition that an increase in (intra) uterine prostaglandin production is a prerequisite to rather than a consequence of the initiation of labor.

  10. 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.

  11. Lipopolysaccharide reduces food passage rate from the crop by a prostaglandin-independent mechanism in chickens

    PubMed Central

    Tachibana, T.; Ogino, M.; Makino, R.; Khan, M. S. I.; Cline, M. A.

    2017-01-01

    ABSTRACT 1. We examined the effect of lipopolysaccharide (LPS), a component of Gram-negative bacteria, on food passage in the digestive tract of chickens (Gallus gallus) in order to clarify whether bacterial infection affects food passage in birds. 2. Food passage in the crop was significantly reduced by intraperitoneal (IP) injection of LPS while it did not affect the number of defecations, suggesting that LPS may affect food passage only in the upper digestive tract. 3. Similar to LPS, prostaglandin E2 (PGE2), one of the mediators of LPS, also reduced crop-emptying rate in chickens while it had no effect on the number of defecations. 4. Pretreatment with indomethacin, which is an inhibitor of cyclooxygenase (COX), a prostaglandin synthase, had no effect on LPS-induced inhibition of crop emptying. 5. IP injection of LPS did not affect the mRNA expression of COX2 in the upper digestive tract of chickens. 6. It is therefore likely that LPS and PGE2 reduced food passage rate in the crop by a prostaglandin-independent pathway in chickens. PMID:27871194

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

    NASA Technical Reports Server (NTRS)

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

    2001-01-01

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

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

    PubMed

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

    2016-03-01

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

  14. Impact of prostaglandin glaucoma drops on platelet-activating factor action: an in vitro study

    PubMed Central

    Moschos, Marilita M; Nitoda, Eirini; Chatziralli, Irini P; Panos, Georgios D; Demopoulos, Constantinos A

    2016-01-01

    Aim The aim of this study was to investigate the effect of different prostaglandin analogs on platelet-activating factor (PAF) levels. Methods Three prostaglandin analogs were selected: bimatoprost 0.3 mg/mL, latanoprost 50 μg/mL, and tafluprost 15 μg/mL. Each drug sample was tested for its ability to cause platelet aggregation, which was measured as PAF-induced aggregation, before and after the addition of various concentrations of the examined sample, creating a linear curve of percentage inhibition (ranging from 0% to 100%) versus different concentrations of the sample. The concentration of the sample that inhibited 50% PAF-induced aggregation was calculated based on this curve, and this value was defined as IC50. In addition, the effect of eye drops on PAF metabolism was examined, through an in vitro analysis on PAF basic metabolic enzymes (PAF-cholinephosphotransferase, PAF-acetyl-CoA:1-O-alkyl-sn-glycero-3-phosphocholine acetyltransferase, and PAF-acetylhydrolase). Results The IC50 values for Lumigan UD® (bimatoprost 0.3 mg/mL), Monoprost® (latanoprost 50 μg/mL), and Saflutan (tafluprost 15 μg/mL) were 8.7, 0.28, and 1.4 μg/mL, respectively. Discussion All three prostaglandin analogs suspended PAF, but bimatoprost induced the most potent inhibition, compared to tafluprost and to the weak effect of latanoprost. PMID:27994439

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

    PubMed Central

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

    2015-01-01

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

  16. 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.

  17. 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.

  18. Lipopolysaccharide reduces food passage rate from the crop by a prostaglandin-independent mechanism in chickens.

    PubMed

    Tachibana, T; Ogino, M; Makino, R; Khan, M S I; Cline, M A

    2017-02-01

    1. We examined the effect of lipopolysaccharide (LPS), a component of Gram-negative bacteria, on food passage in the digestive tract of chickens (Gallus gallus) in order to clarify whether bacterial infection affects food passage in birds. 2. Food passage in the crop was significantly reduced by intraperitoneal (IP) injection of LPS while it did not affect the number of defecations, suggesting that LPS may affect food passage only in the upper digestive tract. 3. Similar to LPS, prostaglandin E2 (PGE2), one of the mediators of LPS, also reduced crop-emptying rate in chickens while it had no effect on the number of defecations. 4. Pretreatment with indomethacin, which is an inhibitor of cyclooxygenase (COX), a prostaglandin synthase, had no effect on LPS-induced inhibition of crop emptying. 5. IP injection of LPS did not affect the mRNA expression of COX2 in the upper digestive tract of chickens. 6. It is therefore likely that LPS and PGE2 reduced food passage rate in the crop by a prostaglandin-independent pathway in chickens.

  19. Monocyte prostaglandins inhibit procollagen secretion by human vascular smooth muscle cells: implications for plaque stability.

    PubMed

    Fitzsimmons, C; Proudfoot, D; Bowyer, D E

    1999-02-01

    Extracellular matrix remodelling occurs during atherosclerosis dictating the structure of the plaque and thus the resistance to rupture. Monocytes and macrophages are believed to play a role in this remodelling. In the present study, filter-separated co-culture has been used to study the effect of monocytes on procollagen turnover by human vascular smooth muscle cells (VSMC). In this system, freshly isolated human peripheral blood monocytes inhibited procollagen secretion from VSMC without affecting either degradation of procollagen, or DNA synthesis by the VSMC. Insertion of a 12 kDa dialysis membrane between the two cell types and treatment with indomethacin showed that the inhibitory factor was of low molecular weight and was cyclooxygenase-dependent. Pre-incubation of each cell type with indomethacin demonstrated that monocyte, but not VSMC cyclooxygenase was required. Thus, the inhibitory effect on procollagen secretion was due, most likely, to monocyte prostaglandins. Neither inhibition of thromboxane synthetase, nor blocking IL-1 activity, reduced the inhibitory activity. Addition of prostaglandins PGE1, PGE2 and PGF2alpha to VSMC cultures caused a reduction in procollagen secretion which was equivalent to, but was not additive with, the maximal effect achieved by monocytes. Monocytes and macrophages are a major source of prostaglandins and these molecules are likely to play an important role in collagen turnover within lesions.

  20. 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.

  1. Prospects for Lentiviral Vector Mediated Prostaglandin F Synthase Gene Delivery in Monkey Eyes In vivo

    PubMed Central

    Lee, Eun Suk; Rasmussen, Carol A.; Filla, Mark S.; Slauson, Sarah R.; Kolb, Aaron W.; Peters, Donna M.; Kaufman, Paul L.; Gabelt, B’Ann True; Brandt, Curtis R.

    2014-01-01

    Currently, the most effective outflow drugs approved for clinical use are prostaglandin F2α analogues, but these require daily topical self-dosing and have various intraocular, ocular surface and extraocular side effects. Lentiviral vector-mediated delivery of the prostaglandin F synthase (PGFS) gene, resulting in long-term reduction of IOP, may eliminate off-target tissue effects and the need for daily topical PGF2α self-administration. Lentiviral vector-mediated delivery of the PGFS gene to the anterior segment has been achieved in cats and non-human primates. Although these results are encouraging, our studies have identified a number of challenges that need to be overcome for prostaglandin gene therapy to be translated into the clinic. Using examples from our work in non-human primates, where we were able to achieve a significant reduction in IOP (2 mm Hg) for 5 months after delivery of the cDNA for bovine PGF synthase, we identify and discuss these issues and consider several possible solutions. PMID:24559478

  2. Contribution of covalent protein modification to the antiinflammatory effects of cyclopentenone prostaglandins.

    PubMed

    Pérez-Sala, Dolores; Cernuda-Morollón, Eva; Pineda-Molina, Estela; Cañada, F Javier

    2002-11-01

    Cyclopentenone prostaglandins, which are produced during inflammatory processes, may exert a negative feedback on inflammation. These reactive compounds may form covalent adducts with thiol groups in glutathione or in proteins. The transcription factor NF-kappaB is key for the expression of numerous proinflammatory genes. We have observed that treatment of mesangial cells with 15-deoxy-Delta(12,14)-prostaglandin J(2) (15d-PGJ(2)) inhibits the cytokine-elicited DNA binding activity of NF-kappaB, both in intact cells and in isolated nuclear extracts, thus suggesting a direct effect on DNA binding. By using a biotinylated 15d-PGJ(2) derivative, we have observed that 15d-PGJ(2) forms an adduct with the p50 subunit of NF-kappaB, as shown by Western blot and detection with horseradish peroxidase-conjugated streptavidin. In contrast, a p50 construct that bears a mutation in the cysteine residue involved in DNA binding (Cys62Ser) and is not susceptible to inhibition by 15d-PGJ(2) does not incorporate biotinylated 15d-PGJ(2). The labeling of several polypeptides after incubation of cells with biotinylated 15d-PGJ(2) suggests that there may be multiple targets for modification by 15d-PGJ(2). We propose that the covalent modification of NF-kappaB (and potentially other proteins) by 15d-PGJ(2) may contribute to the antiinflammatory effects of this prostaglandin.

  3. Changes in ion transport in inflammatory disease.

    PubMed

    Eisenhut, Michael

    2006-03-29

    Ion transport is essential for maintenance of transmembranous and transcellular electric potential, fluid transport and cellular volume. Disturbance of ion transport has been associated with cellular dysfunction, intra and extracellular edema and abnormalities of epithelial surface liquid volume. There is increasing evidence that conditions characterized by an intense local or systemic inflammatory response are associated with abnormal ion transport. This abnormal ion transport has been involved in the pathogenesis of conditions like hypovolemia due to fluid losses, hyponatremia and hypokalemia in diarrhoeal diseases, electrolyte abnormalities in pyelonephritis of early infancy, septicemia induced pulmonary edema, and in hypersecretion and edema induced by inflammatory reactions of the mucosa of the upper respiratory tract. Components of membranous ion transport systems, which have been shown to undergo a change in function during an inflammatory response include the sodium potassium ATPase, the epithelial sodium channel, the Cystic Fibrosis Transmembrane Conductance Regulator and calcium activated chloride channels and the sodium potassium chloride co-transporter. Inflammatory mediators, which influence ion transport are tumor necrosis factor, gamma interferon, interleukins, transforming growth factor, leukotrienes and bradykinin. They trigger the release of specific messengers like prostaglandins, nitric oxide and histamine which alter ion transport system function through specific receptors, intracellular second messengers and protein kinases. This review summarizes data on in vivo measurements of changes in ion transport in acute inflammatory conditions and in vitro studies, which have explored the underlying mechanisms. Potential interventions directed at a correction of the observed abnormalities are discussed.

  4. 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.

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

    SciTech Connect

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

    2015-01-02

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

  6. Prostaglandin E2 Reduces the Release and Infectivity of New Cell-Free Virions and Cell-To-Cell HIV-1 Transfer

    PubMed Central

    Serramía, María Jesús; Martínez-Bonet, Marta; Muñoz-Fernández, María Ángeles

    2014-01-01

    Background The course of human immunodeficiency virus type-1 (HIV-1) infection is influenced by a complex interplay between viral and host factors. HIV infection stimulates several proinflammatory genes, such as cyclooxigense-2 (COX-2), which leads to an increase in prostaglandin (PG) levels in the plasma of HIV-1-infected patients. These genes play an indeterminate role in HIV replication and pathogenesis. The effect of prostaglandin E2 (PGE2) on HIV infection is quite controversial and even contradictory, so we sought to determine the role of PGE2 and the signal transduction pathways involved in HIV infection to elucidate possible new targets for antiretrovirals. Results Our results suggest that PGE2 post-infection treatment acts in the late stages of the viral cycle to reduce HIV replication. Interestingly, viral protein synthesis was not affected, but a loss of progeny virus production was observed. No modulation of CD4 CXCR4 and CCR5 receptor expression, cell proliferation, or activation after PGE2 treatment was detected. Moreover, PGE2 induced an increase in intracellular cAMP (cyclic AMP) levels through the EP2/EP4 receptors. PGE2 effects were mimicked by dbcAMP and by a specific Epac (exchange protein directly activated by cyclic AMP) agonist, 8-Cpt-cAMP. Treatment with PGE2 increased Rap1 activity, decreased RhoA activity and subsequently reduced the polymerization of actin by approximately 30% compared with untreated cells. In connection with this finding, polarized viral assembly platforms enriched in Gag were disrupted, altering HIV cell-to-cell transfer and the infectivity of new virions. Conclusions Our results demonstrate that PGE2, through Epac and Rap activation, alters the transport of newly synthesized HIV-1 components to the assembly site, reducing the release and infectivity of new cell-free virions and cell-to-cell HIV-1 transfer. PMID:24586238

  7. 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.

  8. 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

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

    PubMed

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

    2016-07-01

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

  10. Prostaglandin involvement in the responses of the rabbit eye to water-soluble marihuana-derived material.

    PubMed

    Green, K; Cheeks, K E; Watkins, L; Bowman, K A; McDonald, T F; Ocasio, H; Deutsch, H M; Hodges, L C; Zalkow, L H

    1987-02-01

    Both anticoagulants (heparin and streptokinase) and non-steroidal anti-inflammatory compounds (aspirin and indomethacin) were used against a water-soluble derivative of marihuana, MDM. While the anticoagulants had no effect on the ocular effects of MDM, both aspirin and indomethacin altered the time course and effected the MDM-induced reduction of intraocular pressure. The usual initial hypertensive effect of intravenous MDM was eliminated and the later intraocular pressure fall occurred earlier as well as being inhibited by about 35 to 50%. Assay for prostaglandins revealed that intravenous MDM (3.86 micrograms) caused a marked rise in PGE2 concentration of the aqueous humor and iris-ciliary body during the first hour or two after administration of MDM, but normal values occurred at 4, 6, and 8 hours when the intraocular pressure is reduced by up to 60%. Following intravitreal MDM (0.002 microgram), however, the PGE2 levels remained unchanged over 24 hours, despite the induction of a fall in intraocular pressure between 14 and 18 hours which lasts for many hours. Prostaglandin appears to be involved in the hypertensive phase of intraocular pressure change after intravenous MDM injection; and, while the fall in intraocular pressure may contain a component partially mediated by prostaglandins, there is no evidence that intravitreal MDM induces any effect on prostaglandin levels. The involvement of prostaglandins, therefore, in the mediation of MDM-induced ocular hypotensive effects is apparently small.

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

    SciTech Connect

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

    1987-07-13

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

  12. Inhibition of prostaglandin-H-synthase by o-phenylphenol and its metabolites.

    PubMed

    Freyberger, A; Degen, G H

    1998-10-01

    Chronic administration of o-phenylphenol (OPP) is known to induce urinary bladder tumours in the Fischer rat. The underlying toxic mechanism is poorly understood. Recently, arachidonic acid (ARA)-dependent, prostaglandin-H-synthase (PHS)-catalysed metabolic activation of the OPP metabolite phenylhydroquinone (PHQ) to a genotoxic species was suggested to be involved in OPP toxicity. To investigate this hypothesis in more detail, we have studied the effects of OPP and its metabolites on PHS. When microsomal PHS from ovine seminal vesicles (OSV) was used as enzyme source, both OPP, PHQ, and 2-phenyl-1,4-benzoquinone (PBQ) inhibited PHS-cyclooxygenase. The inhibitory potency was inversely related to the ARA concentration in the assay; at 7 microM ARA IC50-values were: 13 microM (OPP), 17 microM (PHQ), and 190 microM (PBQ). In cells cultured from OSV, which express high PHS activity, 40 microM OPP almost completely suppressed prostaglandin formation. Studies with microsomal PHS demonstrated that PHQ was an excellent substrate for PHS-peroxidase; both ARA and hydrogen peroxide supported oxidation to PBQ. OPP was only a poor substrate for PHS, but inhibited the ARA-mediated and to a lesser extent also the hydrogen peroxide-mediated in vitro oxidation of PHQ. Moreover, PHQ at up to moderately cytotoxic concentrations (50 microM) did not induce micronuclei in OSV cell cultures. Taken together, our findings do not provide evidence for an ARA-dependent, PHS-catalysed formation of genotoxic species from PHQ. Moreover, it seems to be questionable whether such activation can effectively occur in vivo, since OPP and PHQ turned out to be efficient cyclooxygenase inhibitors, and high levels of OPP and PHQ were found at least in the urine of OPP-treated rats. On the other hand, inhibition of the formation of cytoprotective prostaglandins in the urogenital tract may play a crucial role in OPP-induced bladder carcinogenesis.

  13. Maturation of the uterine cervix by repeated intracervical instillation of prostaglandin E2.

    PubMed

    Milliez, J M; Jannet, D; Touboul, C; el Medjadji, M; Paniel, B J

    1991-09-01

    An attempt was made to ripen the uterine cervix in 100 high-risk pregnancy patients (pregnancy between 34 to 41 weeks' gestation), with the use of intracervical instillations of 0.25 mg of prostaglandin E2 mixed with a tylose gel. The maturation process was repeated every 48 hours. Forty-nine patients were delivered of infants after the first maturation and 51 patients required between two and nine instillations. In patients requiring multiple instillations, the mean delay between the first procedure and delivery was 9 +/- 4 days (range, 2.4 to 16 days). Among the 59 nulliparous women, only 23 were delivered of infants after a single maturation and 36 required multiple maturations (p less than 0.02). When the group of patients who were delivered of infants after a single maturation process was compared with the group requiring multiple maturations, no difference could be seen with regard to age, term of pregnancy, or Bishop cervical score at the time of inclusion in the study. The myometrial activity and the onset labor induced by prostaglandin E2, were similar in both groups. Fetal heart rate decelerations occurred in 16.3% (8/49) of the patients with single maturations and in 17.6% (9/51) of the patients who required multiple maturations. The outcome of the pregnancy and the rate of cesarean sections (24% and 27%) were similar in both groups. No patients required cesarean sections because of failed induction of labor. Cervical ripening after repeated applications of 0.25 mg of prostaglandin E2 seems to be safe for the fetus, providing that the patient is closely supervised.

  14. 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

  15. 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.

  16. 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

  17. 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

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

    PubMed

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

    2016-03-01

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

  19. Cervical priming and labor induction by multiple doses of intracervical prostaglandin E2 gel.

    PubMed

    Norchi, S; Zanini, A; Regalia, A L; Pollini, A; Silva, A

    1992-05-01

    One hundred seventy-two term pregnant women with medical or obstetric conditions requiring induction of labor were treated with intracervical administration of 0.5 mg prostaglandin E2 in tylose gel. Multiple administrations were necessary in 42 cases (24.4%), two administrations in 31 cases (18.0%) and three administrations in 11 cases (6.4%). Intracervical administration of PGE2 tylose gel (0.5 mg dose) is useful to prime the cervix, induce labor, and significantly modify Bishop score.

  20. Routine induction of labour with extra-amniotic prostaglandin E2 in a viscous gel.

    PubMed

    Sims, C D; Mellows, H J; Spencer, P J; Craft, I L

    1979-07-01

    Prostaglandin E2, 350 microgram dispersed in a viscous gel, tylose, was introduced into the extra-amniotic space as a single dose in 285 patients to induce labour. With a favourable cervix, 82 per cent of multiparae and 50 per cent of primiparae were successfully induced. With unfavourable induction features, the success rates were 48 per cent and 24 per cent respectively. In the remaining patients, all but four were successfully delivered when intravenous oxytocin was also used. The method was safe, simple and inexpensive and had many advantages for patients and nursing staff.

  1. 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.

  2. Inhibition of Mayaro virus replication by prostaglandin A1 and B2 in Vero cells.

    PubMed

    Ishimaru, D; Marcicano, F G; Rebello, M A

    1998-09-01

    The effect of prostaglandins (PGA1 and PGB2) on the replication of Mayaro virus was studied in Vero cells. PGA1 and PGB2 antiviral activity was found to be dose-dependent. However, while 10 micrograms/ml PGB2 inhibited virus yield by 60%, at the same dose PGA1 suppressed virus replication by more than 90%. SDS-PAGE analysis of [35S]-methionine-labelled proteins showed that PGA1 did not alter cellular protein synthesis. In infected cells, PGA1 slightly inhibited the synthesis of protein C, while drastically inhibiting the synthesis of glycoproteins E1 and E2.

  3. Oral contraceptive use alters the balance of platelet prostaglandin and thromboxane synthesis.

    PubMed

    Schorer, A E; Gerrard, J M; White, J G; Krivit, W

    1978-07-01

    The ability of platelet microsomes to generate platelet aggregating activity on addition of arachidonic acid was evaluated in women taking oral contraceptives and in controls taking no medication but matched for age, sex, and family history. Oral contraceptive users generated significantly more platelet aggregating activity per 100 ug of platelet microsomal protein than controls. Variation in generation of platelet aggregating activity during the menstrual cycle was also observed with highest activity during the third week. These studies show an altered balance of platelet prostaglandin and thromboxane synthesis in oral contraceptive users which may contribute to their increased incidence of thromboembolic phenomena.

  4. Prostaglandin precursors in plasma phospholipids of patients with psoriasis: effects of treatment with coal tar.

    PubMed

    Strong, A M; Horrobin, D F; Manku, M S; Huang, Y S

    1984-05-01

    Plasma phospholipids of patients with psoriasis have significantly reduced levels of dihomogammalinolenic acid (20:3n-6), arachidonic acid (20:4n-6) and adrenic acid (22:4n-6), the precursors of the 1, 2 and homo-2 series of prostaglandins (PGs). Concentrations of the 3 series PG precursor, eicosapentaenoic acid (20:5n-3) were normal. Hospital treatment with a coal tar regime produced a rise in 20:3n-6 to levels which were significantly above normal.

  5. Angiotensin II and renal prostaglandin release in the dog. Interactions in controlling renal blood flow and glomerular filtration rate.

    PubMed

    Bugge, J F; Stokke, E S

    1994-04-01

    The relationship between angiotensin II and renal prostaglandins, and their interactions in controlling renal blood flow (RBF) and glomerular filtration rate (GFR) were investigated in 18 anaesthetized dogs with acutely denervated kidneys. Intrarenal angiotensin II infusion increased renal PGE2 release (veno-arterial concentration difference times renal plasma flow) from 1.7 +/- 0.9 to 9.1 +/- 0.4 and 6-keto-PGF1 alpha release from 0.1 +/- 0.1 to 5.3 +/- 2.1 pmol min-1. An angiotensin II induced reduction in RBF of 20% did not measurably change GFR whereas a 30% reduction reduced GFR by 18 +/- 8%. Blockade of prostaglandin synthesis approximately doubled the vasoconstrictory action of angiotensin II, and all reductions in RBF were accompanied by parallel reductions in GFR. When prostaglandin release was stimulated by infusion of arachidonic acid (46.8 +/- 13.3 and 15.9 +/- 5.4 pmol min-1 for PGE2, and 6-keto-PGF1 alpha, respectively), angiotensin II did not change prostaglandin release, but had similar effects on the relationship between RBF and GFR as during control. In an ureteral occlusion model with stopped glomerular filtration measurements of ureteral pressure and intrarenal venous pressure permitted calculations of afferent and efferent vascular resistances. Until RBF was reduced by 25-30% angiotensin II increased both afferent and efferent resistances almost equally, keeping the ureteral pressure constant. At greater reductions in RBF, afferent resistance increased more than the efferent leading to reductions in ureteral pressure. This pattern was not changed by blockade of prostaglandin synthesis indicating no influence of prostaglandins on the distribution of afferent and efferent vascular resistances during angiotensin II infusion. In this ureteral occlusion model glomerular effects of angiotensin II will not be detected, and it might well be that the shift from an effect predominantly on RBF to a combined effect on both RBF and GFR induced by inhibition

  6. The action of prostaglandin E2 and triamcinolone acetonide on the firing activity of lumbar nerve roots.

    PubMed

    Muramoto, T; Atsuta, Y; Iwahara, T; Sato, M; Takemitsu, Y

    1997-01-01

    Sciatica, due to lumbar disc herniation, is understood electrophysiogically to be an ectopic firing originating from a nerve root. The recent concept of chemical radiculitis implies the involvement, not only of mechanical compression, but also of chemical mediators which contribute to the generation of ectopic firing. The present study demonstrates that prostaglandin E2, a chemical mediator of inflammation, provoked the ectopic firing of nerve roots in a canine in vitro model which indicates that it may play a part in the irritation of nerve roots. In contrast, triamcinolone acetonide suppressed the firing induced by prostaglandin suggesting that steroids may be effective in the treatment of root symptoms.

  7. [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.

  8. Prostaglandin endoperoxide synthetase and the activation of benzo(a)pyrene to reactive metabolites in vivo in guinea pigs

    SciTech Connect

    Garattini, E.; Coccia, P.; Romano, M.; Jiritano, L.; Noseda, A.; Salmona, M.

    1984-11-01

    The role of prostaglandin endoperoxide synthetase in the in vivo activation of benzo(a)pyrene to reactive metabolites capable of interacting irreversibly with cellular macromolecules was studied in guinea pig liver, lung, kidney, spleen, small intestine, colon, and brain. DNA and protein covalent binding experiments were made after systemic administration of acetylsalicylic acid (200 mg/kg) followed by radiolabeled benzo(a)pyrene (4 microgram/kg). Results are compared with a control situation in which the prostaglandin endoperoxide synthetase inhibitor (acetylsalicylic acid) was not administered. No decrease in the level of DNA or protein benzo(a)pyrene-derived covalent binding was observed in any of the tissues studied.

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

    NASA Technical Reports Server (NTRS)

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

    1975-01-01

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

  10. Prostaglandin receptor EP2 in the crosshairs of anti-inflammation, anti-cancer, and neuroprotection.

    PubMed

    Jiang, Jianxiong; Dingledine, Ray

    2013-07-01

    Modulation of a specific prostanoid synthase or receptor provides therapeutic alternatives to nonsteroidal anti-inflammatory drugs (NSAIDs) for treating pathological conditions governed by cyclooxygenase-2 (COX-2 or PTGS2). Among the COX-2 downstream signaling pathways, the prostaglandin E2 (PGE2) receptor EP2 subtype (PTGER2) is emerging as a crucial mediator of many physiological and pathological events. Genetic ablation strategies and recent advances in chemical biology provide tools for a better understanding of EP2 signaling. In the brain, the EP2 receptor modulates some beneficial effects, including neuroprotection, in acute models of excitotoxicity, neuroplasticity, and spatial learning via cAMP-PKA signaling. Conversely, EP2 activation accentuates chronic inflammation mainly through the cAMP-Epac pathway, likely contributing to delayed neurotoxicity. EP2 receptor activation also engages β-arrestin in a G-protein-independent pathway that promotes tumor cell growth and migration. Understanding the conditions under which multiple EP2 signaling pathways are engaged might suggest novel therapeutic strategies to target this key inflammatory prostaglandin receptor.

  11. Prostaglandin receptor EP2 in the crosshairs of anti-inflammation, anti-cancer, and neuroprotection

    PubMed Central

    and, Jianxiong Jiang; Dingledine, Ray

    2014-01-01

    Modulation of a specific prostanoid synthase or receptor provides therapeutic alternatives to non-steroidal anti-inflammatory drugs (NSAIDs) for treating cyclooxygenase-2 (COX-2 or PTGS2)-governed pathological conditions. Among the COX-2 downstream signaling pathways, the prostaglandin E2 (PGE2) receptor EP2 subtype (PTGER2) is emerging as a crucial mediator of many physiological and pathological events. Genetic ablation strategies and recent advances in chemical biology provide tools for a better understanding of EP2 signaling. In the brain, the EP2 receptor modulates some beneficial effects including neuroprotection in acute models of excitotoxicity, neuroplasticity, and spatial learning via cAMP/PKA signaling. Conversely, EP2 activation accentuates chronic inflammation mainly through the cAMP/Epac pathway, likely contributing to delayed neurotoxicity. EP2 receptor activation also engages β-arrestin in a G protein-independent pathway that promotes tumor cell growth and migration. Understanding the conditions under which multiple EP2 signaling pathways are engaged might suggest novel therapeutic strategies targeting this key inflammatory prostaglandin receptor. PMID:23796953

  12. 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

  13. 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.

  14. A dynamic Asp–Arg interaction is essential for catalysis in microsomal prostaglandin E2 synthase

    PubMed Central

    Brock, Joseph S.; Hamberg, Mats; Balagunaseelan, Navisraj; Goodman, Michael; Morgenstern, Ralf; Strandback, Emilia; Samuelsson, Bengt; Rinaldo-Matthis, Agnes; Haeggström, Jesper Z.

    2016-01-01

    Microsomal prostaglandin E2 synthase type 1 (mPGES-1) is responsible for the formation of the potent lipid mediator prostaglandin E2 under proinflammatory conditions, and this enzyme has received considerable attention as a drug target. Recently, a high-resolution crystal structure of human mPGES-1 was presented, with Ser-127 being proposed as the hydrogen-bond donor stabilizing thiolate anion formation within the cofactor, glutathione (GSH). We have combined site-directed mutagenesis and activity assays with a structural dynamics analysis to probe the functional roles of such putative catalytic residues. We found that Ser-127 is not required for activity, whereas an interaction between Arg-126 and Asp-49 is essential for catalysis. We postulate that both residues, in addition to a crystallographic water, serve critical roles within the enzymatic mechanism. After characterizing the size or charge conservative mutations Arg-126–Gln, Asp-49–Asn, and Arg-126–Lys, we inferred that a crystallographic water acts as a general base during GSH thiolate formation, stabilized by interaction with Arg-126, which is itself modulated by its respective interaction with Asp-49. We subsequently found hidden conformational ensembles within the crystal structure that correlate well with our biochemical data. The resulting contact signaling network connects Asp-49 to distal residues involved in GSH binding and is ligand dependent. Our work has broad implications for development of efficient mPGES-1 inhibitors, potential anti-inflammatory and anticancer agents. PMID:26755582

  15. Modulation of ligand-mediated human red cell agglutinability by prostaglandins

    SciTech Connect

    McLawhon, R.W.; Marikovsky, Y.; Weinstein, R.S.

    1986-03-01

    Ethanol induces the transformation of human red cells from bioconcave discs to echinocytes in vitro. In addition, they have observed that ethanol can enhance the agglutination of red cells by the plant lectin wheat germ agglutinin or poly-L-lysine. Incubation of washed human red cells with 5 and 10% ethanol (v/v) in phosphate buffered saline, pH 7.3 at 25/sup 0/C produced a 30% increase in ligand-mediated agglutinability within 12 min. Simultaneous addition of ethanol and one of the following prostaglandin derivatives, PGE/sub 1/, pge/sub 2/, pgf/sub 2/-alpha, or PGl/sub 2/ (10/sup -9/ to 5 x 10/sup -7/ M) prevented the shape-associated increases in red cell agglutinability. Thromboxane-B/sub 2/ had no effect on agglutinability. Prostaglandins did not prevent ethanol-induced red cell shape transformations per se under identical experimental conditions. As intragastric administration of 100% ethanol results in the formation of spiculated red cell thrombi in postcapillary venules of rat gastric mucosa, they postulate that the cytoprotective role of prostanoids in preventing mucosal ulceration may be due in part to their capacity to inhibit intravascular ligand mediated red cell agglutination, hemostasis, and their sequelae, epithelial necrosis. Moreover, the data suggest that ethanol-induced red cell shape transformations and ligand-mediated agglutination represent two distinct and independent biological phenomena.

  16. Aspirin inhibits interleukin 1-induced prostaglandin H synthase expression in cultured endothelial cells

    SciTech Connect

    Wu, K.K.; Sanduja, R.; Tsai, A.L.; Ferhanoglu, B.; Loose-Mitchell, D.S. )

    1991-03-15

    Prostaglandin H (PGH) synthase is a key enzyme in the biosynthesis of prostaglandins, thromboxane, and prostacyclin. In cultured human umbilical vein endothelial cells, interleukin 1 (IL-1) is known to induce the synthesis of this enzyme, thereby raising the level of PGH synthase protein severalfold over the basal level. Pretreatment with aspirin at low concentrations inhibited more than 60% of the enzyme mass and also the cyclooxygenase activity in IL-1-induced cells with only minimal effects on the basal level of the synthase enzyme in cells without IL-1. Sodium salicylate exhibited a similar inhibitory action whereas indomethacin had no apparent effect. Similarly low levels of aspirin inhibited the increased L-({sup 35}S)methionine incorporation into PGH synthase that was induced by IL0-1 and also suppressed expression of the 2.7-kilobase PGH synthase mRNA. These results suggest that in cultured endothelial cells a potent inhibition of eicosanoid biosynthetic capacity can be effected by aspirin or salicylate at the level of PGH synthase gene expression. The aspirin effect may well be due to degradation of salicylate.

  17. 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.

  18. 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.

  19. [Cervical labor induction with prostaglandin E2 in patients with fetal death].

    PubMed

    Avila-Vergara, M A; Morgan-Ortiz, F; Fragoza-Sosa, O; Haro-García, L

    1997-04-01

    The objective was to compare the effectiveness and efficacy of prostaglandin E2 (prepidil gel) plus oxitocin with that of intravenous oxitocin in the treatment of delivery induction in patients complicated with fetal death. Fifteen patients received prepidil gel plus oxitocin and 15 patients oxitocin. In the treatment group only one dosage of 0.5 ng in 2 ml of prepidil gel was administered intracervically and simultaneously oxitocin by intravenous infusion, dosage was increased 2 mUI/min every 30 minutes. In the control group only intravenous oxitocin was administered at the same dosage. The mean duration in hours of delivery in the treatment group was 13.1 +/- h and in the control group was 30.9 +/- 9.1 h. There were statistically significant differences between the groups in reduction of delivery duration (p = 0.0007). It is concluded that prostaglandin E2 plus oxitocin provide better short-term outcomes than oxitocine treatment and gave more short periods of labor in patients with fetal death.

  20. 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.

  1. 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.

  2. Therapeutic Implications of the Prostaglandin Pathway in Alzheimer’s Disease

    PubMed Central

    Cudaback, Eiron; Jorstad, Nikolas L.; Yang, Yue; Montine, Thomas J.; Keene, C. Dirk

    2014-01-01

    An important pathologic hallmark of Alzheimer’s disease (AD) is neuroinflammation, a process characterized in AD by disproportionate activation of cells (microglia and astrocytes, primarily) of the non-specific innate immune system within the CNS. While inflammation itself is not intrinsically detrimental, a delicate balance of pro- and anti-inflammatory signals must be maintained to ensure that long-term exaggerated responses do not damage the brain over time. Non-steroidal anti-inflammatory drugs (NSAIDs) represent a broad class of powerful therapeutics that temper inflammation by inhibiting cyclooxygenase-mediated signaling pathways including prostaglandins, which are the principal mediators of CNS neuroinflammation. While historically used to treat discrete or systemic inflammatory conditions, epidemiologic evidence suggests that protracted NSAID use may delay AD onset, as well as decrease disease severity and rate of progression. Unfortunately, clinical trials with NSAIDs have thus far yielded disappointing results, including premature discontinuation of a large-scale prevention trial due to unexpected cardiovascular side effects. Here we review the literature and make the argument that more targeted exploitation of downstream prostaglandin signaling pathways may offer significant therapeutic benefits for AD while minimizing adverse side effects. Directed strategies such as these may ultimately help to delay the deleterious consequences of brain aging and might someday lead to new therapies for AD and other chronic neurodegenerative diseases. PMID:24434190

  3. 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

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

    PubMed

    Rumzhum, Nowshin N; Ammit, Alaina J

    2016-07-05

    Prostaglandin E2 (PGE2) is a prostanoid with diverse actions in health and disease. In chronic respiratory diseases driven by inflammation, PGE2 has both positive and negative effects. An enhanced understanding of the receptor-mediated cellular signalling pathways induced by PGE2 may help us separate the beneficial properties from unwanted actions of this important prostaglandin. PGE2 is known to exert anti-inflammatory and bronchoprotective actions in human airways. To date however, whether PGE2 increases production of the anti-inflammatory protein MAPK phosphatase 1 (MKP-1) was unknown. We address this herein and use primary cultures of human airway smooth muscle (ASM) cells to show that PGE2 increases MKP-1 mRNA and protein upregulation in a concentration-dependent manner. We explore the signalling pathways responsible and show that PGE2-induces CREB phosphorylation, not p38 MAPK activation, in ASM cells. Moreover, we utilize selective antagonists of EP2 (PF-04418948) and EP4 receptors (GW 627368X) to begin to identify EP-mediated functional outcomes in ASM cells in vitro. Taken together with earlier studies, our data suggest that PGE2 increases production of the anti-inflammatory protein MKP-1 via cAMP/CREB-mediated cellular signalling in ASM cells and demonstrates that EP2 may, in part, be involved.

  5. Dose-dependent effects of prostaglandin E2 in macrophage adhesion and migration.

    PubMed

    Osma-Garcia, Inés C; Punzón, Carmen; Fresno, Manuel; Díaz-Muñoz, Manuel D

    2016-03-01

    Macrophage migration to the focus of infection is a hallmark of the innate immune response. Macrophage spreading, adhesion, and migration through the extracellular matrix require dynamic remodeling of the actin cytoskeleton associated to integrin clustering in podosomes and focal adhesions. Here, we show that prostaglandin E2 (PGE2 ), the main prostaglandin produced by macrophages during inflammation, promote the distinctive dose-dependent formation of podosomes or focal adhesions in macrophages. Low concentrations of PGE2 increased p110γ PI3K expression, phosphorylation of actin-related protein 2, and formation of podosomes, which enhanced macrophage migration in response to chemokines. However, high doses of PGE2 increased phosphorylation of paxillin and focal adhesion kinase, the expression of serine/threonine protein kinase 1, and promoted focal adhesion formation and macrophage adhesion, reducing macrophage chemotaxis. In summary, we describe the dual role of PGE2 as a promoter of macrophage chemotaxis and adhesion, proposing a new model of macrophage migration to the inflammatory focus in the presence of a gradient of PGE2 .

  6. Pyometra in Bitches Induces Elevated Plasma Endotoxin and Prostaglandin F2α Metabolite Levels

    PubMed Central

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

    2006-01-01

    Endotoxemia in bitches with pyometra can cause severe systemic effects directly or via the release of inflammatory mediators. Plasma endotoxin concentrations were measured in ten bitches suffering from pyometra with moderately to severely deteriorated general condition, and in nine bitches admitted to surgery for non-infectious reasons. Endotoxin samples were taken on five occasions before, during and after surgery. In addition, urine and uterine bacteriology was performed and hematological, blood biochemical parameters, prostaglandin F2α metabolite 15-ketodihydro-PGF2α (PG-metabolite), progesterone and oestradiol (E2-17β) levels were analysed. The results confirm significantly increased plasma levels of endotoxin in bitches with pyometra and support previous reports of endotoxin involvement in the pathogenesis of the disease. Plasma concentrations of PG-metabolite were elevated in pyometra bitches and provide a good indicator of endotoxin release since the concentrations were significantly correlated to the endotoxin levels and many other hematological and chemistry parameters. The γ-globulin serum protein electrophoresis fraction and analysis of PG-metabolite can be valuable in the diagnosis of endotoxin involvement if a reliable, rapid and cost-effective test for PG-metabolite analysis becomes readily available in the future. Treatment inhibiting prostaglandin biosynthesis and related compounds could be beneficial for bitches suffering from pyometra. PMID:16722306

  7. Neutrophils mediate Salmonella Typhimurium clearance through the GBP4 inflammasome-dependent production of prostaglandins

    PubMed Central

    Tyrkalska, Sylwia D.; Candel, Sergio; Angosto, Diego; Gómez-Abellán, Victoria; Martín-Sánchez, Fátima; García-Moreno, Diana; Zapata-Pérez, Rubén; Sánchez-Ferrer, Álvaro; Sepulcre, María P.; Pelegrín, Pablo; Mulero, Victoriano

    2016-01-01

    Inflammasomes are cytosolic molecular platforms that alert the immune system about the presence of infection. Here we report that zebrafish guanylate-binding protein 4 (Gbp4), an IFNγ-inducible GTPase protein harbouring a C-terminal CARD domain, is required for the inflammasome-dependent clearance of Salmonella Typhimurium (ST) by neutrophils in vivo. Despite the presence of the CARD domain, Gbp4 requires the universal inflammasome adaptor Asc for mediating its antibacterial function. In addition, the GTPase activity of Gbp4 is indispensable for inflammasome activation and ST clearance. Mechanistically, neutrophils are recruited to the infection site through the inflammasome-independent production of the chemokine (CXC motif) ligand 8 and leukotriene B4, and then mediate bacterial clearance through the Gbp4 inflammasome-dependent biosynthesis of prostaglandin D2. Our results point to GBPs as key inflammasome adaptors required for prostaglandin biosynthesis and bacterial clearance by neutrophils and suggest that transient activation of the inflammasome may be used to treat bacterial infections. PMID:27363812

  8. Prostaglandin D2 Attenuates Bleomycin-Induced Lung Inflammation and Pulmonary Fibrosis

    PubMed Central

    Omori, Keisuke; Nakamura, Tatsuro; Maehara, Toko; Aritake, Kosuke; Urade, Yoshihiro; Murata, Takahisa

    2016-01-01

    Pulmonary fibrosis is a progressive and fatal lung disease with limited therapeutic options. Although it is well known that lipid mediator prostaglandins are involved in the development of pulmonary fibrosis, the role of prostaglandin D2 (PGD2) remains unknown. Here, we investigated whether genetic disruption of hematopoietic PGD synthase (H-PGDS) affects the bleomycin-induced lung inflammation and pulmonary fibrosis in mouse. Compared with H-PGDS naïve (WT) mice, H-PGDS-deficient mice (H-PGDS-/-) represented increased collagen deposition in lungs 14 days after the bleomycin injection. The enhanced fibrotic response was accompanied by an increased mRNA expression of inflammatory mediators, including tumor necrosis factor-α, monocyte chemoattractant protein-1, and cyclooxygenase-2 on day 3. H-PGDS deficiency also increased vascular permeability on day 3 and infiltration of neutrophils and macrophages in lungs on day 3 and 7. Immunostaining showed that the neutrophils and macrophages expressed H-PGDS, and its mRNA expression was increased on day 3and 7 in WT lungs. These observations suggest that H-PGDS-derived PGD2 plays a protective role in bleomycin-induced lung inflammation and pulmonary fibrosis. PMID:27992456

  9. Endotoxin-induced hemodynamic changes in dogs: role of thromboxane and prostaglandin I2.

    PubMed

    Bottoms, G D; Johnson, M A; Roesel, O F

    1983-08-01

    Plasma concentrations of thromboxane and prostaglandin I2 (PGI2) before and after IV injection of endotoxin and resulting hemodynamic changes were evaluated. Effects of flunixin meglumine on plasma concentrations of these prostaglandins and the related hemodynamic changes were also determined. Shock was induced in 2 groups of anesthetized dogs. Four dogs were given endotoxin only and 4 dogs were given endotoxin and then were treated with flunixin meglumine. Arterial blood pressure (BP), cardiac output (CO), and heart rate were measured, and blood samples were collected at postendotoxin hours (PEH) 0, 0.1, 0.25, 0.5, 1, 2, 3, and 4. Plasma thromboxane and PGI2 concentrations were increased in canine endotoxic shock. Thromboxane concentration was highest early in shock, and appeared to be associated with an initial decrease in BP and CO. The increased concentration of PGI2 was associated with systemic hypotension at PEH 1 to 2. Treatment of dogs with flunixin meglumine at PEH 0.07 prevented further increase of thromboxane and blocked the release of PGI2, resulting in an increased CO, BP, and tissue aerobic metabolism.

  10. Cytotoxicity of prostaglandin analog eye drops preserved with benzalkonium chloride in multiple corneoconjunctival cell lines

    PubMed Central

    Ayaki, Masahiko; Iwasawa, Atsuo

    2010-01-01

    Purpose: This study evaluated the cytotoxicity of five prostaglandin analog ophthalmic solutions on four ocular surface cell lines, ie, Chang (human conjunctiva), SIRC (rabbit cornea), RC-1 (rabbit cornea), and BCE C/D-1b (bovine cornea). Methods: Cell viability was measured by neutral red and MTT assays in cells treated for 10, 30, or 60 minutes with various doses of prostaglandins (undiluted, and 2- and 10-fold dilutions). The number of cell lines with viability ≥50% in the presence of selected dilution of the drug (CVS50) was used for comparison. In addition, 24 cell viability comparisons (four cell lines, two assays, and three exposure times) were made between latanoprost (Xalatan®) and each other solution at each dose. A comparison between the newly introduced tafluprost (Tapros®) with 0.01% benzalkonium chloride was also made. Results: The order of cell viability determined by CVS50 was Travatan Z® (travoprost with the SofZia system) > Tapros ≥ Travatan® (travoprost) = Xalatan > Rescula® (unoproston). This was consistent with the results of direct comparisons between Xalatan and the other drugs. There was no clear difference in cell viability between Tapros and benzalkonium chloride. Conclusions: Use of two assays, multiple cell lines, and various dilutions and exposure times provided a unique evaluation of cytotoxicity among ophthalmic solutions. CVS50 was useful for comparison of the cell viability of the solutions. PMID:20823934

  11. 16,16-Dimethyl prostaglandin E2 increases survival in mice following irradiation

    SciTech Connect

    Walden, T.L.; Patchen, M.; Snyder, S.L.

    1987-01-01

    16,16-Dimethyl prostaglandin E2(DiPGE2), a stable analog of PGE2, increases the LD 50/30 survival in CD2F1 male mice when given prior to ionizing radiation. Subcutaneous administration of 40 microgram of DiPGE2 30 min prior to /sup 60/Co gamma irradiation extends the LD 50/30 from 9.39 Gy in the control animals to 16.14 Gy in DiPGE2 treated, with a dose-reduction factor of 1.72p95% confidence limits: 1.62, 1.82. The degree of protection is dependent on both the time of administration and the dose of the prostaglandin. Ten micrograms administered 5 min prior to receiving a lethal dose of 10 Gy provides 90% survival but only 10% survival if administered 30 min prior to irradiation. Experiments to determine the in vivo concentration of DiPGE2 in organs post injection show increased levels over time, but these are not correlated with protection. At 30 min after injection, as much as 80% of the DiPGE2 present in the spleen and plasma is unmetabolized. These results suggest that the protection results from the physiologic action of DiPGE2 rather than direct in vivo detoxification of radicals.

  12. A Novel Selective Prostaglandin E2 Synthesis Inhibitor Relieves Pyrexia and Chronic Inflammation in Rats.

    PubMed

    Sugita, Ryusuke; Kuwabara, Harumi; Sugimoto, Kotaro; Kubota, Kazufumi; Imamura, Yuichiro; Kiho, Toshihiro; Tengeiji, Atsushi; Kawakami, Katsuhiro; Shimada, Kohei

    2016-04-01

    Prostaglandin E2 (PGE2) is a terminal prostaglandin in the cyclooxygenase (COX) pathway. Inhibition of PGE2 production may relieve inflammatory symptoms such as fever, arthritis, and inflammatory pain. We report here the profile of a novel selective PGE2 synthesis inhibitor, compound A [N-[(1S,3S)-3-carbamoylcyclohexyl]-1-(6-methyl-3-phenylquinolin-2-yl)piperidine-4-carboxamide], in animal models of pyrexia and inflammation. The compound selectively suppressed the synthesis of PGE2 in human alveolar adenocarcinoma cell line A549 cells and rat macrophages. In the lipopolysaccharide-induced pyrexia model, this compound selectively reduced PGE2 production in cerebrospinal fluid and showed an anti-pyretic effect. In the adjuvant-induced arthritis model, compound A therapeutically decreased foot swelling in the established arthritis. Our data demonstrates that selective suppression of PGE2 synthesis shows anti-pyretic and anti-inflammatory effects, suggesting that selective PGE2 synthesis inhibitors can be applied as an alternative treatment to nonsteroidal, anti-inflammatory drugs (NSAIDs) or COX-2-selective inhibitors.

  13. Novel membrane-associated prostaglandin E synthase-2 from crustacean arthropods.

    PubMed

    Hansen, Kristella; Varvas, Külliki; Järving, Ivar; Samel, Nigulas

    2014-08-01

    Prostaglandins (PG) have been shown to play important physiological roles in insects and marine invertebrates, yet the knowledge of their biosynthetic pathways is often lacking. Recently, we described cyclooxygenases in two amphipod crustaceans, Gammarus sp. and Caprella sp. In the present study, we report the cloning and characterization of prostaglandin E synthases (PGES) from the same organisms. The amphipod membrane-bound PGES-2-type enzymes share about 40% of the amino acid sequence identity with human mPGES-2, contain a conserved Cys110-x-x-Cys113 motif and have very low heme-binding affinity. The recombinant enzymes purified in the absence of dithiothreitol specifically catalyze the isomerization of PGH2 into PGE2. The PGES activity is increased in the presence of reduced glutathione and inhibited with a sulfhydryl group inhibitor. We assume that the amphipod mPGES-2, unlike in their mammalian counterparts, is responsible for PGE2 synthesis, not only in vitro but also in vivo.

  14. Prostaglandin E(2) and misoprostol induce neurite retraction in Neuro-2a cells.

    PubMed

    Tamiji, Javaneh; Crawford, Dorota A

    2010-07-30

    Prostaglandin E(2) (PGE(2)) is a key lipid-derived compound which mediates important physiological functions in the nervous system via activation of four EP receptors (EP1-4). Recent studies have shown that altered PGE(2) signalling due to abnormal lipid peroxidation and oxidative stress may underlie some pathologies of the nervous system. The prenatal exposure to the drug misoprostol, a prostaglandin type E analogue, has also been linked to a number of neurodevelopmental defects. In the present study, we use ratiometric calcium imaging with fura-2AM as a calcium indicator to determine the effects of PGE(2) and misoprostol on calcium homeostasis in growth cones of mouse neuroblastoma (Neuro-2a) cells. Our results show that both drugs increase the amplitude of calcium transients in growth cones of Neuro-2a cells and induce neurite retraction. Moreover, quantitative real-time PCR also revealed that the mRNA expression level of the four EP receptors was significantly higher during the neurogenesis period in mouse indicating the importance of PGE(2) signalling in the nervous system.

  15. Aspirin-induced gastric mucosal damage: prevention by enteric-coating and relation to prostaglandin synthesis.

    PubMed

    Hawthorne, A B; Mahida, Y R; Cole, A T; Hawkey, C J

    1991-07-01

    1. Gastric damage induced by low-dose aspirin and the protective effect of enteric-coating was assessed in healthy volunteers in a double-blind placebo-controlled cross-over trial using Latin square design. Each was administered placebo, plain aspirin 300 mg daily, plain aspirin 600 mg four times daily, enteric-coated aspirin 300 mg daily, or enteric-coated aspirin 600 mg four times daily for 5 days. Gastric damage was assessed endoscopically, and gastric mucosal bleeding measured. 2. Aspirin 300 mg daily and 600 mg four times daily caused significant increases in gastric injury compared with placebo. Gastric mucosal bleeding was significantly more with the high dose, with a trend towards increased gastric erosions, compared with the low dose. 3. Enteric-coating of aspirin eliminated the injury caused by low dose aspirin and substantially reduced that caused by the higher dose. 4. All dosages and formulations caused similar inhibition of gastric mucosal prostaglandin E2 synthesis. 5. Serum thromboxane levels were suppressed equally with plain and enteric-coated aspirin. 6. In this short-term study in healthy volunteers, gastric toxicity from aspirin was largely topical, independent of inhibition of prostaglandin synthesis, and could be virtually eliminated by the use of an enteric-coated preparation.

  16. 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.

  17. Topical sulfur mustard induces changes in prostaglandins and interleukin-1 alpha in isolated perfused porcine skin

    SciTech Connect

    Zhang, Z.; Riviere, J.E.; Monteiro-Rivier, N.A.

    1995-12-01

    Su1fur mustard BIS(2-CHLOROETHYL) SULFIDE, HD is an alkylating agent that causes severe cutaneous injury. The isolated perfused porcine skin flap (IPPSF) is an in vitro model that has been utilized in cutaneous toxicity research. The objective of this study was to characterize the local IPPSF inflammatory response after topical exposure to 5.0 and 10.0 mg/ml of I (n = 5/treatment, n = 5/control). Biochemical markers of viability CUMULATIVE GLUCOSE UTILIZATION (CGU), vascular resistance (VR), morphological parameters, and venous flux of prostaglandin E2 (PGE2), prostaglandin F2% (PGF2%, and interleukin la (IL la)) were determined. HD caused a dose-related response in the formation of gross blisters, and epidermal-dermal separation. Decreases in CGU and an increase in VR were seen in all HD-treated IPPsFs. Increase of both PGE2 and PGF2a was observed only in 5.0 mg/ml HD treatment, which showed the greatest increase in VR, while the 10.0 mg/nil concentration of HD enhanced the release of IL-1a. These results suggest that HD is a potent dermal toxic agent that induces alterations in glucose metabolism and vascular resistance, which resulted in dose-specific patterns of PGE2, PGF2a and IL-la release.

  18. [Premature rupture of fetal membranes at term: an indication for induced labor with prostaglandins?].

    PubMed

    Lettau, R; Hege, G; Steldinger, R

    1995-01-01

    Premature rupture of membranes (PROM) at term is thought to be related to an increased infection risk for mother and child. A prospective study was conducted to evaluate the efficacy of prostaglandins for induction of labour in 433 cases of PROM presenting after 35 completed weeks of gestation. Intracervical gel or vaginal pessaries were given in dependence on the Bishop-score. Course of delivery and fetal outcome were analysed. In 57.3% single application was sufficient to induce the delivery. Only 1.8% of cases did not respond. 21% of patients were delivered within six hours of the first application and 89.6% during the first 24 hours. The rate of cesarean section was 15.5%. Fetal distress caused by uterine hyperstimulation was observed in 9.9% and required intrapartum tocolysis. A fetal acidosis (pH < 7.15) was present in 4.1%. The neonatal infective morbidity was 0.4%. Severe maternal complications were not observed. We conclude that use of prostaglandins for induction of labour in case of PROM at term seems to be a recommendable measure. In primiparous women or in the presence of an unfavorable cervix-score shorter duration to delivery diminishes the risk of fetal infection.

  19. A dynamic Asp-Arg interaction is essential for catalysis in microsomal prostaglandin E2 synthase.

    PubMed

    Brock, Joseph S; Hamberg, Mats; Balagunaseelan, Navisraj; Goodman, Michael; Morgenstern, Ralf; Strandback, Emilia; Samuelsson, Bengt; Rinaldo-Matthis, Agnes; Haeggström, Jesper Z

    2016-01-26

    Microsomal prostaglandin E2 synthase type 1 (mPGES-1) is responsible for the formation of the potent lipid mediator prostaglandin E2 under proinflammatory conditions, and this enzyme has received considerable attention as a drug target. Recently, a high-resolution crystal structure of human mPGES-1 was presented, with Ser-127 being proposed as the hydrogen-bond donor stabilizing thiolate anion formation within the cofactor, glutathione (GSH). We have combined site-directed mutagenesis and activity assays with a structural dynamics analysis to probe the functional roles of such putative catalytic residues. We found that Ser-127 is not required for activity, whereas an interaction between Arg-126 and Asp-49 is essential for catalysis. We postulate that both residues, in addition to a crystallographic water, serve critical roles within the enzymatic mechanism. After characterizing the size or charge conservative mutations Arg-126-Gln, Asp-49-Asn, and Arg-126-Lys, we inferred that a crystallographic water acts as a general base during GSH thiolate formation, stabilized by interaction with Arg-126, which is itself modulated by its respective interaction with Asp-49. We subsequently found hidden conformational ensembles within the crystal structure that correlate well with our biochemical data. The resulting contact signaling network connects Asp-49 to distal residues involved in GSH binding and is ligand dependent. Our work has broad implications for development of efficient mPGES-1 inhibitors, potential anti-inflammatory and anticancer agents.

  20. Cysteamine and prostaglandin F2 beta stimulate rat gastric mucin release

    SciTech Connect

    Lamont, J.T.; Ventola, A.S.; Maull, E.A.; Szabo, S.

    1983-02-01

    Gastric mucin glycoproteins form an adherent gel over the surface epithelium that is thought to protect the stomach against chemical and physical damage. The purpose of this study was to measure the release of mucin glycoproteins from rat stomach after treatment with cysteamine and prostaglandin F2 beta, two structurally unrelated drugs that have been shown to protect the stomach against the noxious effects of alcohol and other damaging agents. Gastric mucin was separated into soluble (washout) and insoluble (adherent) phases before colorimetric quantitation of total mucin, protein-bound hexose, and sialic acid. Cysteamine produced a dose-dependent increase in release of soluble and gel mucin. Prostaglandin F2 beta caused a dose-dependent release of hexose-containing mucin but had no effect on sialic acid-containing glycoproteins. Sepharose 4B chromatography of both the soluble and adherent mucus revealed that greater than 90% was a high molecular weight glycoprotein fraction. N-Ethylmaleimide, a known inhibitor of cytoprotection by cysteamine, had no effect on mucin secretion. Similarly, indomethacin inhibited mucin secretion by cysteamine but did not significantly influence cytoprotection. Thus the secretion of mucin by cytoprotective agents is unlikely by itself to explain the ability of the stomach to resist chemical or physical damage.

  1. Gastric cytoprotection beyond prostaglandins: cellular and molecular mechanisms of gastroprotective and ulcer healing actions of antacids.

    PubMed

    Tarnawski, Andrzej; Ahluwalia, Amrita; Jones, Michael K

    2013-01-01

    This article updates current views on gastric mucosal defense, injury, protection and ulcer healing with a focus on mucosal protective and ulcer healing actions of antacids. The gastric mucosa is continuously exposed to a variety of noxious factors, both endogenous such as: 0.1N hydrochloric acid, pepsin, bile acids, lysolecithin, H. pylori toxins and exogenous such as NSAIDs, ethanol and others. Gastric mucosal integrity is maintained by pre-epithelial, epithelial and post-epithelial defense mechanisms permitting the mucosa to withstand exposure to the above damaging factors. When mucosal defense is weakened or overwhelmed by injurious factors, injury develops in the form of erosions or ulcers. In the late 1970s Andre Robert and coworkers discovered that microgram amounts of a prostaglandin E2 analog protects the gastric mucosa against a variety of ulcerogenic and necrotizing agents - even such strong inducers of injury as 100% ethanol and boiling water. They proposed a new concept of cytoprotection. Subsequently, other compounds, such as sulfhydryls, sucralfate and epidermal growth factor were shown to exert protective action on gastric mucosa. Additionally, some antacids have been shown to exert a potent mucosal protective action against a variety of injurious factors and accelerate healing of erosions and gastric ulcers. These actions of antacids, especially hydrotalcite - the newest and the most extensively studied antacid - are due to activation of prostaglandin synthesis; binding to and inactivation of pepsin, bile acids and H. pylori toxins; induction of heat shock proteins; and, activation of genes encoding growth factors and their receptors.

  2. Suppression of the cutaneous immune response following topical application of the prostaglandin PGE2

    SciTech Connect

    Rheins, L.A.; Barnes, L.; Amornsiripanitch, S.; Collins, C.E.; Nordlund, J.J.

    1987-04-15

    UVB irradiation (290-320 nm) and topical applications of arachidonic acid (AA) in mice decrease the number of identifiable Langerhans cells and alter the cutaneous immune response. Application of contact allergens such as dinitrofluorobenzene (DNFB) to irradiated or AA-treated skin induces antigen-specific tolerance. Indomethacin (IM), a cyclooxygenase inhibitor, administered orally to mice prior to UVB irradiation or prior to the topical application of arachidonic acid, abrogates suppression of contact hypersensitivity (CHS) to DNFB. This suggests a byproduct of arachidonic acid generated through the cyclooxygenase pathway may be involved in the immune suppression. Topical application of various prostaglandins (PGE2, PGD2, PGF2 alpha, and CTXA2) did not cause alterations in the population density of the identifiable Ia+ dendritic Langerhans cells. PGE2, but no other tested agent, produced a suppression of the CHS response to DNFB. These observations suggests that of the various prostaglandins, PGE2 might be one of several biochemical signals which mediate the suppression of contact hypersensitivity reactions following ultraviolet radiation exposure. However, the mechanisms by which PGE2 produces its suppressive effects have not been identified.

  3. Neuroprotection by selective allosteric potentiators of the EP2 prostaglandin receptor

    PubMed Central

    Jiang, Jianxiong; Ganesh, Thota; Du, Yuhong; Thepchatri, Pahk; Rojas, Asheebo; Lewis, Iestyn; Kurtkaya, Serdar; Li, Lian; Qui, Min; Serrano, Geidy; Shaw, Renee; Sun, Aiming; Dingledine, Ray

    2010-01-01

    Activation of the Gαs-coupled EP2 receptor for prostaglandin E2 (PGE2) promotes cell survival in several models of tissue damage. To advance understanding of EP2 functions, we designed experiments to develop allosteric potentiators of this key prostaglandin receptor. Screens of 292,000 compounds identified 93 that at 20 μM (i) potentiated the cAMP response to a low concentration of PGE2 by > 50%; (ii) had no effect on EP4 or β2 adrenergic receptors, the cAMP assay itself, or the parent cell line; and (iii) increased the potency of PGE2 on EP2 receptors at least 3-fold. In aqueous solution, the active compounds are largely present as nanoparticles that appear to serve as active reservoirs for bioactive monomer. From 94 compounds synthesized or purchased, based on the modification of one hit compound, the most active increased the potency of PGE2 on EP2 receptors 4- to 5-fold at 10 to 20 μM and showed substantial neuroprotection in an excitotoxicity model. These small molecules represent previously undescribed allosteric modulators of a PGE2 receptor. Our results strongly reinforce the notion that activation of EP2 receptors by endogenous PGE2 released in a cell-injury setting is neuroprotective. PMID:20080612

  4. Prostaglandin E2 inhibits platelet-derived growth factor-stimulated cell proliferation through a prostaglandin E receptor EP2 subtype in rat hepatic stellate cells.

    PubMed

    Koide, Shigeki; Kobayashi, Yoshimasa; Oki, Yutaka; Nakamura, Hirotoshi

    2004-09-01

    Prostaglandin (PG) E2 inhibits hepatic stellate cell (HSC) mitogenesis. PGE-specific receptors are divided into four subtypes that are coupled either to Ca2+ mobilization (EP1 and EP3) or to the stimulation of adenyl cyclase (EP2 and EP4). The aims of the current study were to identify PGE receptor subtypes in cultured rat HSC and to examine which PGE receptor subtype(s) mediates the inhibitory effect of PGE2 on platelet-derived growth factor (PDGF)-stimulated proliferation. Reverse transcription-polymerase chain reaction analysis was performed to detect PGE receptor subtype mRNA expression. Cell proliferation was determined by measuring [3H]thymidine incorporation, and intracellular cyclic AMP was measured by radioimmunoassay. Cultured rat HSC expressed mRNAs for all four subtypes of PGE receptor. PGE2- and EP2-selective agonist produced dose-dependent inhibitory effects on PDGF-stimulated proliferation. Neither EP1-, EP3-, nor EP4-selective agonists showed any inhibitory effect. An adenylate cyclase inhibitor strongly blunted the inhibition of DNA synthesis elicited by PGE2 and the EP2 agonist. The EP2 agonist generated higher and more prolonged increases in intracellular cyclic AMP than the EP4 agonist. Activation of the PGE EP2 receptor has an antiproliferative effect in HSC that may be mediated by cyclic AMP-related signal transduction pathways.

  5. Anorexia and cachexia in prostaglandin EP1 and EP3 subtype receptor knockout mice bearing a tumor with high intrinsic PGE2 production and prostaglandin related cachexia.

    PubMed

    Wang, W; Andersson, M; Lönnroth, C; Svanberg, E; Lundholm, K

    2005-03-01

    Previous studies in our laboratory have suggested that prostaglandin (PG) E2 is involved in anorexia/cachexia development in MCG 101 tumor-bearing mice. However, the role of COX pathways in the pathogenesis of cancer anorexia/cachexia is not fully resolved. In the present study, we investigated the role of PGE receptors subtype EP1 and EP3 on the development of anorexia in MCG 101-bearing mice. Our results show that the absence of host EP1 or EP3 receptors did not alter the magnitude of anorexia in tumor-bearers. However, anorexia in tumor-bearing EP1 and EP3 knockouts was not improved by indomethacin treatment as observed in wild type tumor-bearers. By contrast, indomethacin improved body composition similar in EP1 and EP3 knockouts as well as in wild type tumor-bearing animals and tumor growth was retarded in EP1 and promoted in EP3 knock outs. Our results demonstrate that host EP1 and EP3 receptors are involved in the control of local tumor growth, which translates into anorexia, this being the main cause of metabolic adaptive alterations to explain weight loss in this model. Brain EP1 and EP3 subtype receptors do not seem to directly control anorexia, which leaves EP2 and EP4 as potential candidates.

  6. Effects of Long-Term Daily Administration of Prostaglandin-E2 on Maintaining Elevated Proximal Tibial Metaphyseal Cancellous Bone Mass in Male Rats

    NASA Technical Reports Server (NTRS)

    Ke, Hua Zhu; Jee, Webster S. S.; Mori, Satoshi; Li, Xiao Jian; Kimmel, Donald B.

    1992-01-01

    The effects of long-term prostaglandin E(sub 2) (PGE(sub 2)) on cancellous bone in proximal tibial metaphysis were studied in 7 month old male Sprague-Dawley rats given daily subcutaneous injections of 0, 1, 3, and 6 mg PGE(sub 2)/kg/day and sacrificed after 60, 120, and 180 days. Histomorphometric analyses were performed on double fluorescent-labeled undecalcified bone specimens. After 60 days of treatment, PGE(sub 2) produced diffusely labeled trabecular bone area, increased trabecular bone area, eroded and labeled trabecular perimeter, mineral apposition rate, and bone formation rate at all dose levels when compared with age-matched controls. In rats given PGE(sub 2) for longer time periods (120 and 180 days), trabecular bone area, diffusely labeled trabecular bone area, labeled perimeter, mineral apposition, and bone formation rates were sustained at the elevated levels achieved earlier at 60-day treatment. The eroded perimeter continued to increase until 120 days, then plateau. The observation that continuous systemic PGE(sub 2) administration to adult male rats elevated metaphyseal cancellous bone mass to 3.5-fold of the control level within 60 days and maintained it for another 120 days indicates that the powerful skeletal anabolic effects of PGE2 can be sustained with continuous administration .

  7. Elevated expression of prostaglandin receptor and increased release of prostaglandin E2 maintain the survival of CD45RO+ T cells in the inflamed human pleural space

    PubMed Central

    Pace, Elisabetta; Bruno, Tony F; Berenger, Byron; Mody, Christopher H; Melis, Mario; Ferraro, Maria; Tipa, Annalisa; Bruno, Andreina; Profita, Mirella; Bonsignore, Giovanni; Gjomarkaj, Mark

    2007-01-01

    Throughout the body, the distribution and differentiation of T-cell subsets varies in a way that optimizes host responses. The role of activation-induced cell death (AICD) in altering the distribution of T-lymphocyte subsets at an immune or inflammatory sites has been unexplored. The objective of this study was to assess whether pleural macrophages modulate AICD of specific pleural T-lymphocyte subsets. We found that pleural T-lymphocytes spontaneously undergo apoptosis, which is associated to increased expression of both FAS and FAS ligand, to decreased expression of Bcl 2 and to caspase 8 and 3 activation. While pleural T lymphocytes were partly protected from apoptosis, autologous peripheral blood T lymphocytes increased their apoptosis when cultured with exudative pleural fluids. Pleural CD45RO+ T cells, in comparison to pleural CD45RA+ T cells, were more susceptible to apoptosis, but were preferentially protected by exudative pleural fluids. Pleural prostaglandin E 2 (PGE2) was implicated in protecting T-lymphocytes from apoptosis because exudative pleural T lymphocytes highly express PGE2 receptors, and because exudative pleural fluid contained high concentrations of PGE2. Activated pleural macrophages released PGE2 and reduced the spontaneous apoptosis of pleural T lymphocytes and depletion of PGE2 from pleural fluids decreased this protective effect. This study demonstrates that PGE2, released in the pleural fluids following pleural macrophage activation, prolongs the survival of specific T-cell subsets, resulting in differentiation of the T-cell repertoire within the inflamed pleural space. PMID:17386077

  8. 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.

  9. Development of a scintillation proximity binding assay for high-throughput screening of hematopoietic prostaglandin D2 synthase.

    PubMed

    Meleza, Cesar; Thomasson, Bobbie; Ramachandran, Chidambaram; O'Neill, Jason W; Michelsen, Klaus; Lo, Mei-Chu

    2016-10-15

    Prostaglandin D2 synthase (PGDS) catalyzes the isomerization of prostaglandin H2 (PGH2) to prostaglandin D2 (PGD2). PGD2 produced by hematopoietic prostaglandin D2 synthase (H-PGDS) in mast cells and Th2 cells is proposed to be a mediator of allergic and inflammatory responses. Consequently, inhibitors of H-PGDS represent potential therapeutic agents for the treatment of inflammatory diseases such as asthma. Due to the instability of the PGDS substrate PGH2, an in-vitro enzymatic assay is not feasible for large-scale screening of H-PGDS inhibitors. Herein, we report the development of a competition binding assay amenable to high-throughput screening (HTS) in a scintillation proximity assay (SPA) format. This assay was used to screen an in-house compound library of approximately 280,000 compounds for novel H-PGDS inhibitors. The hit rate of the H-PGDS primary screen was found to be 4%. This high hit rate suggests that the active site of H-PGDS can accommodate a large diversity of chemical scaffolds. For hit prioritization, these initial hits were rescreened at a lower concentration in SPA and tested in the LAD2 cell assay. 116 compounds were active in both assays with IC50s ranging from 6 to 807 nM in SPA and 82 nM to 10 μM in the LAD2 cell assay.

  10. Control of cell cycle by metabolites of prostaglandin D2 through a non-cAMP mediated mechanism

    NASA Technical Reports Server (NTRS)

    Hughes-Fulford, M.; Fukushima, M.

    1993-01-01

    The dehydration products of PGD2, 9-deoxy-9 prostaglandin D2(PGJ2), 9-deoxy-delta 9, delta 12, delta 13 dehydroprostaglandin D2 (delta 12 PGJ2), and PGA2 all contain an unsaturated cyclopentenone structure which is characteristic of prostaglandins which effectively inhibit cell growth. It has been suggested that the action of the inhibitory prostaglandins may be through a cAMP mechanism. In this study, we use S49 wild type (WT) and adenylate cyclase variant (cyc-) cells to show that PGD2 and PGJ2 are not acting via a cyclic AMP mechanism. First, the increase in cyclic AMP in wild type S-49 cells is not proportional to its effects on DNA synthesis. More importantly, when S-49 cyc- cells were exposed to PGJ2, the adenylate cyclase (cyc-) mutant had decreased DNA synthesis with no change in its nominal cAMP content. Short-term (2 hours or less) exposure of the cyc- cells to prostaglandin J2 caused an inhibition of DNA synthesis. PGJ2 caused cytolysis at high concentrations. Long-term exposure (>14 hrs) of the cells to PGJ2, delta 12PGJ2 or delta 12, delta 14PGJ2 caused a cell cycle arrest in G1 demonstrating a cell cycle specific mechanism of action for growth inhibition by naturally occurring biological products independent of cAMP.

  11. Mononuclear cell modulation of connective tissue function: suppression of fibroblast growth by stimulation of endogenous prostaglandin production.

    PubMed Central

    Korn, J H; Halushka, P V; LeRoy, E C

    1980-01-01

    The role of immune cell products in modulating connective tissue metabolism was investigated. Supernates of both unstimulated and phytohemagglutinin-stimulated human mononuclear cell cultures suppressed fibroblast proliferation (up to 90%) and concomintantly stimulated fibroblast prostaglandin E(PGE) synthesis (20- to 70-fold). The growth suppression was, at least in part, a secondary result of the increased fibroblast PGE synthesis; growth suppression (a) paralled the increased fibroblast PGE synthesis, (b) was reversed by addition of inhibitors of prostaglandin synthesis (indomethacin, meclofenamate, and eicostaetraynoic acid), and (c) was reproduced by addition of exogenous PGE2 to fibroblast cultures. The prostaglandin-stimulatory, growth-suppressive activity was a product of non-T-lymphocyte, adherent cells and was present within 6 h of mononuclear cell culture. The activity was heat (56 degrees C) and trypsin sensitive, nondialyzable, and appeared in the 12,000-20,000 mol wt fractions by Sephadex G-100 chromatography. The activity in supernates of mononuclear cell cultures was removed by incubation with fibroblasts but not by similar incubation with peripheral blood mononuclear cells. Mononuclear cells release a factor(s) which modulates fibroblast proliferation by altering prostaglandin metabolism. PMID:7356693

  12. Stimulation of production of prostaglandin E in gingival cells exposed to products of human blood mononuclear cells.

    PubMed Central

    D'Souza, S M; Englis, D J; Clark, A; Russell, R G

    1981-01-01

    1. Supernatant media from cultures of unstimulated human peripheral blood mononuclear cells contained one or more factors that increased by several hundred-fold the production of prostaglandin E by fibroblast-like cells derived from both inflamed and normal human gingival tissue. 2. This stimulation occurred in a dose-dependent manner and was completely inhibited by 14 microM-indomethacin. 3. Responsiveness to the factor declined as the age of the cell culture increased. 4. An increase in prostaglandin E production was first observed after a 2h exposure to the mononuclear cell factor(s) and could be prevented by cycloheximide. 5. Brief exposure (0.5 and 1.0 h) to mononuclear cell factor did not increase prostaglandin E production by the cells in a subsequent 72 h incubation in the absence of mononuclear cell factor. 6. Addition of arachidonate (10 microM and 15 microM) further enhanced stimulation of prostaglandin E production in response to mononuclear cell factor. 7. The stimulatory activity was resistant to digestion by trypsin, but was heat-labile, so that only 17% remained after treatment at 56 degrees C for 30 min. PMID:6798975

  13. Stimulation of production of prostaglandin E in gingival cells exposed to products of human blood mononuclear cells.

    PubMed

    D'Souza, S M; Englis, D J; Clark, A; Russell, R G

    1981-08-15

    1. Supernatant media from cultures of unstimulated human peripheral blood mononuclear cells contained one or more factors that increased by several hundred-fold the production of prostaglandin E by fibroblast-like cells derived from both inflamed and normal human gingival tissue. 2. This stimulation occurred in a dose-dependent manner and was completely inhibited by 14 microM-indomethacin. 3. Responsiveness to the factor declined as the age of the cell culture increased. 4. An increase in prostaglandin E production was first observed after a 2h exposure to the mononuclear cell factor(s) and could be prevented by cycloheximide. 5. Brief exposure (0.5 and 1.0 h) to mononuclear cell factor did not increase prostaglandin E production by the cells in a subsequent 72 h incubation in the absence of mononuclear cell factor. 6. Addition of arachidonate (10 microM and 15 microM) further enhanced stimulation of prostaglandin E production in response to mononuclear cell factor. 7. The stimulatory activity was resistant to digestion by trypsin, but was heat-labile, so that only 17% remained after treatment at 56 degrees C for 30 min.

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

    Technology Transfer Automated Retrieval System (TEKTRAN)

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

  15. Prostaglandin A2 influences gene expression in an established insect cell line (BCIRL-HzAm1) cells

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Prostaglandins (PGs) and other eicosanoids are oxygenated metabolites of arachidonic acid and two other C20 polyunsaturated fatty acids. While most well studied in mammals, PGs exert important actions in insects and virtually all other invertebrates. We have been researching the mechanisms of PG a...

  16. Lipid Classes, Fatty Acid Composition, and Glycerolipid Molecular Species of the Red Alga Gracilaria vermiculophylla, a Prostaglandin-Producing Seaweed.

    PubMed

    Honda, Masaki; Ishimaru, Takashi; Itabashi, Yutaka

    2016-01-01

    The red alga Gracilaria vermiculophylla is a well-known producer of prostaglandins, such as PGE2 and PGF2α. In this study, the characteristics of glycerolipids as substrates of prostaglandin production were clarified, and the lipid classes, fatty acid composition, and glycerolipid molecular species were investigated in detail. The major lipid classes were monogalactosyldiacylglycerol (MGDG), digalactosyldiacylglycerol (DGDG), and sulfoquinovosyldiacylglycerol (SQDG), as well as phosphatidylcholine (PC), which accounted for 43.0% of the total lipid profile. Arachidonic acid (20:4n-6), a prostaglandin precursor, and palmitic acid (16:0) were the predominant fatty acids in the total lipid profile. The 20:4n-6 content was significantly high in MGDG and PC (more than 60%), and the 16:0 content was significantly high in DGDG and SQDG (more than 50%). Chiral-phase high-performance liquid chromatography determined that fatty acids were esterified at the sn-1 and sn-2 positions of those lipids. The main glycerolipid molecular species were 20:4n-6/20:4n-6 (sn-1/sn-2) for MGDG (56.5%) and PC (40.0%), and 20:4n-6/16:0 for DGDG (75.4%) and SQDG (58.4%). Thus, it was considered that the glycerolipid molecular species containing one or two 20:4n-6 were the major substrates for prostaglandin production in G. vermiculophylla.

  17. 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.

  18. Acetylsalicylic acid interferes with embryonic kidney growth and development by a prostaglandin-independent mechanism

    PubMed Central

    Welham, Simon J M; Sparrow, Alexander J; Gardner, David S; Elmes, Matthew J

    2017-01-01

    AIM To evaluate the effects of the non-selective, non-steroidal anti-inflammatory drug (NSAID) acetylsalicylic acid (ASA), on ex vivo embryonic kidney growth and development. METHODS Pairs of fetal mouse kidneys at embryonic day 12.5 were cultured ex vivo in increasing concentrations of ASA (0.04-0.4 mg/mL) for up to 7 d. One organ from each pair was grown in control media and was used as the internal control for the experimental contralateral organ. In some experiments, organs were treated with ASA for 48 h and then transferred either to control media alone or control media containing 10 μmol/L prostaglandin E2 (PGE2) for a further 5 d. Fetal kidneys were additionally obtained from prostaglandin synthase 2 homozygous null or heterozygous (PTGS2-/- and PTGS2-/+) embryos and grown in culture. Kidney cross-sectional area was used to determine treatment effects on kidney growth. Whole-mount labelling to fluorescently detect laminin enabled crude determination of epithelial branching using confocal microscopy. RESULTS Increasing ASA concentration (0.1, 0.2 and 0.4 mg/mL) significantly inhibited metanephric growth (P < 0.05). After 7 d of culture, exposure to 0.2 mg/mL and 0.4 mg/mL reduced organ size to 53% and 23% of control organ size respectively (P < 0.01). Addition of 10 μmol/L PGE2 to culture media after exposure to 0.2 mg/mL ASA for 48 h resulted in a return of growth area to control levels. Application of control media alone after cessation of ASA exposure showed no benefit on kidney growth. Despite the apparent recovery of growth area with 10 μmol/L PGE2, no obvious renal tubular structures were formed. The number of epithelial tips generated after 48 h exposure to ASA was reduced by 40% (0.2 mg/mL; P < 0.05) and 47% (0.4 mg/mL; P < 0.01). Finally, growth of PTGS2-/- and PTGS2+/- kidneys in organ culture showed no differences, indicating that PTGS2 derived PGE2 may at best have a minor role. CONCLUSION ASA reduces early renal growth and development but the

  19. 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.

  20. Role of prostaglandins in spinal transmission of the exercise pressor reflex in decerebrated rats.

    PubMed

    Stone, A J; Copp, S W; Kaufman, M P

    2014-09-26

    Previous studies found that prostaglandins in skeletal muscle play a role in evoking the exercise pressor reflex; however the role played by prostaglandins in the spinal transmission of the reflex is not known. We determined, therefore, whether or not spinal blockade of cyclooxygenase (COX) activity and/or spinal blockade of endoperoxide (EP) 2 or 4 receptors attenuated the exercise pressor reflex in decerebrated rats. We first established that intrathecal doses of a non-specific COX inhibitor Ketorolac (100 μg in 10 μl), a COX-2-specific inhibitor Celecoxib (100 μg in 10 μl), an EP2 antagonist PF-04418948 (10 μg in 10 μl), and an EP4 antagonist L-161,982 (4 μg in 10 μl) effectively attenuated the pressor responses to intrathecal injections of arachidonic acid (100 μg in 10 μl), EP2 agonist Butaprost (4 ng in 10 μl), and EP4 agonist TCS 2510 (6.25 μg in 2.5 μl), respectively. Once effective doses were established, we statically contracted the hind limb before and after intrathecal injections of Ketorolac, Celecoxib, the EP2 antagonist and the EP4 antagonist. We found that Ketorolac significantly attenuated the pressor response to static contraction (before Ketorolac: 23 ± 5 mmHg, after Ketorolac 14 ± 5 mmHg; p<0.05) whereas Celecoxib had no effect. We also found that 8 μg of L-161,982, but not 4 μg of L-161,982, significantly attenuated the pressor response to static contraction (before L-161,982: 21 ± 4 mmHg, after L-161,982 12 ± 3 mmHg; p<0.05), whereas PF-04418948 (10 μg) had no effect. We conclude that spinal COX-1, but not COX-2, plays a role in evoking the exercise pressor reflex, and that the spinal prostaglandins produced by this enzyme are most likely activating spinal EP4 receptors, but not EP2 receptors.

  1. 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.

  2. Growth differentiation factor-9 stimulates progesterone synthesis in granulosa cells via a prostaglandin E2/EP2 receptor pathway.

    PubMed

    Elvin, J A; Yan, C; Matzuk, M M

    2000-08-29

    Growth differentiation factor-9 (GDF-9), an oocyte-secreted member of the transforming growth factor beta superfamily, progesterone receptor, cyclooxygenase 2 (Cox2; Ptgs2), and the EP2 prostaglandin E(2) (PGE(2)) receptor (EP2; Ptgerep2) are required for fertility in female but not male mice. To define the interrelationship of these factors, we used a preovulatory granulosa cell culture system in which we added recombinant GDF-9, prostaglandins, prostaglandin receptor agonists, or cyclooxygenase inhibitors. GDF-9 stimulated Cox2 mRNA within 2 h, and PGE(2) within 6 h; however, progesterone was not increased until 12 h after addition of GDF-9. This suggested that Cox2 is a direct downstream target of GDF-9 but that progesterone synthesis required an intermediate. To determine whether prostaglandin synthesis was required for progesterone production, we analyzed the effects of PGE(2) and cyclooxygenase inhibitors on this process. PGE(2) can stimulate progesterone synthesis by itself, although less effectively than GDF-9 (3-fold vs. 6-fold increase over 24 h, respectively). Furthermore, indomethacin or NS-398, inhibitors of Cox2, block basal and GDF-9-stimulated progesterone synthesis. However, addition of PGE(2) to cultures containing both GDF-9 and NS-398 overrides the NS-398 block in progesterone synthesis. To further define the PGE(2)-dependent pathway, we show that butaprost, a specific EP2 agonist, stimulates progesterone synthesis and overrides the NS-398 block. In addition, GDF-9 stimulates EP2 mRNA synthesis by a prostaglandin- and progesterone-independent pathway. Thus, GDF-9 induces an EP2 signal transduction pathway which appears to be required for progesterone synthesis in cumulus granulosa cells. These studies further demonstrate the importance of oocyte-somatic cell interactions in female reproduction.

  3. Neuroinflammation and J2 prostaglandins: linking impairment of the ubiquitin-proteasome pathway and mitochondria to neurodegeneration

    PubMed Central

    Figueiredo-Pereira, Maria E.; Rockwell, Patricia; Schmidt-Glenewinkel, Thomas; Serrano, Peter

    2015-01-01

    The immune response of the CNS is a defense mechanism activated upon injury to initiate repair mechanisms while chronic over-activation of the CNS immune system (termed neuroinflammation) may exacerbate injury. The latter is implicated in a variety of neurological and neurodegenerative disorders such as Alzheimer and Parkinson diseases, amyotrophic lateral sclerosis, multiple sclerosis, traumatic brain injury, HIV dementia, and prion diseases. Cyclooxygenases (COX-1 and COX-2), which are key enzymes in the conversion of arachidonic acid into bioactive prostanoids, play a central role in the inflammatory cascade. J2 prostaglandins are endogenous toxic products of cyclooxygenases, and because their levels are significantly increased upon brain injury, they are actively involved in neuronal dysfunction induced by pro-inflammatory stimuli. In this review, we highlight the mechanisms by which J2 prostaglandins (1) exert their actions, (2) potentially contribute to the transition from acute to chronic inflammation and to the spreading of neuropathology, (3) disturb the ubiquitin-proteasome pathway and mitochondrial function, and (4) contribute to neurodegenerative disorders such as Alzheimer and Parkinson diseases, and amyotrophic lateral sclerosis, as well as stroke, traumatic brain injury (TBI), and demyelination in Krabbe disease. We conclude by discussing the therapeutic potential of targeting the J2 prostaglandin pathway to prevent/delay neurodegeneration associated with neuroinflammation. In this context, we suggest a shift from the traditional view that cyclooxygenases are the most appropriate targets to treat neuroinflammation, to the notion that J2 prostaglandin pathways and other neurotoxic prostaglandins downstream from cyclooxygenases, would offer significant benefits as more effective therapeutic targets to treat chronic neurodegenerative diseases, while minimizing adverse side effects. PMID:25628533

  4. Inhibition of brain prostaglandin endoperoxide synthase-2 prevents the preparturient increase in fetal adrenocorticotropin secretion in the sheep fetus.

    PubMed

    Gersting, Jason; Schaub, Christine E; Keller-Wood, Maureen; Wood, Charles E

    2008-08-01

    Maturation of the fetal hypothalamus-pituitary-adrenal axis is critical for the timely somatic development of the fetus and readiness for birth. Recently, we proposed that prostaglandin generation within the fetal central nervous system is critical for the modulation of hypotension-induced fetal ACTH secretion. The present study was designed to test the hypothesis that the preparturient increase in fetal ACTH secretion is dependent upon fetal central nervous system prostaglandin synthesis mediated by the activity of prostaglandin endoperoxide synthase (PGHS)-2 (cyclooxygenase-2) in the fetal brain. We performed two studies in chronically catheterized fetal sheep. In the first study, we infused nimesulide or vehicle intracerebroventricularly (i.c.v) into singleton fetal sheep and collected blood samples until spontaneous parturition. Nimesulide significantly delayed parturition, and inhibited fetal ACTH and proopiomelanocortin secretion but did not prevent the preparturient increase in fetal plasma cortisol concentration. In the second study, we used twin fetuses. One fetus received intracerebroventricular nimesulide and the other intracerebroventricular vehicle. Nimesulide reduced brain tissue concentrations of prostaglandin estradiol, while not affecting plasma prostaglandin E(2) concentrations, demonstrating an action restricted to the fetal brain. Nimesulide reduced PGHS-2 mRNA and increased PGHS-2 protein, while not altering PGHS-1 mRNA or protein in most brain regions, suggesting an effect of the inhibitor on PGHS-2 turnover and relative specificity for PGHS-2 in vivo. We conclude that the preparturient increase in fetal ACTH and proopiomelanocortin is dependent upon the activity of PGHS-2 in the fetal brain. However, we also conclude that the timing of parturition is not solely dependent upon ACTH in this species.

  5. 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../.

  6. Centrally administered CDP-choline induced cardiovascular responses are mediated by activation of the central phospholipase-prostaglandin signaling cascade.

    PubMed

    Topuz, Bora B; Altinbas, Burcin; Ilhan, Tuncay; Yilmaz, Mustafa S; Erdost, Hatice; Saha, Sikha; Savci, Vahide; Yalcin, Murat

    2014-05-14

    The present study was designed to determine the involvement of central prostaglandin synthesis on the pressor and bradycardic effect of cytidine 5'-diphosphocholine (CDP-choline). Intracerebroventricular (i.c.v.) administration of CDP-choline was made and blood pressure and heart rate were recorded in male Sprague Dawley rats throughout this study. Microdialysis and immunohistochemical studies were performed to measure extracellular total prostaglandin concentration and to show cyclooxygenase-1 and -2 (COX-1 and -2) immunoreactivities, respectively, in the posterior hypothalamic area. Moreover, rats were pretreated (i.c.v) with mepacrine [a phospholipase A2 (PLA2) inhibitor], ibuprofen [a nonselective COX inhibitor], neomycine [a phospholipase C (PLC) inhibitor] or furegrelate [a thromboxane A2 (TXA2) synthesis inhibitor] 5 min prior to the injection of CDP-choline to determine the effects of these inhibitors on cardiovascular responses to CDP-choline. Control rats were pretreated (i.c.v) with saline. CDP-choline caused a dose- and time-dependent increase in blood pressure and decrease in heart rate. Immunohistochemical studies showed that CDP-choline increased COX-1 and -2 immunoreactivities in the posterior hypothalamic area. CDP-choline also elevated hypothalamic extracellular total prostaglandin concentration by 62%, as shown in microdialysis studies. Mepacrine or ibuprofen pretreatments almost completely blocked the pressor and bradycardic responses to CDP-choline while neomycine or furegrelate partially attenuated the drug-induced cardiovascular effects. The results suggest that CDP-choline may stimulate prostaglandin synthesis through the activation of PLA2, cyclooxygenases (COX-1 and -2) and prostaglandins and at least TXA2, may mediate the drug׳s cardiovascular effects.

  7. Radiation Transport

    SciTech Connect

    Urbatsch, Todd James

    2015-06-15

    We present an overview of radiation transport, covering terminology, blackbody raditation, opacities, Boltzmann transport theory, approximations to the transport equation. Next we introduce several transport methods. We present a section on Caseology, observing transport boundary layers. We briefly broach topics of software development, including verification and validation, and we close with a section on high energy-density experiments that highlight and support radiation transport.

  8. Stable expression of lipocalin-type prostaglandin D synthase in cultured preadipocytes impairs adipogenesis program independently of endogenous prostanoids

    SciTech Connect

    Hossain, Mohammad Salim; Chowdhury, Abu Asad; Rahman, Mohammad Sharifur; Nishimura, Kohji; Jisaka, Mitsuo; Nagaya, Tsutomu; Shono, Fumiaki; Yokota, Kazushige

    2012-02-15

    Lipocalin-type prostaglandin D synthase (L-PGDS) expressed preferentially in adipocytes is responsible for the synthesis of PGD{sub 2} and its non-enzymatic dehydration products, PGJ{sub 2} series, serving as pro-adipogenic factors. However, the role of L-PGDS in the regulation of adipogenesis is complex because of the occurrence of several derivatives from PGD{sub 2} and their distinct receptor subtypes as well as other functions such as a transporter of lipophilic molecules. To manipulate the expression levels of L-PGDS in cultured adipocytes, cultured preadipogenic 3T3-L1 cells were transfected stably with a mammalian expression vector having cDNA encoding murine L-PGDS oriented in the sense direction. The isolated cloned stable transfectants with L-PGDS expressed higher levels of the transcript and protein levels of L-PGDS, and synthesized PGD{sub 2} from exogenous arachidonic acid at significantly higher levels. By contrast, the synthesis of PGE{sub 2} remained unchanged, indicating no influence on the reactions of cyclooxygenase (COX) and PGE synthase. Furthermore, the ability of those transfectants to synthesize {Delta}{sup 12}-PGJ{sub 2} increased more greatly during the maturation phase. The sustained expression of L-PGDS in cultured stable transfectants hampered the storage of fats during the maturation phase of adipocytes, which was accompanied by the reduced gene expression of adipocyte-specific markers reflecting the down-regulation of the adipogenesis program. The suppressed adipogenesis was not rescued by either exogenous aspirin or peroxisome proliferator-activated receptor {gamma} (PPAR{gamma}) agonists including troglitazone and {Delta}{sup 12}-PGJ{sub 2}. Taken together, the results indicate the negative regulation of the adipogenesis program by the enhanced expression of L-PGDS through a cellular mechanism involving the interference of the PPAR{gamma} signaling pathway without the contribution of endogenous pro-adipogenic prostanoids

  9. 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.

  10. Eosinophils in human oral squamous carcinoma; role of prostaglandin D2.

    PubMed

    Davoine, Francis; Sim, Adrian; Tang, Charlie; Fisher, Sibina; Ethier, Caroline; Puttagunta, Lakshmi; Wu, Yingqi; McGaw, W Tim; Yu, Donald; Cameron, Lisa; Adamko, Darryl J; Moqbel, Redwan

    2013-01-31

    Eosinophils are often predominant inflammatory leukocytes infiltrating oral squamous carcinoma (OSC) sites. Prostaglandins are secreted by oral carcinomas and may be involved in eosinophil infiltration. The objective of this study was to determine the factors contributing to eosinophil migration and potential anti-neoplastic effects on OSC. Eosinophil degranulation was evaluated by measuring release of eosinophil peroxidase (EPO). Eosinophil chemotaxis towards OSC cells was assessed using artificial basement membrane. Eosinophil infiltration was prominent within the tissue surrounding the OSC tumor mass. We observed growth inhibition of the OSC cell line, SCC-9, during co-culture with human eosinophils, in vitro, which correlated with EPO activity that possesses growth inhibitory activity. The PGD2 synthase inhibitor, HQL-79, abrogated migration towards SCC-9. Our data suggest that OSC-derived PGD2 may play an important role via CRTH2 (the PGD2 receptor on eosinophils) in eosinophil recruitment and subsequent anti-tumor activity through the action of eosinophil cationic proteins.

  11. 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.

  12. Defining the therapeutic time window for suppressing the inflammatory prostaglandin E2 signaling after status epilepticus

    PubMed Central

    Du, Yifeng; Kemper, Timothy; Qiu, Jiange; Jiang, Jianxiong

    2016-01-01

    Neuroinflammation is a common feature in nearly all neurological and some psychiatric disorders. Resembling its extraneural counterpart, neuroinflammation can be both beneficial and detrimental depending on the responding molecules. The overall effect of inflammation on disease progression is highly dependent on the extent of inflammatory mediator production and the duration of inflammatory induction. The time-dependent aspect of inflammatory responses suggests that the therapeutic time window for quelling neuroinflammation might vary with molecular targets and injury types. Therefore, it is important to define the therapeutic time window for anti-inflammatory therapeutics, as contradicting or negative results might arise when different treatment regimens are utilized even in similar animal models. Herein, we discuss a few critical factors that can help define the therapeutic time window and optimize treatment paradigm for suppressing the cyclooxygenase-2/prostaglandin-mediated inflammation after status epilepticus. These determinants should also be relevant to other anti-inflammatory therapeutic strategies for the CNS diseases. PMID:26689339

  13. Facilitation of suction termination using extra-amniotic prostaglandins in gel.

    PubMed

    Craft, I L; Evans, D V; Richfield, L B

    1979-07-01

    Extra-amniotic prostaglandin E2 (PGE2) suspended in a slow release gel (Tylose) was instilled in 35 patients prior to a planned surgical termination in an attempt to dilate the cervix, minimize cervical trauma, and reduce the possible risk of cervical trauma, and reduce the possible risk of cervical incompetence and its sequelae. Dilatation occurred in all patients to a minimum of 8 mm and 74% aborted before surgical evacuation performed 6 to 24 hours after injection. No serious side effects occurred. Extra-amniotic PGE2 in gel should be considered as a primary procedure when the cervix is obviously immature on examination. If the cervix is found to be tight and unyielding at surgical dilatation, the latter procedure should be dicontinued and PGE2 in gel injected.

  14. Induction of therapeutic abortion in early pregnancy with mifepristone in combination with prostaglandin pessary.

    PubMed

    Rodger, M W; Baird, D T

    1987-12-19

    Therapeutic abortion was induced in 100 women in early pregnancy (less than 56 days' amenorrhoea) with a combination of the antigestagen mifepristone (RU 486) and a synthetic prostaglandin analogue, gemeprost. Mifepristone in oral doses of 400-600 mg was followed 48 h later by a gemeprost vaginal pessary (0.5-1.0 mg). Bleeding was induced in all women 22-70 h after the mifepristone dose and although bleeding continued for 4-43 days (median 12) the total measured blood-loss was only a median of 72.5 ml (range 15-398). Complete abortion occurred in 95 women. Surgical evacuation of the uterus for minimum debris was required in the remaining 5. Only 10 women had diarrhoea or pain that required opioid analgesia. The combination of mifepristone and gemeprost provides a safe and effective alternative to surgical evacuation of the uterus for therapeutic abortion in early pregnancy.

  15. 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.

  16. [Using prostaglandin E1 in microvascular reconstruction of the upper extremity after acute trauma].

    PubMed

    Slodicka, R; Lautenbach, M; Eisenschenk, A

    2002-01-01

    The operative treatment of hand and upper extremity trauma with injury of main vessels becomes a daily standard work in trauma and microsurgical replantation centers. The techniques of vessel and soft tissue reconstruction are well known. The outcome of the replantation depends on various factors. Main influences are the intraoperative status of the vessel wall and the unobstructed flow in the vessel after the operation. Another factor for successful replantation is the homeostasis of the patient. It can be influenced by many drugs which are applied according to a replantation schema. Aim of this therapy is the correction of the rheologic properties of a patient. In a patient group of 25 treated with Prostaglandin E1 (Prostavasin) we observed better wound healing with a 80% rate of successful replantation and microvascular vessel reconstruction.

  17. Effect of prostaglandin E1 on certain renal actions of parathyroid hormone

    PubMed Central

    Beck, Nama P.; DeRubertis, Frederick R.; Michelis, Michael F.; Fusco, Robert D.; Field, James B.; Davis, Bernard B.

    1972-01-01

    Parathyroid hormone increased basal adenyl cyclase activity and that increase was inhibited by prostaglandin E1 (PGE1). Tissue cyclic 3′,5′-adenosine monophosphate (cyclic AMP) concentrations were increased by parathyroid hormone and that increase was likewise inhibited by PGE1. Both parathyroid hormone and dibutyryl cyclic AMP increased 32P incorporation into renal cortical phospholipids. PGE1 diminished the effect of parathyroid hormone but not dibutyryl cyclic AMP to influence that parameter. PGE1 likewise modulated the effect of parathyroid hormone but not dibutyryl cyclic AMP to decrease fractional phosphate reabsorption by the renal tubule. It is suggested that PGE1 inhibits the effect of parathyroid hormone by decreasing its effect on adenyl cyclase. Such interaction may be important in modulating the intracellular action of parathyroid hormone on kidney cortex. PMID:4344730

  18. Export of cyclic AMP by avian red cells and inhibition by prostaglandin A/sub 1/

    SciTech Connect

    Heasley, L.E.

    1985-01-01

    The mechanism by which PGA/sub 1/ inhibits cAMP export by avian red cells was studied, to provide details on the molecular mechanism of a prostaglandin action and on the process of cAMP export itself. The interaction of PGA/sub 1/ with pigeon red cells is a multi-step process of uptake, metabolism and secretion. (/sup 3/H)PGA rapidly enters red cells and is promptly metabolized (V/sub max/ greater than or equal to 1 nmol/min/10/sup 7/ cells) to a compound (5) that remains in the aqueous layer after ethyl acetate extraction. Chromatographic analyses, amino acid content and fast atom bombardment mass spectrometry reveal that the polar metabolite is conjugated with glutathione (PGA/sub 1/-GSH) at C-11 via a thioether bond and is largely (80%) reduced to the C-9 hydroxyl derivative.

  19. Effect of dietary vitamin E or selenium on prostaglandin dehydrogenase in hyperoxic rat lung

    NASA Technical Reports Server (NTRS)

    North, L. N.; Mathias, M. M.; Schatte, C. L.

    1984-01-01

    Weanling male rats were fed semipurified diets supplemented with 0, 60, or 600 IU/kg vitamin E or 0, 100, or 1000 ppb selenium. One group was injected daily with vitamin E at a rate equivalent to consumption of 60 IU/kg. Animals from all groups were sacrificed after exposure to normobaric oxygen or air for 48 h. Lung tissue was analyzed for the combined activity of prostaglandin dehydrogenase and reductase. Using the decline in enzyme activity as an indicator of susceptibility to oxygen poisoning, protection against hyperoxia was directly related to the level of vitamin E supplementation. Selenium supplemented at 100 ppb provided significant protection when compared to 0 ppb or 1000 ppb. The latter dose may have been marginally toxic. Thus dietary supplementation of vitamin E and selenium may influence the relative susceptibility of an animal to pulmonary oxygen poisoning.

  20. 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

  1. [Epidural anesthesia and local administration of high-dose prostaglandin in obstetrics. A dangerous combination].

    PubMed

    Veeckman, L; Müller, E; Van Aken, H

    1989-07-01

    The use of high epidural anesthesia for cesarean section has generally been accepted as a safe and comfortable means of intra- and post-operative pain relief in recent years. However, the accompanying vasomotor blockade of the lower body and the sometimes impaired cardiac reflex activity restrict the use of concomitant--even local--medication. Described are the deleterious side effects on hemodynamic stability and patient comfort of an intramyometrically administered synthetic prostaglandin E (PGE2)-compound (dinoprostone) given to three female patients under high epidural anesthesia during cesarean section. Differentiation of the various symptoms is made in relation to their epidural or PGE origin or to a combination of the two. A striking therapeutic resistance of the hypotension of a sufficiently volume-expanded patient to even large doses of ephedrine is discussed as representing possible PGE-mediated suppression of peripheral norepinephrine release.

  2. [Prevention and treatment of NSAIDs-induced gastrointestinal complications by prostaglandin derivatives].

    PubMed

    Suzuki, Yasuo; Saito, Eiko; Wakabayashi, Takayuki; Suwa, Akira

    2007-10-01

    Non-steroidal anti-inflammatory drugs(NSAIDs) are widely used for the treatment of many rheumatic diseases. Gastrointestinal ulcers are the most important complication during long-term NSAIDs therapy and sometimes, serious complications, such as perforation, stenosis, and bleeding occurs. Recently, use of COX-2 selective NSAIDs reduced such complications, however the increase of cardiovascular risks has been reported. Administration of misoprostol, one of the prostaglandin derivatives has been proven to be effective for both prevention and treatment of gastrointestinal ulcers associated with NSAIDs therapy and is recommended by the Japanese guidelines. In addition, the reduction of NSAIDs-related serious complications, such as perforation, stenosis, and bleeding have been reported with misoprostol therapy. The important side effects include abdominal pain, flatulence, and diarrhea.

  3. Acute effect of potassium canrenoate administration on renin-angiotensin, kallikrein-kinin and prostaglandin systems.

    PubMed

    Lahera, V; Cachofeiro, V; Duran, F; Cañizo, F J; Rodriguez, F J; Tresguerres, J A

    1988-01-01

    1. To investigate the possible effects of potassium canrenoate (PC) on plasma renin activity (PRA) and on renal prostaglandins (PGS) and kinins under elevated sodium and/or potassium intakes, a single dose of PC was administered to four groups of Wistar male rats. 2. They were fed a normal diet (C), a diet supplemented with 4% of NaCl, (Na), with 1% of KCl: (K) or both supplements (NaK). 3. PRA and urinary PGS excretion did not show changes after PC administration, but total urinary kinins showed higher values after the treatment in all groups. 4. A diuretic but not natriuretic effect was observed only in C animals. 5. In conclusion, the single dose of PC was able to stimulate urinary kinins and to spare potassium independently of dietary electrolyte supplements that were able to block the diuretic effect of the drug.

  4. Prostaglandin E2 impairs osteogenic and facilitates adipogenic differentiation of human bone marrow stromal cells.

    PubMed

    Noack, Carolin; Hempel, Ute; Preissler, Carolin; Dieter, Peter

    2015-03-01

    The synthetic glucocorticoid dexamethasone (dex) is a mandatory additive to induce osteogenic differentiation of bone marrow stromal cell (BMSC) in vitro; however it is also known to promote the pathogenesis of osteoporotic bone disease in vivo. In this study human (h)BMSC were cultured in osteogenic medium containing β-glycerophosphate and ascorbate (OM) and in OM containing dex (OM/D). It was seen that dex induced in human (h)BMSC both, osteogenic and adipogenic differentiation markers. Dex reveals its anti-inflammatory effect by reducing endogenous prostaglandin E2 (PGE2) formation and by suppressing the inducible enzymes cyclooxygenase 2 and microsomal PGE2 synthase 1. It was further seen that dex enhanced the expression of prostaglandin receptors, mainly EP2 and EP4 receptor subtypes. We thus hypothesized that dex enforces the susceptibility of hBMSC to respond to exogenous PGE2. Permanent exposure of hBMSC which were cultured in OM/D to PGE2, decreased osteogenic and increased adipogenic differentiation markers. The effects of PGE2 were preferentially mediated by receptor subtypes EP2 and EP4; EP1 was partially involved in pro-adipogenic effects, and EP3 was partially involved in anti-osteogenic effects. These results suggest that dex suppresses the formation of endogenous PGE2 but also enables hBMSC to respond to PGE2 due to the induction of PGE2 receptors EP2 and EP4. PGE2 then shifts in hBMSC the balance from osteogenic to adipogenic differentiation.

  5. Cloning, functional expression, and characterization of the human prostaglandin E2 receptor EP2 subtype.

    PubMed

    Bastien, L; Sawyer, N; Grygorczyk, R; Metters, K M; Adam, M

    1994-04-22

    A cDNA clone encoding the human prostaglandin (PG) E2 receptor EP2 subtype has been isolated from a human lung cDNA library. The 1.9-kilobase pair cDNA, hEP2, encodes for a 488-amino acid protein with a predicted molecular mass of 53,115 and has the seven putative transmembrane domains characteristic of G protein-coupled receptors. The specific binding of [3H]PGE2 to COS cell membranes transfected with the hEP2 cDNA was of high affinity with an equilibrium dissociation constant (Kd) of 1 nM and the rank order of potency for prostaglandins in competition for [3H]PGE2 specific binding was PGE1 = PGE2 > iloprost > PGF2 alpha > PGD2. In competition studies using more selective prostanoid-receptor agonist and antagonists, the [3H]PGE2 specific binding was competed by MB28767, an EP3 agonist, but not by the EP1-preferring antagonists AH6809 and SC19220, or by the EP2 agonist butaprost. Electrophysiological studies of Xenopus oocytes co-injected with hEP2 and cystic fibrosis transmembrane conductance regulator (cAMP-activated Cl- channel) cDNAs detected PGE2-specific inward Cl- currents, demonstrating that the hEP2 cDNA encoded a functional receptor which produced an increase in cAMP levels. Thus, we have cloned the human EP2 receptor subtype which is functionally coupled to increase in cAMP. Northern blot analysis showed that hEP2 is expressed as a 3.8-kilobase mRNA in a number of human tissues with the highest expression levels present in the small intestine.

  6. Identification of prostaglandin E2 receptor subtype 2 as a receptor activated by OxPAPC.

    PubMed

    Li, Rongsong; Mouillesseaux, Kevin P; Montoya, Dennis; Cruz, Daniel; Gharavi, Navid; Dun, Martin; Koroniak, Lukasz; Berliner, Judith A

    2006-03-17

    Oxidized 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphorylcholine (OxPAPC), which has been shown to accumulate in atherosclerotic lesions and other sites of chronic inflammation, activates endothelial cells (EC) to bind monocytes by activation of endothelial beta1 integrin and subsequent deposition of fibronectin on the apical surface. Our previous studies suggest this function of OxPAPC is mediated via a Gs protein-coupled receptor (GPCR). PEIPC (1-palmitoyl-2-epoxyisoprostane E2-sn-glycero-3-phosphorylcholine) is the most active lipid in OxPAPC that activates this pathway. We screened a number of candidate GPCRs for their interaction with OxPAPC and PEIPC, using a reporter gene assay; we identified prostaglandin E2 receptor EP2 and prostaglandin D2 receptor DP as responsive to OxPAPC. We focused on EP2, which is expressed in ECs, monocytes, and macrophages. OxPAPC component PEIPC, but not POVPC, activated EP2 with an EC50 of 108.6 nmol/L. OxPAPC and PEIPC were also able to compete with PGE2 for binding to EP2 in a ligand-binding assay. The EP2 specific agonist butaprost was shown to mimic the effect of OxPAPC on the activation of beta1 integrin and the stimulation of monocyte binding to endothelial cells. Butaprost also mimicked the effect of OxPAPC on the regulation of tumor necrosis factor-alpha and interleukin-10 in monocyte-derived cells. EP2 antagonist AH6809 blocked the activation of EP2 by OxPAPC in HEK293 cells and blocked the interleukin-10 response to PEIPC in monocytic THP-1 cells. These results suggest that EP2 functions as a receptor for OxPAPC and PEIPC, either as the phospholipid ester or the released fatty acid, in both endothelial cells and macrophages.

  7. Endocannabinoids, through opioids and prostaglandins, contribute to fever induced by key pyrogenic mediators.

    PubMed

    Fraga, Daniel; Zanoni, Cristiane I S; Zampronio, Aleksander R; Parada, Carlos A; Rae, Giles A; Souza, Glória E P

    2016-01-01

    This study aims to explore the contribution of endocannabinoids on the cascade of mediators involved in LPS-induced fever and to verify the participation of prostaglandins and endogenous opioids in fever induced by anandamide (AEA). Body temperature (Tc) of male Wistar rats was recorded over 6h, using a thermistor probe. Cerebrospinal fluid concentration of PGE2 and β-endorphin were measured by ELISA after the administration of AEA. Intracerebroventricular administration of the CB1 receptor antagonist AM251 (5μg, i.c.v.), reduced the fever induced by IL-1β (3ng, i.c.v.), TNF-α (250ng, i.c.v.), IL-6 (300ng, i.c.v.), corticotrophin release factor (CRH; 2.5μg, i.c.v.) and endothelin (ET)-1 (1pmol, i.c.v.), but not the fever induced by PGE2 (250ng, i.c.v.) or PGF2α (250ng, i.c.v.). Systemic administration of indomethacin (2mgkg(-1), i.p.) or celecoxib (5mgkg(-1), p.o.) reduced the fever induced by AEA (1μg, i.c.v.), while naloxone (1mgkg(-1), s.c.) abolished it. The increases of PGE2 and β-endorphin concentration in the CSF induced by AEA were abolished by the pretreatment of rats with AM251. These results suggest that endocannabinoids are intrinsically involved in the pyretic activity of cytokines (IL-1β, TNF-α, IL-6), CRH and ET-1 but not the PGE2 or PGF2α induced fevers. However, anandamide via CB1 receptor activation induces fever that is dependent on the synthesis of prostaglandin and opioids.

  8. 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.

  9. Terutroban, a thromboxane/prostaglandin endoperoxide receptor antagonist, prevents hypertensive vascular hypertrophy and fibrosis.

    PubMed

    Gelosa, Paolo; Sevin, Gulnur; Pignieri, Alice; Budelli, Silvia; Castiglioni, Laura; Blanc-Guillemaud, Vanessa; Lerond, Laurence; Tremoli, Elena; Sironi, Luigi

    2011-03-01

    Thromboxane A(2) and other eicosanoids such as isoprostanes contribute to vascular proliferation and atherosclerosis by binding to the thromboxane/prostaglandin endoperoxide receptors. The effects of terutroban, a thromboxane/prostaglandin endoperoxide receptor antagonist, on aorta remodeling were evaluated in spontaneously hypertensive stroke-prone rats (SHRSPs), a model of severe hypertension, endothelial dysfunction, vascular inflammation, and cerebrovascular diseases. Male SHRSPs were allocated to three groups receiving a standard diet (n = 5) or a high-sodium permissive diet plus vehicle (n = 6) or plus terutroban (30 mg · kg(-1) · day(-1); n = 6). After 6 wk of dietary treatment, all of the animals were injected with bromodeoxyuridine and simultaneously euthanized for aorta collection. The aortic media thickness-to-lumen ratio significantly (P < 0.0001) increased in the salt-loaded rats compared with the rats fed a standard diet, whereas terutroban treatment completely prevented media thickening (P < 0.001). When compared with vehicle, terutroban was also effective in preventing cell proliferation in the media, as indicated by the reduced number of bromodeoxyuridine-positive (P < 0.0001) and proliferating cell nuclear antigen-positive cells (P < 0.0001). Severe fibrosis characterized by a significant accumulation of collagen and fibronectin in the vascular wall was observed in the vehicle-treated rats (P < 0.01) but was completely prevented by terutroban (P < 0.001). The latter also inhibited heat shock protein-47 (P < 0.01) and TGF-1β expression (P < 0.001), which were significantly increased by the high-salt diet. In conclusion, terutroban prevents the development of aorta hyperplasia and has beneficial effects on fibrotic processes by affecting TGF-β and heat shock protein-47 expression in SHRSPs. These findings provide mechanistic data supporting the beneficial effects of terutroban in preventing or retarding atherogenesis.

  10. Inflammatory prostaglandin E2 signaling in a mouse model of Alzheimer’s disease

    PubMed Central

    Shi, Ju; Wang, Qian; Johansson, Jenny U.; Liang, Xibin; Woodling, Nathaniel S.; Priyam, Prachi; Loui, Taylor M.; Merchant, Milton; Breyer, Richard M.; Montine, Thomas J.; Andreasson, Katrin

    2012-01-01

    Objective There is significant evidence for a central role of inflammation in the development of Alzheimer’s disease (AD). Epidemiological studies indicate that chronic use of non-steroidal anti-inflammatory drugs (NSAIDs) reduces the risk of developing AD in healthy aging populations. As NSAIDs inhibit the enzymatic activity of the inflammatory cyclooxygenases COX-1 and COX-2, these findings suggest that downstream prostaglandin signaling pathways function in the pre-clinical development of AD. Here, we investigate the function of prostaglandin E2 (PGE2) signaling through its EP3 receptor in the neuroinflammatory response to Aβ peptide. Methods The function of PGE2 signaling through its EP3 receptor was examined in vivo a model of subacute neuroinflammation induced by administration of Aβ42 peptides. Our findings were then confirmed in young adult APPSwe-PS1 ΔE9 transgenic mice. Results Deletion of the PGE2 EP3 receptor in a model of Aβ42 peptide-induced neuroinflammation reduced pro-inflammatory gene expression, cytokine production, and oxidative stress. In the APPSwe-PS1 ΔE9 model of Familial AD, deletion of the EP3 receptor blocked induction of pro-inflammatory gene and protein expression and lipid peroxidation. In addition, levels of Aβ peptides were significantly decreased, as were BACE-1 and β-CTF levels, suggesting that generation of Aβ peptides may be increased as a result of pro-inflammatory EP3 signaling. Finally, deletion of EP3 receptor significantly reversed the decline in pre-synaptic proteins seen in APPSwe-PS1 ΔE9 mice. Interpretation Our findings identify the PGE2 EP3 receptor as a novel pro-inflammatory, pro-amyloidogenic, and synaptotoxic signaling pathway, and suggest a role for COX-PGE2-EP3 signaling in the development of AD. PMID:22915243

  11. Serotonin modulates the cytokine network in the lung: involvement of prostaglandin E2

    PubMed Central

    Ménard, G; Turmel, V; Bissonnette, E Y

    2007-01-01

    Serotonin, well known for its role in depression, has been shown to modulate immune responses. Interestingly, the plasma level of serotonin is increased in symptomatic asthmatic patients and the use of anti-depressants, known to reduce serotonin levels, provokes a decrease in asthma symptoms and an increase in pulmonary function. Thus, we tested the hypothesis that serotonin affects alveolar macrophage (AM) cytokine production, altering the cytokine network in the lung and contributing to asthma pathogenesis. AMs were treated with different concentrations of serotonin (10-11−10-9 M) or 5-HT1 and 5-HT2 receptor agonists for 2 h prior stimulation. T helper 1 (Th1) and Th2 cytokines, prostaglandin-E2 (PGE2) and nitric oxide (NO) were measured in cell-free supernatants. Serotonin significantly inhibited the production of tumour necrosis factor (TNF) and interleukin (IL)-12, whereas IL-10, NO and PGE2 production were increased. These immunomodulatory effects of serotonin were mimicked by 5-HT2 receptor agonist but were not abrogated by 5-HT2 receptor antagonist, suggesting the implication of other 5-HT receptors. Inhibitors of cyclooxygenase and antibody to PGE2 abrogated the inhibitory and stimulatory effect of serotonin on TNF and IL-10 production, respectively, whereas NO synthase inhibitor eliminated serotonin-stimulated IL-10 increase. Furthermore, PGE2 significantly increased AM IL-10 and NO production. These results suggest that serotonin alters the cytokine network in the lung through the production of PGE2. The reduction of Th1-type cytokine by serotonin may contribute to asthma pathogenesis. PMID:17822443

  12. The complex pattern of cytokines in sepsis. Association between prostaglandins, cachectin, and interleukins.

    PubMed Central

    Ertel, W; Morrison, M H; Wang, P; Ba, Z F; Ayala, A; Chaudry, I H

    1991-01-01

    Although the cytokines tumor necrosis factor (TNF), interleukin-1 (IL-1), and interleukin-6 (IL-6) are important mediators of hemodynamic, metabolic, and immunologic alterations in the host during sepsis, it is not known whether there is any association between the release of these cytokines and prostanoids during sepsis. Sepsis induced by cecal ligation and puncture in rats led to a persistent elevation (p less than 0.05) of plasma TNF until 10 hours, steadily increasing (p less than 0.05) IL-1 plasma levels, and enhanced (p less than 0.05) IL-6 plasma levels at all time points compared to the sham group. Prostaglandin E2 plasma levels were elevated (p less than 0.05) at 5 hours (153 +/- 29 pg/mL; control: 47 +/- 11 pg/mL) and 10 hours (96 +/- 16 pg/mL; control: 21 +/- 5 pg/mL). Prostaglandin E2 production by splenic macrophages (sM phi) from septic animals was increased (p less than 0.05) at 5 hours (9.1 +/- 2.2 ng/mL) and 10 hours (5.6 +/- 1.5 ng/mL) compared to controls (3.3 +/- 0.3 ng/mL at 5 hours; 1.3 +/- 1.3 ng/mL at 10 hours). Incubation of sM phi from septic animals with ibuprofen enhanced (p less than 0.05) IL-1 and TNF synthesis, while IL-6 production was reduced (p less than 0.05). These results indicate that the alterations in prostanoid release and elevated plasma prostanoids may regulate the release and consequently the circulating levels of cytokines during sepsis. PMID:1867521

  13. Effects of dimethyl prostaglandin A1 on herpes simplex virus and human immunodeficiency virus replication

    NASA Technical Reports Server (NTRS)

    Hughes-Fulford, M.; McGrath, M. S.; Hanks, D.; Erickson, S.; Pulliam, L.

    1992-01-01

    We have investigated the direct effect of dimethyl prostaglandin A1 (dmPGA1) on the replication of herpes simplex virus (HSV) and human immunodeficiency virus type 1 (HIV-1). dmPGA1 significantly inhibited viral replication in both HSV and HIV infection systems at concentrations of dmPGA1 that did not adversely alter cellular DNA synthesis. The 50% inhibitory concentration (ID50) for several HSV type 1 (HSV-1) strains ranged from 3.8 to 5.6 micrograms/ml for Vero cells and from 4.6 to 7.3 micrograms/ml for human foreskin fibroblasts. The ID50s for two HSV-2 strains varied from 3.8 to 4.5 micrograms/ml for Vero cells; the ID50 was 5.7 micrograms/ml for human foreskin fibroblasts. We found that closely related prostaglandins did not have the same effect on the replication of HSV; dmPGE2 and dmPGA2 caused up to a 60% increase in HSV replication compared with that in untreated virus-infected cells. HIV-1 replication in acutely infected T cells (VB line) and chronically infected macrophages was assessed by quantitative decreases in p24 concentration. The effective ID50s were 2.5 micrograms/ml for VB cells acutely infected with HIV-1 and 5.2 micrograms/m for chronically infected macrophages. dmPGA1 has an unusual broad-spectrum antiviral activity against both HSV and HIV-1 in vitro and offers a new class of potential therapeutic agents for in vivo use.

  14. The 5-lipoxygenase inhibitor, zileuton, suppresses prostaglandin biosynthesis by inhibition of arachidonic acid release in macrophages

    PubMed Central

    Rossi, A; Pergola, C; Koeberle, A; Hoffmann, M; Dehm, F; Bramanti, P; Cuzzocrea, S; Werz, O; Sautebin, L

    2010-01-01

    BACKGROUND AND PURPOSE Zileuton is the only 5-lipoxygenase (5-LOX) inhibitor marketed as a treatment for asthma, and is often utilized as a selective tool to evaluate the role of 5-LOX and leukotrienes. The aim of this study was to investigate the effect of zileuton on prostaglandin (PG) production in vitro and in vivo. EXPERIMENTAL APPROACH Peritoneal macrophages activated with lipopolysaccharide (LPS)/interferon γ (LPS/IFNγ), J774 macrophages and human whole blood stimulated with LPS were used as in vitro models and rat carrageenan-induced pleurisy as an in vivo model. KEY RESULTS Zileuton suppressed PG biosynthesis by interference with arachidonic acid (AA) release in macrophages. We found that zileuton significantly reduced PGE2 and 6-keto prostaglandin F1α (PGF1α) levels in activated mouse peritoneal macrophages and in J774 macrophages. This effect was not related to 5-LOX inhibition, because it was also observed in macrophages from 5-LOX knockout mice. Notably, zileuton inhibited PGE2 production in LPS-stimulated human whole blood and suppressed PGE2 and 6-keto PGF1α pleural levels in rat carrageenan-induced pleurisy. Interestingly, zileuton failed to inhibit the activity of microsomal PGE2 synthase1 and of cyclooxygenase (COX)-2 and did not affect COX-2 expression. However, zileuton significantly decreased AA release in macrophages accompanied by inhibition of phospholipase A2 translocation to cellular membranes. CONCLUSIONS AND IMPLICATION Zileuton inhibited PG production by interfering at the level of AA release. Its mechanism of action, as well as its use as a pharmacological tool, in experimental models of inflammation should be reassessed. PMID:20880396

  15. Estrogen Promotes Luteolysis by Redistributing Prostaglandin F2α Receptors Within Primate Luteal Cells*

    PubMed Central

    Kim, Soon Ok; Markosyan, Nune; Pepe, Gerald J.; Duffy, Diane M.

    2015-01-01

    Prostaglandin F2α (PGF2α) has been proposed as a functional luteolysin in primates. However, administration of PGF2α or prostaglandin synthesis inhibitors in vivo both initiate luteolysis. These contradictory findings may reflect changes in PGF2α receptors (PTGFR) or responsiveness to PGF2α at a critical point during the life span of the corpus luteum. The current study addressed this question using ovarian cells and tissues from female cynomolgus monkeys and luteinizing granulosa cells from healthy women undergoing follicle aspiration. PTGFRs were present in the cytoplasm of monkey granulosa cells, while PTGFRs were localized to the perinuclear region of large, granulosa-derived monkey luteal cells by mid-late luteal phase. A PTGFR agonist decreased progesterone production by luteal cells obtained at mid-late and late luteal phases but did not decrease progesterone production by granulosa or luteal cells from younger corpora lutea. These findings are consistent with a role for perinuclear PTGFRs in functional luteolysis. This concept was explored using human luteinizing granulosa cells maintained in vitro as a model for luteal cell differentiation. In these cells, PTGFRs relocated from the cytoplasm to the perinuclear area in an estrogen- and estrogen receptor-dependent manner. Similar to our findings with monkey luteal cells, human luteinizing granulosa cells with perinuclear PTGFRs responded to a PTGFR agonist with decreased progesterone production. These data support the concept that PTGFR stimulation promotes functional luteolysis only when PTGFRs are located in the perinuclear region. Estrogen receptor-mediated relocation of PTGFRs within luteal cells may be a necessary step in the initiation of luteolysis in primates. PMID:25687410

  16. [Hematopoietic prostaglandin D synthase inhibitors for the treatment of duchenne muscular dystrophy].

    PubMed

    Kamauchi, Shinya; Urade, Yoshihiro

    2011-11-01

    Duchenne muscular dystrophy (DMD) is a severe X-linked muscle disease, characterized by progressive skeletal muscle atrophy and weakness. DMD is caused by mutations in the dystrophin gene, which encodes for the cytoskeletal protein dystrophin. DMD is one of the most common types of muscular dystrophies, affecting approximately 1 in 3,500 boys. There is no complete cure for this disease. Clinical trials for gene transfer therapy as a treatment for DMD have been performed but mainly in animal models. Hematopoietic prostaglandin (PG) D synthase (H-PGDS) was found to be induced in grouped necrotic muscle fibers of DMD patients and animal models, mdx mice, and DMD dogs. We found an orally active H-PGDS inhibitor (HQL-79) and determined the 3D structure of the inhibitor-human H-PGDS complex by X-ray crystallography. Oral administration of HQL-79 markedly suppressed prostaglandin D2 (PGD2) production, reduced necrotic muscle volume, and improved muscle strength in mdx dystrophic mice. Based on the high-resolution 3D structures of the inhibitor-H-PGDS complex, we designed alternative H-PGDS inhibitors, which were 100- to 3000-times more potent than HQL-79, as assessed by in vitro and in vivo analyses. We used these novel inhibitors for the treatment of DMD dogs and confirmed that oral administration of these inhibitors prevented skeletal muscle atrophy and weakness by decreasing PGD2 production. These results indicate that PGD2, synthesized by H-PGDS, is involved in the expansion of muscle necrosis in DMD. Thus, inhibition of H-PGDS by using inhibitors is a novel therapy for DMD.

  17. Phenytoin potentiates interleukin-1-induced prostaglandin biosynthesis in human gingival fibroblasts.

    PubMed Central

    Modéer, T.; Brunius, G.; Iinuma, M.; Lerner, U. H.

    1992-01-01

    1. The effect of phenytoin (PHT) on prostaglandin E2 (PGE2) biosynthesis in human gingival fibroblasts stimulated by interleukin-1 (IL-1 alpha, IL-1 beta) or by tumour necrosis factor alpha (TNF alpha) was studied. 2. IL-1 alpha (1.5-6.0 ng ml-1) and IL-1 beta (30-300 pg ml-1), dose-dependently, stimulated PGE2 formation, in 24 h cultures, with IL-beta being the most potent agonist. 3. PHT (2.5-20 micrograms ml-1) did not induce PGE2 formation itself but potentiated IL-1 alpha- and IL-1 beta-induced PGE2 formation in the gingival fibroblasts in a manner dependent on the concentrations of both IL-1 and PHT. 4. IL-1 beta (0.1-1.0 ng ml-1) induced release of [3H]-arachidonic acid ([3H]-AA) from prelabelled fibroblasts that was potentiated by PHT (20 micrograms ml-1). 5. TNF-alpha (greater than or equal to 0.01 micrograms ml-1) significantly stimulated the biosynthesis of PGE2 by a process that was potentiated by PHT. 6. Addition of exogenous arachidonic acid (AA) (greater than or equal to 1 microM) caused an increase of PGE2 formation in the fibroblasts that was not potentiated by PHT (20 micrograms ml-1). 7. The results indicate that treatment with PHT results in upregulation of prostaglandin biosynthesis in gingival fibroblasts challenged with IL-1 or TNF alpha, at least partly due to enhanced level of phospholipase A2 activity. PMID:1504741

  18. Protection against ethanol injury by prostaglandin in a human intestinal cell line: role of microtubules.

    PubMed

    Banan, A; Smith, G S; Rieckenberg, C L; Kokoska, E R; Miller, T A

    1998-01-01

    Prostaglandins have been shown to protect the gastrointestinal (GI) epithelium from injury induced by various luminal insults independent of their known acid-inhibitory effects, a process termed "cytoprotection." The mechanism of this protective action remains unknown. The present investigation determined the role of microtubules (a major cytoskeletal component) in GI injury induced by ethanol (EtOH) and its prevention by 16,16-dimethylprostaglandin E2 (dmPGE2) using cells from a human colonic cell line known as Caco-2 cells. These cells were preincubated in Eagle's minimum essential medium with and without dmPGE2 (2.6 microM) for 15 min and subsequently incubated in media containing 1, 2.5, 5, 7.5, and 10% EtOH. The effects on cell viability and tubulin (the major protein backbone of microtubules) were then determined. EtOH concentrations > or = 2.5% extensively disrupted the microtubules as demonstrated by fragmentation, kinking, and perturbation of the microtubule organizer center. EtOH treatment also led to a significant decrease in the S2 (polymerized) fraction and an increase in the S1 (monomeric) pool of tubulin. Concomitant with these effects were marked decreases in cellular viability. DmPGE2 pretreatment abolished the disruption of microtubules, significantly increased the S2 fraction of tubulin, and increased cellular viability in cultures exposed to EtOH. Furthermore, pretreatment with colchicine, an inhibitor of microtubule assembly, prevented the cytoprotective action of dmPGE2. Taxol, a microtubule stabilizing agent, mimicked the effects of dmPGE2 by also enhancing microtubule integrity and increasing cellular viability in cells exposed to EtOH. Our data indicate that organization and stabilization of microtubules may play an essential role in the mechanism of prostaglandin-induced protection.

  19. Prostaglandins and radical oxygen species are involved in microvascular effects of hyperoxia.

    PubMed

    Rousseau, A; Tesselaar, E; Henricson, J; Sjöberg, F

    2010-01-01

    Hyperoxia causes vasoconstriction in most tissues, by mechanisms that are not fully understood. We investigated microvascular effects of breathing 100% oxygen in healthy volunteers, using iontophoresis to deliver acetylcholine (ACh) and sodium nitroprusside (SNP). Aspirin and vitamin C were used to test for involvement of prostaglandins and radical oxygen species. Forearm skin perfusion was measured using laser Doppler perfusion imaging. Results were analysed using dose-response modelling. The response to ACh was reduced by 30% during oxygen breathing compared to air breathing [0.98 (0.81-1.15) PU vs. 1.45 (1.30-1.60) PU, p < 0.001]. ED(50) values were unchanged [2.25 (1.84-2.75) vs. 2.21 (1.79-2.74), not significant]. Aspirin pre-treatment abolished the difference in response between oxygen breathing and air breathing [maximum: 1.03 (0.90-1.16) vs. 0.89 (0.77-1.01), not significant; ED(50): 1.83 (1.46-2.30) vs. 1.95 (1.65-2.30), not significant]. ACh-mediated vasodilatation during 100% oxygen breathing was partially restored after pre-treatment with vitamin C. Breathing 100% oxygen did not change the microvascular response to SNP [1.45 (1.28-1.62) vs. 1.40 (1.26-1.53), not significant]. These results favour the hypothesis that hyperoxic vasoconstriction is mediated by inhibition of prostaglandin synthesis. Radical oxygen species may be involved as vitamin C, independently of aspirin, partially restored ACh-mediated vasodilatation during hyperoxia.

  20. 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.

  1. Possible involvement of brain prostaglandin E2 and prostanoid EP3 receptors in prostaglandin E2 glycerol ester-induced activation of central sympathetic outflow in the rat.

    PubMed

    Shimizu, Takahiro; Tanaka, Kenjiro; Nakamura, Kumiko; Taniuchi, Keisuke; Yawata, Toshio; Higashi, Youichirou; Ueba, Tetsuya; Dimitriadis, Fotios; Shimizu, Shogo; Yokotani, Kunihiko; Saito, Motoaki

    2014-07-01

    We recently reported that intracerebroventricularly administered 2-arachidonoylglycerol elevated plasma noradrenaline and adrenaline by brain monoacylglycerol lipase- (MGL) and cyclooxygenase-mediated mechanisms in the rat. These results suggest that 2-arachidonoylglycerol is hydrolyzed by MGL to free arachidonic acid, which is further metabolized to prostaglandins (PGs) by cyclooxygenase in the brain, thereby elevating plasma noradrenaline and adrenaline. On the other hand, 2-arachidonoylglycerol can be also metabolized by cyclooxygenase to PG glycerol esters (PG-Gs), which seems to be hydrolyzed by MGL to free PGs. Here, we examined the involvement of brain PG-Gs in the elevation of plasma noradrenaline and adrenaline regarding PGE2-G and prostanoid EP receptors using anesthetized male Wistar rats. Intracerebroventricularly administered PGE2-G (1.5 and 3 nmol/animal) dose-dependently elevated plasma noradrenaline but not adrenaline. PGE2-G also elevated systolic, mean and diastolic blood pressure and heart rate. The PGE2-G-induced elevation of plasma noradrenaline was attenuated by JZL184 (MGL inhibitor). Intracerebroventricularly administered PGE2 (0.3 and 1.5 nmol/animal) and sulprostone (0.1 and 0.3 nmol/animal) (EP1/EP3 agonist) also elevated plasma noradrenaline but not adrenaline in a dose-dependent manner. The sulprostone-induced elevation was attenuated by L-798,106 (EP3 antagonist), but not by SC-51322 (EP1 antagonist). L-798,106 also attenuated the PGE2-G- and PGE2-induced elevation of plasma noradrenaline, while PF-04418948 (EP2 antagonist) and L-161,982 (EP4 antagonist) had no effect on the PGE2-G-induced response. These results suggest a possibility that brain PGE2-G produced from 2-arachidonoylglycerol can be hydrolyzed to free PGE2, thereby activating central sympathetic outflow by brain prostanoid EP3 receptor-mediated mechanisms in the rat.

  2. 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.

  3. Autocrine and paracrine mechanisms of prostaglandin E₂ action on trophoblast/conceptus cells through the prostaglandin E₂ receptor (PTGER2) during implantation.

    PubMed

    Waclawik, Agnieszka; Kaczynski, Piotr; Jabbour, Henry N

    2013-10-01

    The conceptus and endometrium secrete large amounts of prostaglandin E₂ (PGE₂) into the porcine uterine lumen during the periimplantation period. We hypothesized that PGE₂ acts on conceptus/trophoblast cells through auto- and paracrine mechanisms. Real-time RT-PCR analysis revealed that PGE₂ receptor (PTGER)2 mRNA was 14-fold greater in conceptuses/trophoblasts on days 14-25 (implantation and early placentation period) vs preimplantation day 10-13 conceptuses (P < .05). Similarly, expression of PTGER2 protein increased during implantation. Conceptus expression of PTGER4 mRNA and protein did not differ on days 10-19. PGE₂ stimulated PTGER2 mRNA expression in day 15 trophoblast cells through PTGER2 receptor signaling. PGE₂ elevated aromatase expression and estradiol-17β secretion by trophoblast cells. Moreover, PGE₂ and the PTGER2 agonist, butaprost, increased the adhesive capacity of both human HTR-8/SVneo trophoblast and primary porcine trophoblast cells to extracellular matrix. This PGE₂-induced alteration in trophoblast cell adhesion to extracellular matrix was abolished by incubation of these cells with AH6809 (PTGER2 antagonist), ITGAVB3-directed tetrapeptide arg-gly-asp-ser or integrin ITGAVB3 antibody. PGE₂ stimulated adhesion of porcine trophoblast cells via the estrogen receptor and MEK/MAPK signaling pathway. PGE₂ induced phosphorylation of MAPK1/MAPK3 through PTGER2 and up-regulated expression of cell adhesion proteins such as focal adhesion kinase and intercellular adhesion molecule-1. Our study indicates that elevated PGE₂ in the periimplantation uterine lumen stimulates conceptus PTGER2 expression, which in turn promotes trophoblast adhesion via integrins, and synthesis and secretion of the porcine embryonic signal estradiol-17β. Moreover, the mechanism through which PGE₂ increases trophoblast adhesion is not species specific because it is PTGER2- and integrin-dependent in both porcine and human trophoblast cells.

  4. Hyperforin, an Anti-Inflammatory Constituent from St. John's Wort, Inhibits Microsomal Prostaglandin E(2) Synthase-1 and Suppresses Prostaglandin E(2) Formation in vivo.

    PubMed

    Koeberle, Andreas; Rossi, Antonietta; Bauer, Julia; Dehm, Friederike; Verotta, Luisella; Northoff, Hinnak; Sautebin, Lidia; Werz, Oliver

    2011-01-01

    The acylphloroglucinol hyperforin (Hyp) from St. John's wort possesses anti-inflammatory and anti-carcinogenic properties which were ascribed among others to the inhibition of 5-lipoxygenase. Here, we investigated whether Hyp also interferes with prostanoid generation in biological systems, particularly with key enzymes participating in prostaglandin (PG)E(2) biosynthesis, i.e., cyclooxygenases (COX)-1/2 and microsomal PGE(2) synthase (mPGES)-1 which play key roles in inflammation and tumorigenesis. Similar to the mPGES-1 inhibitors MK-886 and MD-52, Hyp significantly suppressed PGE(2) formation in whole blood assays starting at 0.03-1 μM, whereas the concomitant generation of COX-derived 12(S)-hydroxy-5-cis-8,10-trans-heptadecatrienoic acid, thromboxane B(2), and 6-keto PGF(1α) was not significantly suppressed up to 30 μM. In cell-free assays, Hyp efficiently blocked the conversion of PGH(2) to PGE(2) mediated by mPGES-1 (IC(50) = 1 μM), and isolated COX enzymes were not (COX-2) or hardly (COX-1) suppressed. Intraperitoneal (i.p.) administration of Hyp (4 mg kg(-1)) to rats impaired exudate volume and leukocyte numbers in carrageenan-induced pleurisy associated with reduced PGE(2) levels, and Hyp (given i.p.) inhibited carrageenan-induced mouse paw edema formation (ED(50) = 1 mg kg(-1)) being superior over indomethacin (ED(50) = 5 mg kg(-1)). We conclude that the suppression of PGE(2) biosynthesis in vitro and in vivo by acting on mPGES-1 critically contributes to the anti-inflammatory efficiency of Hyp.

  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. 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

  7. 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).

  8. DDE-induced eggshell thinning in birds: effects of p,p'-DDE on the calcium and prostaglandin metabolism of the eggshell gland.

    PubMed

    Lundholm, C D

    1997-10-01

    1. The focus of this review is the effects and mechanism of action of p,p'-DDE on eggshell formation in birds. Inhibition of prostaglandin synthesis in the eggshell gland mucosa is a probable mechanism for p,p'-DDE-induced eggshell thinning. 2. The duck is sensitive to p,p'-DDE-induced eggshell thinning but the domestic fowl is not, and studies comparing the two species in regard to the calcium and prostaglandin metabolism of the eggshell gland have shown that eggshell thinning induced by p,p'-DDE in ducks is accompanied by reduced activity of prostaglandin synthetase, reduced levels of prostaglandin E2, and reduced uptake of 45Ca by the eggshell gland mucosa. The content of calcium, bicarbonate, chloride, sodium, and potassium are also reduced in the eggshell gland lumen in ducks exhibiting eggshell thinning. None of these effects are seen in the domestic fowl. 3. Inhibition of prostaglandin synthesis is a specific effect of p,p'-DDE. The detrimental effects of p,p'-DDE on the eggshell gland seem to be unique when comparing the compound with structurally related substances, i.e., similar treatment regimens with o,p'-DDE, p,p'-DDT, o,p'-DDT, and p,p'-DDD do not cause eggshell thinning in ducks. Neither do they inhibit prostaglandin synthesis in the eggshell gland mucosa. 4. Administration of other compounds that do inhibit prostaglandin synthesis, e.g., indomethacin, does cause the same effects as those seen with p,p'-DDE, i.e., eggshell thinning and the described effects on the calcium and prostaglandin metabolism of the eggshell gland.

  9. 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

  10. Synthesis and in vitro cytotoxicity of cross-conjugated prostaglandin A and J series and their hydroxy derivatives.

    PubMed

    Żurawiński, Remigiusz; Mikołajczyk, Marian; Cieślak, Marcin; Królewska, Karolina; Kaźmierczak-Barańska, Julia

    2015-07-07

    The synthesis of two cross-conjugated prostaglandin analogues of known neurotrophic activity and their new hydroxy derivatives was accomplished starting from the diastereoisomeric (+)-camphor protected 3-[(dimethoxyphosphoryl)methyl]-4,5-dihydroxycyclopent-2-enones. The cytotoxicity of these compounds was determined against HeLa, K562, HL-60 human cancer cell lines and normal human cells (HUVEC). We found that NEPP11 and its C7-hydroxy derivative demonstrated high anticancer activity against the HeLa and HL-60 human cancer cell lines at concentrations ranging from 1 to 2 μM. Moreover, the C7-hydroxy derivative of NEPP11 displayed high cytotoxic selectivity between cancer cell lines and normal human cells. On the other hand, the J-type prostaglandin analogue of NEPP11 and its C13-hydroxy derivatives were much less toxic or nontoxic against the cancer and normal cells at concentrations up to 1 mM.

  11. The role of dietary polyunsaturated fatty acids and prostaglandins in reducing blood pressure and improving thrombogenic indices.

    PubMed

    Iacono, J M; Dougherty, R M

    1983-01-01

    Evidence linking dietary fats to blood pressure and thrombogenic indices is reviewed. Results of dietary studies performed at Beltsville, Maryland, have demonstrated that under controlled dietary conditions, i.e., when total fat intake is maintained at 25% fat calories with a P/S ratio of 1, at either a fixed or free-choice salt intake and where the body weight is maintained relatively constant, blood pressure can be lowered and platelet aggregation indices can be improved in men and women in the 40-60 age group. Results of a pilot epidemiologic study of farmers aged 40-45 in Finland and Italy generally confirm the experimental nutrition studies reported above. A possible explanation of these results based on the conversion of linoleic acid to prostaglandins as well as the physiological actions of prostaglandins is discussed.

  12. 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

  13. Flavan-3-ols isolated from some medicinal plants inhibiting COX-1 and COX-2 catalysed prostaglandin biosynthesis.

    PubMed

    Noreen, Y; Serrano, G; Perera, P; Bohlin, L

    1998-08-01

    Extracts from the four plant species Atuna racemosa Raf. ssp. racemosa, Syzygium corynocarpum (A. Gray) C. Muell., Syzygium malaccense (L.) Merr. & Perry and Vantanea peruviana Macbr., traditionally used for inflammatory conditions, were fractionated using a cyclooxygenase-1 catalysed prostaglandin biosynthesis in vitro assay. The flavan-3-ol derivatives (+)-catechin, (+)-gallocatechin, 4'-O-Me-ent-gallocatechin, ouratea-catechin and ouratea-proanthocynidin A were isolated as active principles. The IC50 values ranged from 3.3 microM to 138 microM whilst indomethacin under the same test conditions had an IC50 value of 1.1 microM. The flavonol rhamnosides mearnsitrin, myricitrin and quercitrin were also isolated. When further tested for inhibitory effect on cyclooxygenase-2 catalysed prostaglandin biosynthesis, the five flavan-3-ol derivatives exhibited from equal to weaker inhibitory potencies, as compared to their cyclooxygenase-1 inhibitory effects. The flavonol rhamnosides were inactive towards both enzymes.

  14. The cyclopentenone 15-deoxy-Δ12,14-prostaglandin J2 binds to and activates H-Ras

    PubMed Central

    Oliva, José Luis; Pérez-Sala, Dolores; Castrillo, Antonio; Martínez, Natalia; Cañada, F. Javier; Boscá, Lisardo; Rojas, José M.

    2003-01-01

    The cyclopentenone 15-deoxy-Δ12,14-prostaglandin J2 (15d-PGJ2) induces cell proliferation and mitogen-activated protein kinase activation. Here, we describe that these effects are mediated by 15d-PGJ2-elicited H-Ras activation. We demonstrate that this pathway is specific for H-Ras through the formation of a covalent adduct of 15d-PGJ2 with Cys-184 of H-Ras, but not with N-Ras or K-Ras. Mutation of C184 inhibited H-Ras modification and activation by 15d-PGJ2, whereas serum-elicited stimulation was not affected. These results describe a mechanism for the activation of the Ras signaling pathway, which results from the chemical modification of H-Ras by formation of a covalent adduct with cyclopentenone prostaglandins. PMID:12684535

  15. [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.

  16. Antioxidant and gastric cytoprotective prostaglandins properties of Cassia sieberiana roots bark extract as an anti-ulcerogenic agent

    PubMed Central

    2012-01-01

    Background Cassia sieberiana is a savannah tree with a wide phytotherapeutic application including the use of its roots in the management of various stomach disorders including gastric ulcer, stomach pains and indigestion. The aim of the study is to evaluate the antioxidant, gastric cytoprotective prostaglandins, secretory phospholipase A2, phytochemical and acute toxicity properties of Cassia sieberiana roots bark extract in a bid to justify its phytotherapeutic applications in gastric ulcer. Methods Antioxidant and radical scavenging activities of the roots bark extract of Cassia sieberiana were assayed. Serum secretory phospholipase A2 (sPLA2) concentration and activity and the formation of gastric mucosal prostaglandins E2 (PGE2) and I2 (PGI2) were also assessed. Comparisons between means were performed using analysis of variance (ANOVA) followed by Students Standard Newman-Keuls post hoc analysis to determine statistical significance. P < 0.05 was considered significant. Results The extract was found to possess significant ferric reducing antioxidant power and can scavenge hydroxyl radicals. The extract also possesses DPPH scavenging activity, can chelate ferrous ion and a dose-dependent protective effect against lipid peroxidation and free radical generation. Prostaglandin studies showed that the roots bark extract dose dependently increased gastric mucosal PGE2 and PGI2 levels and also decreased serum sPLA2 activity. Phytochemical analyses suggest that the roots extract contains polyhydroxyl/phenolic substances. Acute toxicity test showed no sign of toxicity up to a dose level of 2000 mg/kg body weight p.o. Conclusions C. sieberiana roots extract possesses significant antioxidant and gastric cytoprotective prostaglandin properties as well as serum secretory phospholipase A2 inhibitory activity which could be due to its content of polyhydroxy and/or phenolic substances. This may justify its use as an anti-ulcerogenic agent in traditional medicine in

  17. Secretion of prostaglandins and leukotrienes by endometrial cells in cows with subclinical and clinical endometritis.

    PubMed

    Barański, Wojciech; Łukasik, Karolina; Skarżyński, Dariusz; Sztachańska, Marta; Zduńczyk, Sławomir; Janowski, Tomasz

    2013-10-15

    The aims of this study were (1) to measure the secretion of prostaglandin F2α (PGF2α), prostaglandin E2 (PGE2), leukotriene B4 (LTB4), and leukotriene C4 (LTC4) by endometrial cells collected by a cytobrush from healthy cows and cows with subclinical and clinical endometritis in the fourth week postpartum, and (2) to evaluate the relationship between the mediators' levels of secretion and the number of polymorphonuclear neutrophils (PMNs) in the uterine smears of cows with subclinical endometritis. The study included cows without any signs of clinical endometritis (n = 63) and cows with clinical endometritis as a positive control (ENDOM, n = 12). Two different threshold ratios (>5% and >18% of PMNs) were used to categorize the cows without clinical signs as with or without cytologic endometritis (CE). Considering the first or second threshold, the animals with CE were included in group CE POS I or CE POS II, whereas the healthy cows were assigned to group CE NEG I or CE NEG II, respectively. The prevalence of CE was 68.25% (42/63) and 57.14% (36/63) according to the first and second thresholds, respectively. The highest level of secretion of all of the measured mediators occurred in the ENDOM group and differed significantly (P < 0.05) from the CE POS and CE NEG groups, regardless of the threshold. PGF2α secretion in the CE POS II group (1629 pg/mL) was significantly lower (P < 0.05) when compared with the CE NEG II group (2797 pg/mL), whereas there was no significant difference between the CE POS I and CE NEG I groups. PGE2 secretion differed between both groups with CE; higher concentrations were measured in the CE POS II group (6.68 ng/mL) when compared with the CE POS I (2.4 ng/mL) and CE NEG II (2.37 ng/mL) groups (P < 0.05). No significant differences were observed in the LTB4 and LTC4 secretion between the CE POS and CE NEG groups, considering both thresholds. It seems that CE does not fully mimic the inflammatory cascade associated with clinical signs

  18. Prostaglandins inhibit secretion of histamine and pancreastatin from isolated rat stomach ECL cells

    PubMed Central

    Lindström, Erik; Håkanson, Rolf

    1998-01-01

    The present study examines the effect of naturally occurring prostanoids and prostaglandin (PG) congeners on gastrin- and pituitary adenylate cyclase-activating peptide (PACAP)-evoked histamine and pancreastatin secretion from isolated rat stomach ECL cells. ECL cells (75–85% purity) were isolated from rat stomach using pronase digestion followed by repeated counter-flow elutriation and cultured for 48 h before secretion experiments. The release of histamine and pancreastatin was determined by radioimmunoassay. None of the PGs tested stimulated the release of either histamine or pancreastatin. PGE1 and PGE2 inhibited both gastrin- and PACAP-evoked histamine and pancreastatin secretion (IC50=1–2×10−10 M). Most other naturally occuring prostanoids and PG congeners had no or little inhibitory effect. The PGE analogues misoprostol and sulprostone were more potent (IC50=0.9×10−11 M and 2×10−11 M respectively) than PGE1 and PGE2. The rank order of potency was misoprostol>sulprostone>PGE1=PGE2, suggesting the involvement of the so-called EP3 receptor. The effects of PGs on the stomach ECL cells may be direct or indirect, for instance through the stimulated release of somatostatin from contaminating D cells (2–3%). However, the amount of somatostatin in the cell culture after 48 h was below the limit of detection, and somatostatin immunoneutralization did not prevent misoprostol from inhibiting secretion from the ECL cells. The misoprostol-induced inhibition was reversed by pertussis toxin suggesting the involvement of G-protein subunits Gα0 and/or Gαi. In view of the potency by which PGE1, PGE2, misoprostol and sulprostone inhibited the stimulated release of histamine and pancreastatin, we suggest that the ECL cells represent a primary target for prostaglandins acting via an EP3 receptor in the oxyntic mucosa. The results suggest that the clinically useful effect of misoprostol as an anti-ulcer drug reflects its ability to inhibit stomach ECL

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

    PubMed

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

    2011-11-01

    Prostaglandin E(2) (PGE(2)) is a lipid mediator that is produced via the metabolism of arachidonic acid by cyclooxygenase enzymes. In the lung, PGE(2) acts as an anti-inflammatory factor and plays an important role in tissue repair processes. Although several studies have examined the role of PGE(2) in the pathogenesis of pulmonary fibrosis in rodents, results have generally been conflicting, and few studies have examined the therapeutic effects of PGE(2) on the accompanying lung dysfunction. In this study, an established model of pulmonary fibrosis was used in which 10-12-wk-old male C57BL/6 mice were administered a single dose (1.0 mg/kg) of bleomycin via oropharyngeal aspiration. To test the role of prostaglandins in this model, mice were dosed, via surgically implanted minipumps, with either vehicle, PGE(2) (1.32 μg/h), or the prostacyclin analog iloprost (0.33 μg/h) beginning 7 days before or 14 days after bleomycin administration. Endpoints assessed at 7 days after bleomycin administration included proinflammatory cytokine levels and measurement of cellular infiltration into the lung. Endpoints assessed at 21 days after bleomycin administration included lung function assessment via invasive (FlexiVent) analysis, cellular infiltration, lung collagen content, and semiquantitative histological analysis of the degree of lung fibrosis (Ashcroft method). Seven days after bleomycin administration, lymphocyte numbers and chemokine C-C motif ligand 2 expression were significantly lower in PGE(2)- and iloprost-treated animals compared with vehicle-treated controls (P < 0.05). When administered 7 days before bleomycin challenge, PGE(2) also protected against the decline in lung static compliance, lung fibrosis, and collagen production that is associated with 3 wk of bleomycin exposure. However, PGE(2) had no therapeutic effect on these parameters when administered 14 days after bleomycin challenge. In summary, PGE(2) prevented the decline in lung static compliance and

  20. 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.

  1. Prostaglandin E Receptor Subtype 4 Signaling in the Heart: Role in Ischemia/Reperfusion Injury and Cardiac Hypertrophy

    PubMed Central

    Cai, Yin; Tang, Eva Hoi Ching; Ma, Haichun

    2016-01-01

    Prostaglandin E2 (PGE2) is an endogenous lipid mediator, produced from the metabolism of arachidonic acids, upon the sequential actions of phospholipase A2, cyclooxygenases, and prostaglandin E synthases. The various biological functions governed by PGE2 are mediated through its four distinct prostaglandin E receptors (EPs), designated as EP1, EP2, EP3, and EP4, among which the EP4 receptor is the one most widely distributed in the heart. The availability of global or cardiac-specific EP4 knockout mice and the development of selective EP4 agonists/antagonists have provided substantial evidence to support the role of EP4 receptor in the heart. However, like any good drama, activation of PGE2-EP4 signaling exerts both protective and detrimental effects in the ischemic heart disease. Thus, the primary object of this review is to provide a comprehensive overview of the current progress of the PGE2-EP4 signaling in ischemic heart diseases, including cardiac hypertrophy and myocardial ischemia/reperfusion injury. A better understanding of PGE2-EP4 signaling should promote the development of more effective therapeutic approaches to treat the ischemic heart diseases without triggering unwanted side effects. PMID:27190998

  2. [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.

  3. 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

  4. Enhanced production of prostaglandins and plasminogen activator during activation of human articular chondrocytes by products of mononuclear cells.

    PubMed

    Meats, J E; McGuire, M K; Ebsworth, N M; Englis, D J; Russell, R G

    1984-01-01

    We have examined the way in which products of cultured human blood mononuclear cells activate human articular chondrocytes. Conditioned medium from mononuclear cells enhanced the production of prostaglandin E by cultured human chondrocytes and also stimulated fibrinolytic activity in these cultures. These two effects may be interrelated, since the increased fibrinolysis in response to products of mononuclear cells was partially inhibited by indomethacin, an inhibitor of prostaglandin biosynthesis. The increased fibrinolysis is probably attributable to plasminogen activator, since it was strongly dependent on the presence of plasminogen. Increased amounts of PGE and chondroitin sulphate were also released from intact fragments of cartilage exposed to medium from cultured mononuclear cells. The time course and dose dependence of these effects were studied. The addition of exogenous arachidonic acid markedly enhanced production of PGE2. Ultrogel AcA54 was used to fractionate medium from cultured mononuclear cells and the chondrocyte-stimulating activity eluted with an apparent molecular weight between 12 000 and 25 000 daltons. Adherent and non-adherent mononuclear blood cells were also partially separated and conditioned medium from each was assayed for chondrocyte-stimulating factors. Both populations released factor(s) which increased the production of prostaglandin E by chondrocytes, but more activity came from the adherent mononuclear cells. The possible interrelationship between the chondrocyte activating factor studied here and others described in the literature is discussed.

  5. Rocuronium Bromide Inhibits Inflammation and Pain by Suppressing Nitric Oxide Production and Enhancing Prostaglandin E2 Synthesis in Endothelial Cells

    PubMed Central

    2016-01-01

    Purpose Rocuronium bromide is a nondepolarizing neuromuscular blocking drug and has been used as an adjunct for relaxation or paralysis of the skeletal muscles, facilitation of endotracheal intubation, and improving surgical conditions during general anesthesia. However, intravenous injection of rocuronium bromide induces injection pain or withdrawal movement. The exact mechanism of rocuronium bromide-induced injection pain or withdrawal movement is not yet understood. We investigated whether rocuronium bromide treatment is involved in the induction of inflammation and pain in vascular endothelial cells. Methods For this study, calf pulmonary artery endothelial (CPAE) cells were used, and 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay, Western blot, nitric oxide detection, and prostaglandin E2 immunoassay were conducted. Results Rocuronium bromide treatment inhibited endothelial nitric oxide synthase and suppressed nitric oxide production in CPAE cells. Rocuronium bromide activated cyclooxygenase-2, inducible nitric oxide synthase and increased prostaglandin E2 synthesis in CPAE cells. Conclusions Rocuronium bromide induced inflammation and pain in CPAE cells. Suppressing nitric oxide production and enhancing prostaglandin E2 synthesis might be associated with rocuronium bromide-induced injection pain or withdrawal movement. PMID:28043117

  6. Targeted prostaglandin E2 inhibition enhances antiviral immunity through induction of type I interferon and apoptosis in macrophages.

    PubMed

    Coulombe, François; Jaworska, Joanna; Verway, Mark; Tzelepis, Fanny; Massoud, Amir; Gillard, Joshua; Wong, Gary; Kobinger, Gary; Xing, Zhou; Couture, Christian; Joubert, Philippe; Fritz, Jörg H; Powell, William S; Divangahi, Maziar

    2014-04-17

    Aspirin gained tremendous popularity during the 1918 Spanish Influenza virus pandemic, 50 years prior to the demonstration of their inhibitory action on prostaglandins. Here, we show that during influenza A virus (IAV) infection, prostaglandin E2 (PGE2) was upregulated, which led to the inhibition of type I interferon (IFN) production and apoptosis in macrophages, thereby causing an increase in virus replication. This inhibitory role of PGE2 was not limited to innate immunity, because both antigen presentation and T cell mediated immunity were also suppressed. Targeted PGE2 suppression via genetic ablation of microsomal prostaglandin E-synthase 1 (mPGES-1) or by the pharmacological inhibition of PGE2 receptors EP2 and EP4 substantially improved survival against lethal IAV infection whereas PGE2 administration reversed this phenotype. These data demonstrate that the mPGES-1-PGE2 pathway is targeted by IAV to evade host type I IFN-dependent antiviral immunity. We propose that specific inhibition of PGE2 signaling might serve as a treatment for IAV.

  7. Transport Experiments

    NASA Technical Reports Server (NTRS)

    Hall, Timothy M.; Wuebbles, Donald J.; Boering, Kristie A.; Eckman, Richard S.; Lerner, Jean; Plumb, R. Alan; Rind, David H.; Rinsland, Curtis P.; Waugh, Darryn W.; Wei, Chu-Feng

    1999-01-01

    MM II defined a series of experiments to better understand and characterize model transport and to assess the realism of this transport by comparison to observations. Measurements from aircraft, balloon, and satellite, not yet available at the time of MM I [Prather and Remsberg, 1993], provide new and stringent constraints on model transport, and address the limits of our transport modeling abilities. Simulations of the idealized tracers the age spectrum, and propagating boundary conditions, and conserved HSCT-like emissions probe the relative roles of different model transport mechanisms, while simulations of SF6 and C02 make the connection to observations. Some of the tracers are related, and transport diagnostics such as the mean age can be derived from more than one of the experiments for comparison to observations. The goals of the transport experiments are: (1) To isolate the effects of transport in models from other processes; (2) To assess model transport for realistic tracers (such as SF6 and C02) for comparison to observations; (3) To use certain idealized tracers to isolate model mechanisms and relationships to atmospheric chemical perturbations; (4) To identify strengths and weaknesses of the treatment of transport processes in the models; (5) To relate evaluated shortcomings to aspects of model formulation. The following section are included:Executive Summary, Introduction, Age Spectrum, Observation, Tropical Transport in Models, Global Mean Age in Models, Source-Transport Covariance, HSCT "ANOY" Tracer Distributions, and Summary and Conclusions.

  8. Efficiency of oestrous synchronization by GnRH, prostaglandins and socio-sexual cues in the North African Maure goats.

    PubMed

    Rekik, M; Ben Othmane, H; Lassoued, N; Sakly, C

    2014-06-01

    This study aims to develop at different seasons, for local North African Maure goats, synchronizing protocols simultaneously to the standard 'S' protocol using progestagens in association with prostaglandins and gonadotropin. In late May, 40 goats were assigned to either the 'S' protocol or to a protocol where oestrus and ovulation were induced by the buck effect in single-injection progesterone-treated goats and provoking early luteolysis using prostaglandin 9 days after exposure to bucks 'B'. During the 72 h after the treatments ended, 15 and 5 goats expressed oestrus in the 'S' and 'B' protocols (p < 0.01). Mean time to oestrus was shorter for 'S' than for 'B' goats. Ovulation rate averaged 2.1 ± 0.22 and 1.60 ± 0.35 for, respectively, 'S' and 'B' goats (p > 0.05). During mid-September, 60 goats were assigned to either 'S' treatment, 'PGF' treatment where oestrus and ovulation were synchronized using two injections of prostaglandin 11 days apart or to 'GnRH' treatment where the goats had their oestrus and ovulation synchronized with a GnRH (day 0)-prostaglandin (day 6)-GnRH (day 9) sequence. More 'S' goats were detected in oestrus over the 96-h period after the end of the treatments (88.8, 73.7 and 55% in 'S', 'PGF' and 'GnRH' treatments, respectively; p < 0.05). Mean ovulation rates were 2.3 ± 0.27, 1.33 ± 0.27 and 1.33 ± 0.27 for, respectively, 'S', 'PGF' and 'GnRH' goats (p < 0.001). Despite a similar ovulatory response to 'S' protocol, efficiency of prostaglandin and GnRH-based treatments should be tested in mid-breeding season.

  9. Lipopolysaccharides, cytokines, and nitric oxide affect secretion of prostaglandins and leukotrienes by bovine mammary gland epithelial cells.

    PubMed

    Piotrowska-Tomala, K K; Siemieniuch, M J; Szóstek, A Z; Korzekwa, A J; Woclawek-Potocka, I; Galváo, A M; Okuda, K; Skarzynski, D J

    2012-11-01

    The aims of this study were to determine the effects of lipopolysaccharides (LPS), tumor necrosis factor (TNF), interleukin 1 alpha (IL-1α), nitric oxide donor (NONOate), or the combination of TNF + IL-1α + NONOate on the following: (i) secretion of prostaglandin (PG)-F(2α), PGE(2), leukotriene (LT)-B(4), and LTC(4) by epithelial cells of the teat cavity and lactiferous sinus of bovine mammary gland; (ii) messenger RNA (mRNA) transcription of enzymes responsible for arachidonic acid (AA) metabolism (prostaglandin-endoperoxide synthase 2 [PTGS2], prostaglandin E synthase [PTGES], prostaglandin F synthase [PGFS], and arachidonate 5-lipooxygenase [ALOX5]); and (iii) proliferation of the cells. The cells were stimulated for 24 h. Prostaglandins and LT were measured by enzyme immunoassay, mRNA transcription of enzymes was determined by real-time reverse transcription polymerase chain reaction, and the cell viability was measured by 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide. All factors increased PG secretion, but the highest stimulation was observed after TNF and IL-1α (P < 0.001). Tumor necrosis factor, NONOate, and TNF + IL-1α + NONOate increased LTB(4) production (P < 0.01), whereas LTC(4) was increased by LPS, TNF, and IL-1α (P < 0.01). Lipopolysaccharides, TNF, IL-1α, and the reagents combination increased PTGS2, PTGES, and PGFS mRNA transcription (P < 0.01), whereas ALOX5 mRNA transcription was increased only by TNF (P < 0.001). Lipopolysaccharides, TNF, IL-1α, NONOate, and the combination of reagents increased the cell number (P < 0.001). Mediators of acute-clinical Escherichia coli mastitis locally modulate PG and LT secretion by the epithelial cells of the teat cavity and lactiferous sinus, which might be a useful first line of defense for the bovine mammary gland. Moreover, the modulation of PG and LT secretion and the changing ratio of luteotropic (PGE(2), LTB(4)) to luteolytic (PGF(2α), LTC(4)) metabolites may contribute to

  10. Water-soluble HPMA copolymer--prostaglandin E1 conjugates containing a cathepsin K sensitive spacer.

    PubMed

    Pan, Huaizhong; Kopecková, Pavla; Wang, Dong; Yang, Jiyuan; Miller, Scott; Kopecek, Jindrich

    2006-07-01

    A novel bone targeting, N-(2-hydroxypropyl)methacrylamide (HPMA) copolymer based, prostaglandin E1 (PGE1) delivery system was designed, synthesized and characterized. PGE1 was bound to the polymer backbone via a spacer, composed of a cathepsin K sensitive tetrapeptide (Gly-Gly-Pro-Nle) and a self-eliminating 4-aminobenzyl alcohol structure. The HPMA copolymer conjugates were prepared by photo-initiated free radical copolymerization of HPMA, PGE1-containing macromonomer, and optionally a comonomer containing a reactive p-nitrophenyl ester group. The latter group was used as attachment points for the D-aspartic acid octapeptide targeting moieties. Incubation of the PGE1-containing macromonomer and HPMA copolymer-PGE1 conjugates with cathepsin K resulted in release of unmodified PGE1. The rate of release depended on the composition of the conjugate. The higher the PGE1 content in the conjugate, the slower the PGE1 release. This appeared to be the result of association of hydrophobic side-chains in aqueous media, which rendered the formation of the enzyme substrate complex more difficult. The data seems to indicate that HPMA copolymer-PGE1 conjugates have a potential in the treatment of osteoporosis and other bone diseases.

  11. Role of putative neurotransmitters in the central gastric antisecretory effect of prostaglandin E2 in rats.

    PubMed Central

    Puurunen, J.

    1985-01-01

    The role of putative neurotransmitters of the central nervous system in the central gastric antisecretory effect of prostaglandin E2 (PGE2) was investigated in pylorus-ligated rats. Pretreatment of the rats with an intracerebroventricular (i.c.v.) injection of 6-hydroxydopamine (6-OHDA) prevented the antisecretory effect of the i.c.v. administration of PGE2, whereas pretreatment with 5,6-dihydroxytryptamine (5,6-DHT) plus p-chlorophenylalanine (PCPA) had no effect. I.c.v.-administered phentolamine and idazoxan antagonized the inhibition of gastric secretion induced by i.c.v. PGE2, whereas prazosin, propranolol and sulpiride injected via the same route were ineffective. Diphenhydramine, cimetidine, naloxone and theophylline, all administered i.c.v., did not modify the antisecretory effect of i.c.v. PGE2. The results suggest that an activation of alpha 2-adrenoceptors in the brain is involved in the central gastric antisecretory effect of PGE2, whereas neither central 5-hydroxytryptamine receptors, alpha 1- or beta-adrenoceptors, D2-dopamine receptors, histamine or opioid receptors nor adenosine seem to play any role here. PMID:2862940

  12. Metabolism of phenylhydroquinone by prostaglandin (H) synthase: possible implications in o-phenylphenol carcinogenesis.

    PubMed

    Kolachana, P; Subrahmanyam, V V; Eastmond, D A; Smith, M T

    1991-01-01

    o-Phenylphenol (OPP) and its sodium salt sodium ortho-phenylphenate (NaOPP) are broad spectrum fungicides and antibacterial agents. Both are urinary bladder and renal carcinogens in the Fischer 344 rat. OPP is converted by mixed-function oxidases in the liver to phenylhydroquinone (PHQ). Since appreciable amounts of prostaglandin (H) synthase (PGS) are found in rat bladder and kidney-medullary papilla, the target sites of OPP- and NaOPP-induced tumors, we hypothesized that a secondary PGS-mediated activation of PHQ to phenylbenzoquinone (PBQ) may occur in the bladder and kidney. We have studied the metabolism of PHQ by PGS in the presence of arachidonic acid and hydrogen peroxide as co-factors. These studies showed that PHQ is indeed metabolized to a product having identical spectral and electrochemical properties to PBQ. The disappearance of PHQ with time was stoichiometric to the formation of PBQ. Less than 10% of PHQ was converted to PBQ in the absence of enzyme, indicating that auto-oxidation may play only a minor role in the conversion of PHQ to PBQ. Similar results were obtained when PGS was replaced with either myeloperoxidase or horseradish peroxidase and hydrogen peroxide as co-factor. These studies suggest that the peroxidative metabolism of PHQ by PGS to the reactive PBQ could play an important role in OPP-induced urinary bladder and kidney carcinogenesis in rats.

  13. The mouse prostaglandin E receptor EP2 subtype: cloning, expression, and northern blot analysis.

    PubMed

    Katsuyama, M; Nishigaki, N; Sugimoto, Y; Morimoto, K; Negishi, M; Narumiya, S; Ichikawa, A

    1995-09-25

    A functional cDNA clone for the mouse prostaglandin (PG) E receptor EP2 subtype was isolated from a mouse cDNA library. The mouse EP2 receptor consists of 362 amino acid residues with seven putative transmembrane domains. [3H]PGE2 bound specifically to the membrane of Chinese hamster ovary cells stably expressing the cloned receptor. This binding was displaced by unlabeled prostanoids in the order of PGE2 = PGE1 > iloprost, a stable PGI2 agonist > PGF2 alpha > PGD2. Binding was also inhibited by butaprost (an EP2 agonist) and to a lesser extent by M&B 28767 (an EP3 agonist), but not by sulprostone (an EP1 and EP3 agonist) or SC-19220 (an EP1 antagonist). PGE2 and butaprost increased the cAMP level in the Chinese hamster ovary cells in a concentration-dependent manner. Northern blot analysis revealed that EP2 mRNA is expressed most abundantly in the uterus, followed by the spleen, lung, thymus, ileum, liver, and stomach.

  14. Cloning and expression of a cDNA for mouse prostaglandin E receptor EP2 subtype.

    PubMed

    Honda, A; Sugimoto, Y; Namba, T; Watabe, A; Irie, A; Negishi, M; Narumiya, S; Ichikawa, A

    1993-04-15

    A functional cDNA clone encoding mouse EP2 subtype of prostaglandin (PG) E receptor was isolated from a mouse cDNA library by cross-hybridization with the mouse EP3 subtype PGE receptor cDNA. The mouse EP2 receptor consists of 513 amino acid residues with putative seven-transmembrane domains. In contrast to EP3 receptor, this receptor possesses long third intracellular loop and carboxyl-terminal tail. [3H] PGE2 specifically bound to the membrane of mammalian COS cells transfected with the cDNA. The binding to the membrane was displaced with unlabeled PG in the order of PGE2 = PGE1 > iloprost > or = PGF2 alpha > or = PGD2. The binding was also inhibited by misoprostol, an EP2 and EP3 agonist, but not by sulprostone, an EP1 and EP3 agonist, and SC-19220, an EP1 antagonist. PGE2 markedly increased cAMP level in COS cells transfected with the cDNA. These results suggest that this receptor is EP2 subtype. Northern blot analysis demonstrated that the EP2 mRNA is widely expressed in various tissues, the abundant expression being observed in ileum, thymus, and mastocytoma P-815 cells.

  15. Acceleration of intestinal polyposis through prostaglandin receptor EP2 in Apc(Delta 716) knockout mice.

    PubMed

    Sonoshita, M; Takaku, K; Sasaki, N; Sugimoto, Y; Ushikubi, F; Narumiya, S; Oshima, M; Taketo, M M

    2001-09-01

    Arachidonic acid is metabolized to prostaglandin H(2) (PGH(2)) by cyclooxygenase (COX). COX-2, the inducible COX isozyme, has a key role in intestinal polyposis. Among the metabolites of PGH(2), PGE(2) is implicated in tumorigenesis because its level is markedly elevated in tissues of intestinal adenoma and colon cancer. Here we show that homozygous deletion of the gene encoding a cell-surface receptor of PGE(2), EP2, causes decreases in number and size of intestinal polyps in Apc(Delta 716) mice (a mouse model for human familial adenomatous polyposis). This effect is similar to that of COX-2 gene disruption. We also show that COX-2 expression is boosted by PGE(2) through the EP2 receptor via a positive feedback loop. Homozygous gene knockout for other PGE(2) receptors, EP1 or EP3, did not affect intestinal polyp formation in Apc(Delta 716) mice. We conclude that EP2 is the major receptor mediating the PGE2 signal generated by COX-2 upregulation in intestinal polyposis, and that increased cellular cAMP stimulates expression of more COX-2 and vascular endothelial growth factor in the polyp stroma.

  16. Prostaglandin E₂ inhibits human lung fibroblast chemotaxis through disparate actions on different E-prostanoid receptors.

    PubMed

    Li, Ying-Ji; Wang, Xing-Qi; Sato, Tadashi; Kanaji, Nobuhiro; Nakanishi, Masanori; Kim, Miok; Michalski, Joel; Nelson, Amy J; Sun, Jian-Hong; Farid, Maha; Basma, Hesham; Patil, Amol; Toews, Myron L; Liu, Xiangde; Rennard, Stephen I

    2011-01-01

    The migration of fibroblasts is believed to play a key role in both normal wound repair and abnormal tissue remodeling. Prostaglandin E (PGE)(2), a mediator that can inhibit many fibroblast functions including chemotaxis, was reported to be mediated by the E-prostanoid (EP) receptor EP2. PGE(2), however, can act on four receptors. This study was designed to determine if EP receptors, in addition to EP2, can modulate fibroblast chemotaxis. Using human fetal lung fibroblasts, the expression of all four EP receptors was demonstrated by Western blotting. EP2-selective and EP4-selective agonists inhibited both chemotaxis toward fibronectin in the blindwell assay and migration in a wound-closure assay. In contrast, EP1-selective and EP3-selective agonists stimulated cell migration in both assay systems. These results were confirmed using EP-selective antagonists. The role of both EP2 and EP4 receptors in mediating the PGE(2) inhibition of chemotaxis was also confirmed by small interfering RNA suppression. Furthermore, the role of EP receptors was confirmed by blocking the expected signaling pathways. Taken together, these results demonstrate that PGE(2) can act on multiple EP receptors in human lung fibroblasts, to exert disparate effects. Alterations in EP receptor expression may have the potential to alter PGE(2) action. Targeting specific EP receptors may offer therapeutic opportunities in conditions characterized by abnormal tissue repair and remodeling.

  17. Timely interaction between prostaglandin and chemokine signaling is a prerequisite for successful fertilization.

    PubMed

    Tamba, Shigero; Yodoi, Rieko; Segi-Nishida, Eri; Ichikawa, Atsushi; Narumiya, Shuh; Sugimoto, Yukihiko

    2008-09-23

    Timely interaction between the egg and sperm is required for successful fertilization; however, little is known about the signaling therein. Prostaglandin (PG) E receptor EP2-deficient (Ptger2(-/-)) female mice exhibit a severe fertilization defect. We investigated the molecular events leading to this failure. We found increased gene expression for chemokines, such as Ccl2, Ccl7, and Ccl9, in Ptger2(-/-) cumulus cells (the somatic cells surrounding the egg) compared with wild-type cells. Furthermore, under physiological conditions, cumulus-derived chemokine signaling was found to have a dual action; CCL7 facilitates sperm migration to the cumulus-egg complex and integrin-mediated cumulus extracellular matrix (ECM) assembly to protect eggs. However, in the absence of PGE(2)-EP2 signaling, chronic CCL7 signaling results in excessive integrin engagement to the ECM, making the cumulus ECM resistant to sperm hyaluronidase, thereby preventing sperm penetration. Our findings indicate that PGE(2)-EP2 signaling negatively regulates the autocrine action of chemokines and prevents excessive cumulus ECM assembly. This interaction between PG and chemokine signaling is required for successful fertilization.

  18. 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.

  19. 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.

  20. Dynamics of Radical Intermediates in Prostaglandin H Synthase-1 Cyclooxygenase Reactions is Modulated by Multiple Factors.

    PubMed

    Wu, Gang; Tsai, Ah-Lim

    2016-01-01

    Prostaglandin H synthase (PGHS) catalyzes the biosynthesis of PGG2 and PGH2, the precursor of all prostanoids, from arachidonic acid (AA). PGHS exhibits two enzymatic activities following a branched-chain radical mechanism: 1) a peroxidase activity (POX) that utilizes hydroperoxide through heme redox cycles to generate the critical Tyr385 tyrosyl radical for coupling both enzyme activities; 2) the cyclooxygenase (COX) activity inserting two oxygen molecules into AA to generate endoperoxide/hydroperoxide PGG2 through a series of radical intermediates. Upon the generation of Tyr385 radical, COX catalysis is initiated, with C13 pro-S hydrogen abstraction from AA by Tyr385 radical to generate arachidonyl substrate radical. Oxygen provides a large driving force for the subsequent fast steps leading to the formation of PGG2, including radical redistributions, ring formations, and rearrangements. On the other hand, if the supply of oxygen is severed, equilibrium between arachidonyl radical and tyrosyl radical(s) biases largely towards the latter. In this study, we demonstrate that such equilibrium is shifted by many factors, including temperature, chemical structures of fatty acid substrates and limited supply of oxygen. We also, for the first time, reveal that this equilibrium is significantly affected by co-substrates of POX. The presence of efficient POX co-substrates, which reduces heme to its ferric state, apparently biases the equilibrium towards arachidonyl radical. Therefore a dynamic interplay exists between the two activities of PGHS.

  1. [Use of prostaglandins in pregnancy termination in the 1st and 2d trimester].

    PubMed

    Rath, W

    1987-11-06

    Successful termination of pregnancy can be achieved at any stage of gestation by the administration of prostaglandins (PG). The methods used for preoperative cervical priming are: intramuscular and intramural-cervical injection of sulprostone, as well as intracervical application of PG-containing gel preparations. According to our own extensive investigations, intracervical application of 50 micrograms sulprostone-tylose gel is superior to other procedures of cervical priming as regards efficiency and acceptance. For termination of second trimester pregnancy a combined procedure is advisable, namely cervical priming (e.g. intracervical PG gel application) and induction of labour (e.g. intramuscular sulprostone). The advantages of this method as compared with the exclusively systemic administration of PGs are: a higher success rate, a lower incidence of undesired concomitant side effects and the avoidance of serious complications (e.g. cervical rupture). In our experience administration of PGs is not contraindicated under certain well-defined conditions, even in the case of previous uterine operations.

  2. Prostaglandin E2 in tylose gel for cervical ripening before induction of labor.

    PubMed

    Turner, J E; Burke, M S; Porreco, R P; Weiss, M A

    1987-11-01

    Two hundred seventeen women who received 3 mg of prostaglandin E2 (PGE2) gel applied to the cervix followed by adjunctive oxytocin were compared to 94 patients whose labor was induced with oxytocin alone (OA). Postdatism, pregnancy-induced hypertension and rupture of the membranes were the major indications for induction of labor, accounting for 70% of the PGE2 group and 88% of the OA group. Mean initial cervical scores were found to be significantly less favorable among PGE2 patients as compared with OA patients. Though PGE2 was associated with a significant improvement in mean cervical scores, responsiveness of the cervix to PGE2, as determined by clinical examination, was not necessary for a successful induction. Failed inductions were infrequent in both groups. Nulliparous PGE2 patients with unfavorable cervical scores had fewer cesarean sections (CSs) and shorter labors than did their OA counterparts. Complications were uncommon but largely due to the subsequent use of oxytocin. Patients with prior CSs were safely induced following PGE2 cervical ripening.

  3. Gamma-type gliadins cause secretion of prostaglandin E2 in patients with coeliac disease.

    PubMed

    Friis, S; Anthonsen, D; Norén, O; Sjöström, H

    1994-12-16

    Coeliac disease is induced by polypeptides in the prolamin fraction of wheat, termed gliadin. It has previously been demonstrated that the alpha-, the beta- and the gamma-gliadin fractions contain toxic components and it has furthermore been strongly indicated that alpha-type gliadins are toxic. Due to insufficient protein separation methods there has been no information as to whether also the gamma-type gliadins are injurious in coeliac disease. We have therefore purified one alpha-type (alpha-39) and two gamma-type gliadins (gamma-36 and gamma-47) in a preparative scale by a combination of different ion exchange chromatographies. The purity was analyzed by high performance liquid chromatography and by polyacrylamide gel electrophoresis in the presence of sodium dodecyl sulphate, while the typing was based on determination of N-terminal amino acid sequence. Six patients with coeliac disease in remission were included in the study. Each of the purified gliadins was given by an intestinal perfusion technique to two patients. The perfusion fluid was collected and analyzed for the concentration of prostaglandin E2 (PGE2) as a marker for a toxic effect. All patients reacted with increased PGE2 secretion. For the first time it is clearly demonstrated that gamma-type gliadins are active in coeliac disease.

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

    PubMed Central

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

    2011-01-01

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

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

    PubMed Central

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

    2015-01-01

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

  6. Proteomic studies on protein modification by cyclopentenone prostaglandins: expanding our view on electrophile actions.

    PubMed

    Garzón, Beatriz; Oeste, Clara L; Díez-Dacal, Beatriz; Pérez-Sala, Dolores

    2011-10-19

    Cyclopentenone prostaglandins (cyPG) are lipid mediators that participate in the mechanisms regulating inflammation and tumorigenesis. cyPG are electrophilic compounds that act mainly through the covalent modification of cellular proteins. The stability of many cyPG-protein adducts makes them suitable for proteomic analysis. Indeed, methodological advances in recent years have allowed identifying many cyPG targets, including components of pro-inflammatory transcription factors, cytoskeletal proteins, signaling kinases and proteins involved in redox control. Insight into the diversity of cyPG targets is providing a better understanding of their mechanism of action, uncovering novel links between resolution of inflammation, proliferation and redox regulation. Moreover, identification of the target residues has unveiled the selectivity of protein modification by these electrophiles, providing valuable information for potential pharmacological applications. Among the challenges ahead, the detection of proteins modified by endogenous cyPG and the quantitative aspects of the modification require further efforts. Importantly, only a few years after the appearance of the first proteomic studies, research on cyPG targets is yielding new paradigms for redox and electrophilic signaling.

  7. Inhibition of prostaglandin E2 production by flavone and its related compounds.

    PubMed

    Kaneko, Tadayoshi; Chiba, Hiroshige; Horie, Norio; Kato, Takao; Kobayashi, Masaki; Hashimoto, Ken; Kusama, Kaoru; Sakagami, Hiroshi

    2010-01-01

    We have previously reported that among 12 major ingredients of Sairei-to, Scutellariae radix inhibited prostaglandin E(2) (PGE(2)) production by lipopolysaccharide (LPS)-activated mouse macrophage-like RAW264.7 cells more efficiently than other ingredients, and wogonin, a major flavonoid from Scutellariae radix, showed greater inhibitory activity and membrane permeability than baicalein and baicalin. Here the effects of six other flavonoids, with similar structures, on membrane permeability and PGE(2) production were investigated. 7-Methoxyflavone inhibited the LPS-stimulated PGE(2) production to the greatest extent, followed by flavone>wogonin (5,7-dihydroxy-8-methoxyflavone)> 7,8-dimethoxyflavone>chrysin (5,7-dihydroxyflavone)> baicalein (5,6,7-trihydroxyflavone)>chromone. 7-Methoxyflavone also showed the highest membrane permeability, followed by flavone>chrysin>7,8-dimethoxy-flavone>wogonin>baicalein. When PGE(2) inhibitory activity was expressed per molecule incorporated into the cells, wogonin produced the greatest inhibition, further substantiating its anti-inflammatory potency.

  8. Prostaglandin signaling suppresses beneficial microglial function in Alzheimer’s disease models

    PubMed Central

    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.

    2014-01-01

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

  9. Kinetics of prostaglandin production in various inflammatory lesions, measured in draining lymph.

    PubMed Central

    Johnston, M. G.; Hay, J. B.; Movat, H. Z.

    1979-01-01

    Efferent lymph was collected over long periods via catheters surgically placed in popliteal and prefemoral lymph nodes of sheep. Prostaglandin (PG) E and F equivalents were measured with a radioimmunoassay. After stimulation with heat-killed Escherichia coli, PG levels rose dramatically in the efferent lymph but were undetectable in the contralateral control lymphatics or in the systemic circulation. When E coli were infused directly into a lymph node, the PG levels in the effluent lymph were inhibited with indomethacin. Carrageenan, delayed hypersensitivity, and lymphocyte transfer reactions were also studied. In the classic acute inflammations (caused by E coli and carrageenan) the PG levels rose early in the response (first 4 to 6 hours) compared with delayed production in the immune reactions. With PPD, PG levels peaked between 10 and 20 hours after injections, while PG rose 127 hours after allogeneic lymphocytes were injected. These results are discussed in relation to the role of PG in inflammation, and the use of the sheep lymphatic model in PG research is emphasized. Images Figure 5 Figure 6 Figures 7 and 8 Figure 1 Figure 2 Figures 3 and 4 PMID:373461

  10. Niacin ameliorates ulcerative colitis via prostaglandin D2-mediated D prostanoid receptor 1 activation.

    PubMed

    Li, Juanjuan; Kong, Deping; Wang, Qi; Wu, Wei; Tang, Yanping; Bai, Tingting; Guo, Liang; Wei, Lumin; Zhang, Qianqian; Yu, Yu; Qian, Yuting; Zuo, Shengkai; Liu, Guizhu; Liu, Qian; Wu, Sheng; Zang, Yi; Zhu, Qian; Jia, Daile; Wang, Yuanyang; Yao, Weiyan; Ji, Yong; Yin, Huiyong; Nakamura, Masataka; Lazarus, Michael; Breyer, Richard M; Wang, Lifu; Yu, Ying

    2017-03-24

    Niacin, as an antidyslipidemic drug, elicits a strong flushing response by release of prostaglandin (PG) D2 However, whether niacin is beneficial for inflammatory bowel disease (IBD) remains unclear. Here, we observed niacin administration-enhanced PGD2 production in colon tissues in dextran sulfate sodium (DSS)-challenged mice, and protected mice against DSS or 2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced colitis in D prostanoid receptor 1 (DP1)-dependent manner. Specific ablation of DP1 receptor in vascular endothelial cells, colonic epithelium, and myeloid cells augmented DSS/TNBS-induced colitis in mice through increasing vascular permeability, promoting apoptosis of epithelial cells, and stimulating pro-inflammatory cytokine secretion of macrophages, respectively. Niacin treatment improved vascular permeability, reduced apoptotic epithelial cells, promoted epithelial cell update, and suppressed pro-inflammatory gene expression of macrophages. Moreover, treatment with niacin-containing retention enema effectively promoted UC clinical remission and mucosal healing in patients with moderately active disease. Therefore, niacin displayed multiple beneficial effects on DSS/TNBS-induced colitis in mice by activation of PGD2/DP1 axis. The potential efficacy of niacin in management of IBD warrants further investigation.

  11. Epigenetic control of microsomal prostaglandin E synthase-1 by HDAC-mediated recruitment of p300.

    PubMed

    Fork, Christian; Vasconez, Andrea E; Janetzko, Patrick; Angioni, Carlo; Schreiber, Yannick; Ferreirós, Nerea; Geisslinger, Gerd; Leisegang, Matthias S; Steinhilber, Dieter; Brandes, Ralf P

    2017-02-01

    Nonsteroidal anti-inflammatory drugs are the most widely used medicine to treat pain and inflammation, and to inhibit platelet function. Understanding the expression regulation of enzymes of the prostanoid pathway is of great medical relevance. Histone acetylation crucially controls gene expression. We set out to identify the impact of histone deacetylases (HDACs) on the generation of prostanoids and examine the consequences on vascular function. HDAC inhibition (HDACi) with the pan-HDAC inhibitor, vorinostat, attenuated prostaglandin (PG)E2 generation in the murine vasculature and in human vascular smooth muscle cells. In line with this, the expression of the key enzyme for PGE2 synthesis, microsomal PGE synthase-1 (PTGES1), was reduced by HDACi. Accordingly, the relaxation to arachidonic acid was decreased after ex vivo incubation of murine vessels with HDACi. To identify the underlying mechanism, chromatin immunoprecipitation (ChIP) and ChIP-sequencing analysis were performed. These results suggest that HDACs are involved in the recruitment of the transcriptional activator p300 to the PTGES1 gene and that HDACi prevented this effect. In line with the acetyltransferase activity of p300, H3K27 acetylation was reduced after HDACi and resulted in the formation of heterochromatin in the PTGES1 gene. In conclusion, HDAC activity maintains PTGES1 expression by recruiting p300 to its gene.

  12. Frataxin deficiency increases cyclooxygenase 2 and prostaglandins in cell and animal models of Friedreich's ataxia

    PubMed Central

    Hayashi, Genki; Shen, Yan; Pedersen, Theresa L.; Newman, John W.; Pook, Mark; Cortopassi, Gino

    2014-01-01

    An inherited deficiency of the mitochondrial protein frataxin causes Friedreich's ataxia (FRDA); the mechanism by which this deficiency triggers neuro- and cardio-degeneration is unclear. Microarrays of neural tissue of animal models of the disease showed decreases in antioxidant genes, and increases in inflammatory genes. Cyclooxygenase (COX)-derived oxylipins are important mediators of inflammation. We measured oxylipin levels using tandem mass spectrometry and ELISAs in multiple cell and animal models of FRDA. Mass spectrometry revealed increases in concentrations of prostaglandins, thromboxane B2, 15-HETE and 11-HETE in cerebellar samples of knockin knockout mice. One possible explanation for the elevated oxylipins is that frataxin deficiency results in increased COX activity. While constitutive COX1 was unchanged, inducible COX2 expression was elevated over 1.35-fold (P < 0.05) in two Friedreich's mouse models and Friedreich's lymphocytes. Consistent with higher COX2 expression, its activity was also increased by 58% over controls. COX2 expression is driven by multiple transcription factors, including activator protein 1 and cAMP response element-binding protein, both of which were elevated over 1.52-fold in cerebella. Taken together, the results support the hypothesis that reduced expression of frataxin leads to elevation of COX2-mediated oxylipin synthesis stimulated by increases in transcription factors that respond to increased reactive oxygen species. These findings support a neuroinflammatory mechanism in FRDA, which has both pathomechanistic and therapeutic implications. PMID:25104852

  13. Effect of prostaglandin reductase 1 (PTGR1) on gastric carcinoma using lentivirus-mediated system.

    PubMed

    Yang, Shuo; Luo, Fen; Wang, Jun; Mao, Xiang; Chen, Zongyou; Wang, Zhiming; Guo, Fenghua

    2015-01-01

    Gastric carcinoma is a digestive related malignant tumor with poor diagnosis and prognosis for advanced patients. PTGR1 (prostaglandin reductase 1), as a potential cancer biomarker, has not been reported in gastric carcinoma occurrence. To investigate the role of PTGR1 on gastric carcinoma cells, human PTGR1 was efficiently silenced by lentivirus-mediated system in MGC-803 cells confirmed by quantitative real-time PCR (qRT-PCR) and western blot. Then cell proliferation, colony formation and cell cycle were determined after knockdown of PTGR1 by MTT assay, colony assay and flow cytometry, respectively and data suggested that PTGR1 down regulated MGC-803 cells significantly suppressed the proliferation and colony formation ability and induced cell cycle arrest in the G0/G1 phase compared to controls (P < 0.001). Further investigation demonstrated knockdown of PTGR1 influenced cell proliferation and cell cycle via activating p21 and p53 signaling pathway described by Western blot assay. Our findings indicate that PTGR1 may be an oncogene in human gastric carcinoma and identified as a diagnosis and prognosis target for gastric carcinoma.

  14. Involvement of prostaglandins and histamine in radiation-induced temperature responses in rats

    SciTech Connect

    Kandasamy, S.B.; Hunt, W.A. )

    1990-01-01

    Exposure of rats to 1-15 Gy of gamma radiation induced hyperthermia, whereas exposure to 20-150 Gy produced hypothermia. Since radiation exposure induced the release of prostaglandins (PGs) and histamine, the role of PGs and histamine in radiation-induced temperature changes was examined. Radiation-induced hyper- and hypothermia were antagonized by pretreatment with indomethacin, a cyclooxygenase inhibitor. Intracerebroventricular administration of PGE2 and PGD2 induced hyper- and hypothermia, respectively. Administration of SC-19220, a specific PGE2 antagonist, attenuated PGE2- and radiation-induced hyperthermia, but it did not antagonize PGD2- or radiation-induced hypothermia. Consistent with an apparent role of histamine in hypothermia, administration of disodium cromoglycate (a mast cell stabilizer), mepyramine (H1-receptor antagonist), or cimetidine (H2-receptor antagonist) attenuated PGD2- and radiation-induced hypothermia. These results suggest that radiation-induced hyperthermia is mediated via PGE2 and that radiation-induced hypothermia is mediated by another PG, possibly PGD2, via histamine.

  15. Histamine stimulation of prostaglandin and HETE synthesis in human endothelial cells

    SciTech Connect

    Revtyak, G.E.; Hughes, M.J.; Johnson, A.R.; Campbell, W.B.

    1988-08-01

    Endothelial cells (EC) cultured from human umbilical artery (UA) and vein (UV) metabolized (/sup 14/C)arachidonic acid to prostaglandins (PGs), monohydroxyeicosatetraenoic acids (HETEs), and epoxyeicosatrienoic acids (EETs). Major radioactive products were identified as 6-keto-PGF1 alpha, PGE2, PGF2 alpha, 12-hydroxy heptadecatrienoic acid, 15-HETE, and 11-HETE. In addition, extracts from UV ECs contained 12-HETE, 5-HETE, 14,15-EET, and 5,6-EET as minor products, whereas extracts from UA ECs contained only 12-HETE as a minor product. UA ECs also produced metabolites comigrating with 14,15-EET, 11,12-EET, 8,9-EET, and 5,6-EET. Histamine increased the release of (/sup 14/C)PGs and (/sup 14/C)HETEs from (/sup 14/C)arachidonic acid-labeled ECs. Indomethacin, aspirin, and nordihydroguauretic acid completely inhibited synthesis of both (/sup 14/C)PGs and (/sup 14/C)HETEs from exogenous (/sup 14/C)arachidonic acid in these cells. Microsomes metabolized (/sup 14/C)arachidonic acid to the same (/sup 14/C)PGs and (/sup 14/C)HETEs as intact cells. Pretreatment of microsomes with indomethacin completely inhibited formation of these products. These data indicate that UA ECs and UV ECs metabolize endogenous and exogenous arachidonic acid to both PGs and HETEs. Also 15-HETE and 11-HETE appear to be synthesized by a microsomal enzyme with the properties of cyclooxygenase.

  16. Major urinary metabolites of 6-keto-prostaglandin F2α in mice.

    PubMed

    Kuklev, Dmitry V; Hankin, Joseph A; Uhlson, Charis L; Hong, Yu H; Murphy, Robert C; Smith, William L

    2013-07-01

    Western diets are enriched in omega-6 vs. omega-3 fatty acids, and a shift in this balance toward omega-3 fatty acids may have health benefits. There is limited information about the catabolism of 3-series prostaglandins (PG) formed from eicosapentaenoic acid (EPA), a fish oil omega-3 fatty acid that becomes elevated in tissues following fish oil consumption. Quantification of appropriate urinary 3-series PG metabolites could be used for noninvasive measurement of omega-3 fatty acid tone. Here we describe the preparation of tritium- and deuterium-labeled 6-keto-PGF2α and their use in identifying urinary metabolites in mice using LC-MS/MS. The major 6-keto-PGF2α urinary metabolites included dinor-6-keto-PGF2α (~10%) and dinor-13,14-dihydro-6,15-diketo-PGF1α (~10%). These metabolites can arise only from the enzymatic conversion of EPA to the 3-series PGH endoperoxide by cyclooxygenases, then PGI3 by prostacyclin synthase and, finally, nonenzymatic hydrolysis to 6-keto-PGF2α. The 6-keto-PGF derivatives are not formed by free radical mechanisms that generate isoprostanes, and thus, these metabolites provide an unbiased marker for utilization of EPA by cyclooxygenases.

  17. Recovery from Hematopoietic Injury by Modulating Prostaglandin E2 Signaling Post-Irradiation

    PubMed Central

    Hoggatt, Jonathan; Singh, Pratibha; Stilger, Kayla N.; Plett, P. Artur; Sampson, Carol H.; Chua, Hui Lin; Orschell, Christie M.; Pelus, Louis M.

    2012-01-01

    While high dose total body irradiation (TBI) is used therapeutically, the proliferation of nuclear weapons, increasing use of nuclear power, and worldwide radical terrorism underscore the need to develop countermeasures to a radiological mass casualty event. The hematopoietic syndrome of the acute radiation syndrome (HS-ARS) results from severe compromise to the hematopoietic system, including lymphocytopenia, neutropenia, thrombocytopenia, and possible death from infection and/or hemorrhage. Given adequate time to recover, expand, and appropriately differentiate, bone marrow hematopoietic stem cells (HSC) and progenitor cells (HPC) may overcome HS-ARS and restore homeostasis of the hematopoietic system. Prostaglandin E2 (PGE2) has been shown to have pleiotropic effects on hematopoiesis, acting to inhibit apoptosis and promote self-renewal of HSC, while inhibiting HPC proliferation. We assessed the radio-mitigating potential of modulating PGE2 signaling in a mouse model of HS-ARS. Treatment with the PGE2 analog 16,16 dimethyl PGE2 (dmPGE2) 6 hours post-irradiation or inhibition of PGE2 synthesis via delayed administration of the non-steroidal anti-inflammatory drug (NSAID) Meloxicam resulted in increased survival of lethally irradiated mice. Both early dmPGE2 and delayed Meloxicam treatment were associated with increased HPC activity 35 days following irradiation, demonstrating enhanced recovery of hematopoiesis. Our results define two different treatment modalities that are highly effective and safe to administer, and can be readily available. PMID:23206586

  18. 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.

  19. Discovery and Characterization of 2-Acylaminoimidazole Microsomal Prostaglandin E Synthase-1 Inhibitors.

    PubMed

    Schiffler, Matthew A; Antonysamy, Stephen; Bhattachar, Shobha N; Campanale, Kristina M; Chandrasekhar, Srinivasan; Condon, Bradley; Desai, Prashant V; Fisher, Matthew J; Groshong, Christopher; Harvey, Anita; Hickey, Michael J; Hughes, Norman E; Jones, Scott A; Kim, Euibong J; Kuklish, Steven L; Luz, John G; Norman, Bryan H; Rathmell, Richard E; Rizzo, John R; Seng, Thomas W; Thibodeaux, Stefan J; Woods, Timothy A; York, Jeremy S; Yu, Xiao-Peng

    2016-01-14

    As part of a program aimed at the discovery of antinociceptive therapy for inflammatory conditions, a screening hit was found to inhibit microsomal prostaglandin E synthase-1 (mPGES-1) with an IC50 of 17.4 μM. Structural information was used to improve enzyme potency by over 1000-fold. Addition of an appropriate substituent alleviated time-dependent cytochrome P450 3A4 (CYP3A4) inhibition. Further structure-activity relationship (SAR) studies led to 8, which had desirable potency (IC50 = 12 nM in an ex vivo human whole blood (HWB) assay) and absorption, distribution, metabolism, and excretion (ADME) properties. Studies on the formulation of 8 identified 8·H3PO4 as suitable for clinical development. Omission of a lipophilic portion of the compound led to 26, a readily orally bioavailable inhibitor with potency in HWB comparable to celecoxib. Furthermore, 26 was selective for mPGES-1 inhibition versus other mechanisms in the prostanoid pathway. These factors led to the selection of 26 as a second clinical candidate.

  20. A synthetic prostaglandin E1 analog, alprostadil alfadex, relaxes sphincter of Oddi in humans.

    PubMed

    Koshitani, Tatsuya; Kodama, Tadashi; Sato, Hideki; Takaaki, Junpei; Imamura, Yoichi; Kato, Keimei; Wakabayashi, Naoki; Tokita, Kazuhiko; Mitsufuji, Shoji

    2002-01-01

    It is well established that prostaglandins (PGs) exert potent pharmacological actions on vascular and nonvascular smooth muscle, although their effects on the sphincter of Oddi (SO) remain to be elucidated. The aim of this study was to investigate the effect of PGE1 on motility of the human SO. Twenty patients appearing for routine endoscopic retrograde cholangiopancreatography (ERCP) examination were studied. Each patient was randomly allocated to receive an intravenous infusion of normal saline (six patients), or alprostadil alfadex, a synthetic PGE1 analog, at a dose of either 0.05 or 0.1 microg/kg/min (seven patients for each condition). Endoscopic biliary manometry was done with a recording of basal SO pressure, amplitude of SO phasic contractions, and phasic contractile frequency before and 5 min after intravenous infusions, using a 4-French microtransducer catheter. There was no significant change in SO motor variables following application of normal saline. Alprostadil alfadex significantly decreased basal SO pressure at a dose of 0.05 microg/kg/min, and significantly decreased all parameters at a dose of 0.1 microg/kg/min. A synthetic PGE1 analog, alprostadil alfadex, effectively inhibits motility of the human SO. This drug may be of clinical application as a SO-relaxing agent.

  1. Prostaglandin E2 restrains macrophage maturation via E prostanoid receptor 2/protein kinase A signaling

    PubMed Central

    Zasłona, Zbigniew; Serezani, Carlos H.; Okunishi, Katsuhide; Aronoff, David M.

    2012-01-01

    Prostaglandin E2 (PGE2) is a lipid mediator that acts by ligating 4 distinct G protein–coupled receptors, E prostanoid (EP) 1 to 4. Previous studies identified the importance of PGE2 in regulating macrophage functions, but little is known about its effect on macrophage maturation. Macrophage maturation was studied in vitro in bone marrow cell cultures, and in vivo in a model of peritonitis. EP2 was the most abundant PGE2 receptor expressed by bone marrow cells, and its expression further increased during macrophage maturation. EP2-deficient (EP2−/−) macrophages exhibited enhanced in vitro maturation compared with wild-type cells, as evidenced by higher F4/80 expression. An EP2 antagonist also increased maturation. In the peritonitis model, EP2−/− mice exhibited a higher percentage of F4/80high/CD11bhigh cells and greater expression of macrophage colony-stimulating factor receptor (M-CSFR) in both the blood and the peritoneal cavity. Subcutaneous injection of the PGE2 analog misoprostol decreased M-CSFR expression in bone marrow cells and reduced the number of peritoneal macrophages in wild-type mice but not EP2−/− mice. The suppressive effect of EP2 ligation on in vitro macrophage maturation was mimicked by a selective protein kinase A agonist. Our findings reveal a novel role for PGE2/EP2/protein kinase A signaling in the suppression of macrophage maturation. PMID:22234697

  2. Alterations in locomotor activity induced by radioprotective doses of 16,16-dimethyl prostaglandin E2

    SciTech Connect

    Landauer, M.R.; Walden, T.L.; Davis, H.D.; Dominitz, J.A.

    1987-01-01

    16,16-Dimethyl prostaglandin E2 (DiPGE2) is an effective radioprotectant when administered before irradiation. A notable side effect of this compound is sedation. In separate experiments, the dose-response determinations of the time course of locomotor activity and 30-day survival after 10 Gy gamma irradiation (LD100) were made. Adult male CD2F1 mice were injected subcutaneously with vehicle or DiPGE2 in doses ranging from 0.01 to 40 micrograms per mouse. A dose of 0.01 micrograms did not result in alterations in locomotor behaviour or enhance survival. Doses greater than 1 microgram produced ataxia and enhanced radiation survival in a dose-dependent fashion. Full recovery of locomotor activity did not occur until 6 and 30 hr after injection for the 10 microgram and 40 microgram groups, respectively. Radioprotection was observed when DiPGE2 was administered preirradiation but not postirradiation. Doses of 1 and 10 micrograms were maximally effective as a radioprotectant if injected 5 min prior to irradiation (80%-90% survival). A dose of 40 micrograms resulted in 100% survival when injected 5-30 min before irradiation. Therefore, increasing doses of DiPGE2 resulted in an enhanced effectiveness as a radioprotectant. However, the doses that were the most radioprotective were also the most debilitating to the animal.

  3. 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.

  4. Role of carbonic anhydrase in bone resorption induced by prostaglandin E2 in vitro

    NASA Technical Reports Server (NTRS)

    Hall, G. E.; Kenny, A. D.

    1985-01-01

    The possible role of carbonic anhydrase in bone resorption induced by prostaglandin E2 (PGE2) was studied using an in vitro neonatal mouse calvarial culture system. PGE2 (10 to the -6th M) was effective in stimulating resorption, as assessed by calcium release into culture media. This enhanced resorption was accompanied by significant increases in calvarial carbonic anhydrase activity over control values at 48 and 96 h. At 48 h, bones treated with PGE2 had 20 percent more carbonic anhydrase activity than controls. By 96 h, treated bones contained 79 percent more carbonic anhydrase activity than controls. PGE2-induced bone resorption was inhibited by the carbonic anhydrase inhibitor acetazolamide in a dose-dependent fashion from 10 to the -5th to 10 to the -4th M with 77 percent inhibition observed at 10 to the -4th M. The acetazolamide analogue CL 13,850 (N-t-butylacetazolamide), which does not inhibit carbonic anhydrase, failed to inhibit PGE2-induced resorption. These results are consistent with the hypothesis that carbonic anhydrase is a necessary component of the osteoclastic bone resorptive mechanism.

  5. Cyclooxygenase inactivation kinetics during reaction of prostaglandin H synthase-1 with peroxide.

    PubMed

    Wu, Gang; Kulmacz, Richard J; Tsai, Ah-Lim

    2003-11-25

    The peroxidase and cyclooxygenase activities of prostaglandin H synthase-1 (PGHS-1) both become irreversibly inactivated during reaction with peroxide. Sequential stopped-flow absorbance measurements with a chromogenic peroxidase cosubstrate previously were used to evaluate the kinetics of peroxidase inactivation during reaction of PGHS-1 with peroxide [Wu, G., et al. (1999) J. Biol. Chem. 274, 9231-7]. This approach has now been adapted to use a chromogenic cyclooxygenase substrate to analyze the detailed kinetics of cyclooxygenase inactivation during reaction of PGHS-1 with several hydroperoxides. In the absence of added reducing cosubstrates, which maximizes the levels of oxidized enzyme intermediates expected to lead to inactivation, cyclooxygenase activity was lost as fast as, or somewhat faster than, peroxidase activity. Cyclooxygenase inactivation kinetics appeared to be sensitive to the structure of the peroxide used. The addition of reducing cosubstrate during reaction of PGHS-1 with peroxide protected the peroxidase activity to a much greater degree than the cyclooxygenase activity. The results suggest a new concept of PGHS inactivation: that distinct damage can occur at the two active sites during side reactions of Intermediate II, which forms during reaction of PGHS with peroxide and which contains two oxidants, a ferryl heme in the peroxidase site, and a tyrosyl free radical in the cyclooxygenase site.

  6. 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.

  7. 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.

  8. Melatonin reduces pancreatic prostaglandins production and protects against caerulein-induced pancreatitis in rats.

    PubMed

    Chen, Han-Ming; Chen, Jih-Chang; Ng, Chip-Jin; Chiu, De-Fa; Chen, Miin-Fu

    2006-01-01

    Melatonin has been used to treat experimental pancreatitis, although not all the drug's therapeutic mechanisms of melatonin have been defined. Prostaglandins (PGs) are proinflammatory mediators that exert their effects mainly locally during inflammatory diseases. The present study was undertaken to examine whether treatment with melatonin influences local PG production. An acute pancreatitis model in male Sprague-Dawley rats (225-275 g) was established by continuously infusing caerulein (15 mg/kg/hr). Mean arterial pressure and pancreatic perfusion were monitored continuously. Melatonin was delivered via the intraperitoneal route at doses of either 2 or 10 mg/kg, 30 min after caerulein injection. Malondialdehyde and glutathione levels of the pancreas and liver and the trypsinogen activation peptide levels in the serum were measured at the end of the experiment (8 hr after infusion of caerulein). Intraperitoneal injection of melatonin (2 and 10 mg/kg) reduced the reduction in systemic arterial pressure and decreased pancreatic perfusion in the rat model of caerulein pancreatitis. Moreover, melatonin treatment changed local PG production toward control level. Higher dose of melatonin was somewhat more effective in preventing the caerulein-induced alterations than was the lower dose.

  9. Reactive Oxygen Species Mediated Prostaglandin E2 Contributes to Acute Response of Epithelial Injury

    PubMed Central

    Hu, Yi-Ping; Zhang, Yi-Fan; Wang, Ying; Yu, Wei-Rong

    2017-01-01

    Reactive oxygen species (ROS) generated after tissue injury play a crucial role during wound healing through initiating acute inflammation, clarifying infection and dead tissue, and mediating various intracellular signal transduction. Prostaglandin E2 (PGE2) has been identified as one of the major factors responsible for inflammation and tissue repair. In this study, we tested our hypothesis that ROS produced by damaged human keratinocytes induces the synthesis of PGE2. In vitro epithelial wounding model was used to observe the production of ROS and secretion of PGE2 as well as the involved signal pathway. The mechanical injury caused the rapid production of ROS in in vitro cultured keratinocytes, which was significantly blocked by an inhibitor of nicotinamide adenine dinucleotide phosphate oxidase. The increased intracellular ROS caused by mechanical injury stimulates PGE2 production in a time-dependent manner via the activation of cyclooxygenase-2 (COX-2), which was stimulated by phosphorylation of extracellular signal-regulated protein kinase (ERK). These results indicate ROS-induced ERK activation leading to the activation of COX-2 and the synthesis of PGE2 in human keratinocytes responding to mechanical injury in the acute phase. PMID:28280524

  10. Low physiological levels of prostaglandins E2 and F2α improve human sperm functions.

    PubMed

    Rios, Mariana; Carreño, Daniela V; Oses, Carolina; Barrera, Nelson; Kerr, Bredford; Villalón, Manuel

    2016-03-01

    Prostaglandins (PGs) have been reported to be present in the seminal fluid and cervical mucus, affecting different stages of sperm maturation from spermatogenesis to the acrosome reaction. This study assessed the effects of low physiological PGE2 and PGF2α concentrations on human sperm motility and on the ability of the spermatozoa to bind to the zona pellucida (ZP). Human spermatozoa were isolated from seminal samples with normal concentration and motility parameters and incubated with 1μM PGE2, 1μM PGF2α or control solution to determine sperm motility and the ability to bind to human ZP. The effects of both PGs on intracellular calcium levels were determined. Incubation for 2 or 18h with PGE2 or PGF2α resulted in a significant (P<0.05) increase in the percentage of spermatozoa with progressive motility. In contrast with PGF2α, PGE2 alone induced an increase in sperm intracellular calcium levels; however, the percentage of sperm bound to the human ZP was doubled for both PGs. These results indicate that incubation of human spermatozoa with low physiological levels of PGE2 or PGF2α increases sperm functions and could improve conditions for assisted reproduction protocols.

  11. Studies involving the induction of prostaglandin synthesis following cell transformation by herpes simplex virus type 2

    SciTech Connect

    Krebs, C.R.

    1987-01-01

    The purpose of this study was to determine the effect of HSV-2 transformation on cellular metabolic processes, specifically the metabolism of arachidonic acid (20:4) and prostaglandin (PG) synthesis. Results obtained by labeling cells with (/sup 3/H)20:4 and analyzing the release of radioactivity into overlay culture medium demonstrate that while nontransformed rat embryo fibroblasts (REF) possess phospholipase to catalyze the release of 20:4 from membrane phospholipids, transformation of REF cells by photoinactivated HSV-2 virions induces cyclooxygenase to convert 20:4 substrate primarily to PGE/sub 2/ and PGF/sub 2..cap alpha../. Induction of 20:4 deacylation in nontransformed and HSV-2 transformed cells as well as PG synthesis in transformed cells is further enhanced by the tumor promoter (12-O-tetradecanoylphorbol-13-acetate (TPA) and calcium ionophore A23187. Phospholipase and cyclooxygenase appear to be coupled in their regulation in HSV-2 transformed tumor-derived rat fibrosarcoma (RFS) cells. Three times more (/sup 3/H)20:4 is incorporated into the phosphatidylserine/phosphatidylinositol (PS/PI) fraction in HSV-2 transformed cells compared to REF cells; additionally, this fraction serves as the primary donor of (/sup 3/H)20:4 released from TPA-stimulated transformed cells.

  12. Prostaglandin A1 metabolism and inhibition of cyclic AMP extrusion by avian erythrocytes

    SciTech Connect

    Heasley, L.E.; Brunton, L.L.

    1985-09-25

    Prostaglandins (PG) inhibit active cyclic AMP export from pigeon red cells, PGA1 and PGA2 most potently. To probe the mechanism of this action of PGA1, the authors have studied the interaction of (TH)PGA1 with suspensions of pigeon red cells. The interaction of PGA1 with pigeon red cells is a multistep process of uptake, metabolism, and secretion. (TH) PGA1 rapidly enters red cells and is promptly metabolized to a compound(s) that remains in the aqueous layer after ethylacetate extraction. The glutathione-depleting agent, diamide, inhibits formation of the PGA1 metabolite. The red cells secrete the polar metabolite of PGA1 by a saturable mechanism that lowered temperatures inhibit. Because uptake and metabolism progress with much greater rates than metabolite secretion, red cells transiently concentrate the polar compound intracellularly. Onset and reversal of inhibition of cyclic AMP export by PGA1 coincide with accumulation and secretion of PGA1 metabolite, suggesting that the polar metabolite acts at an intracellular site to inhibit cyclic AMP efflux.

  13. Prostaglandins in the perilymph of guinea pig with type II collagen induced ear diseases

    SciTech Connect

    Takeda, T.; Chiang, T.; Kitano, H.; Sudo, N.; Kim, S.Y.; Ha, S.; Woo, V.; Wolf, B.; Floyd, R.; Yoo, T.J.

    1986-03-01

    The authors have studied the prostaglandins (PGs) in the perilymph from guinea pig with type II collagen induced autoimmune ear disease. Hartly guinea pigs were immunized with type II collagen in CFA and auditory brain stem responses (ABR) were measured at 2, 3, 4, and 6 months after initial immunization perilymph was obtained and the levels of PGE2 and 6 keto-PGFl..cap alpha.. were measured by radioimmunoassays. Temporal bones were examined for the histopathologic changes. Immunized guinea pigs showed the evidence of hearing loss by ABR. The temporal bones showed the following changes: spiral ganglia degeneration, mild to moderate degree of degeneration in organ of Corti, infrequent very mild endolymphatic hydrops and labrynthitis. The perilymph from immunized animals contained about 5 times more PGE2 and about 3 times more 6 keto-PGFl..cap alpha.. than control animals. However, between these two groups, there was no difference in the CSF and sera levels of PGE2 and 6 keto-PGFl..cap alpha... Thus, this study suggests that these inflammatory mediators might be involved in the pathogenesis of collagen induced autoimmune inner ear disease.

  14. Exercise status affects skin perfusion via prostaglandin, nitric oxide, and EDHF pathways in diabetes.

    PubMed

    Colberg, Sheri R; Azoury, Krystel R; Parson, Henri K; Vinik, Aaron I

    2009-03-01

    Participation in regular exercise training improves dorsal skin perfusion, while type 2 diabetes mellitus (T2 DM) often limits it via reductions in the action or release of vasodilatory compounds. This study was undertaken to investigate the relative contributions of prostaglandins (PG), nitric oxide (NO), and endothelial-derived hyperpolarizing factor (EDHF) in dorsal foot skin perfusion in individuals with and without T2 DM and a sedentary lifestyle. Participants included 24 individuals with T2 DM and 28 nondiabetic controls whose exercise status was determined via questionnaire. Their dorsal foot skin perfusion was measured at rest using laser Doppler assessment during localized heating to 44 degrees C with oral aspirin (ASA, 325 mg) treatment. In addition, they received an infusion via a subcutaneous microdialysis probe of either saline (left foot) or L-NAME, a NOS-inhibitor (right foot). Compared to normative data without ASA, heat-stimulated perfusion in regular exercisers (n=22) was significantly more suppressed by ASA and by ASA/L-NAME than in sedentary individuals (n=30). Chronic exercisers exhibit a greater reliance on PG and lesser involvement of EDHF with unchanged NO compared to sedentary individuals, who rely more on EDHF and less on PG release. One possible exception may be diabetic, sedentary individuals, who may rely somewhat more on NO than EDHF. These results suggest that regular exercise may exhibit the greatest effect on the normal functioning of these vasodilatory pathways, although diabetes and a sedentary state together may somewhat alter their relative importance.

  15. Prostaglandin H synthase kinetics in the two-phase aqueous-micellar system.

    PubMed

    Ponomareva, Olga A; Trushkin, Nikita A; Filimonov, Ivan S; Krivoshey, Alexandr V; Barkhatov, Vladimir I; Mitrofanov, Sergey I; Vrzheshch, Petr V

    2016-09-01

    Reaction mixture for PGHS (prostaglandin-H-synthase) is a two-phase system including micellar hydrophobic phase and hydrophilic aqueous phase. Reagents added to the mixture are distributed between phases, thus concentrations of reagents dissolved in phases can differ significantly from their overall contents. Using dynamic light scattering we found that the hydrophobic phase produced by tween-20 consists of micelles, which radius (4-5nm) does not depend on either tween-20 overall content (0.1%-1% v/v) or arachidonic acid (AA) addition (10-1000μM) or PGHS addition (1μM). Tween-20 overall content changing from 0.1% to 2% v/v dramatically affected COX kinetic, but accounting AA distribution between phases allowed us to estimate "true" parameters, independent of the tween-20 overall content and the concentration of another substrate: KM(Ox) equals 9.8μM O2 in the aqueous phase or 0.0074bar in the gaseous phase, KM(AA) equals 5400μM AA in the phase of tween-20 micelles and 5400/PμM AA in the aqueous phase (P is the distribution ratio for the AA between the aqueous phase and the hydrophobic phase (P≫1000)). This approach allowed to evaluate PS, the distribution ratio for the AA between the hydrophobic phase and the PGHS active center (PS ~310). This coefficient indicates the AA selectivity toward the cyclooxygenase active center.

  16. Prostaglandin F2α upregulates Slit/Robo expression in mouse corpus luteum during luteolysis.

    PubMed

    Zhang, Xuejing; Li, Jianhua; Liu, Jiali; Luo, Haoshu; Gou, Kemian; Cui, Sheng

    2013-09-01

    Prostaglandin F2 α (PGF2 α) is a key factor in the triggering of the regression of the corpus luteum (CL). Furthermore, it has been reported that Slit/Robo signaling is involved in the regulation of luteolysis. However, the interactions between PGF2 α and Slit/Robo in the progression of luteolysis remain to be established. This study was designed to determine whether luteolysis is regulated by the interactions of PGF2 α and Slit/Robo in the mouse CL. Real-time PCR and immunohistochemistry results showed that Slit2 and its receptor Robo1 are highly and specifically co-expressed in the mouse CL. Functional studies showed that Slit/Robo participates in mouse luteolysis by enhancing cell apoptosis and upregulating caspase3 expression. Both in vitro and in vivo studies showed that PGF2 α significantly increases the expression of Slit2 and Robo1 during luteolysis through protein kinase C-dependent ERK1/2 and P38 MAPK signaling pathways, whereas an inhibitor of Slit/Robo signaling significantly decreases the stimulating effect of PGF2 α on luteolysis. These findings indicate that Slit/Robo signaling plays important roles in PGF2 α-induced luteolysis by mediating the PGF2 α signaling pathway in the CL.

  17. Prostaglandin E2 promotes tumor progression by inducing myeloid-derived suppressor cells.

    PubMed

    Sinha, Pratima; Clements, Virginia K; Fulton, Amy M; Ostrand-Rosenberg, Suzanne

    2007-05-01

    A causative relationship between chronic inflammation and cancer has been postulated for many years, and clinical observations and laboratory experiments support the hypothesis that inflammation contributes to tumor onset and progression. However, the precise mechanisms underlying the relationship are not known. We recently reported that the proinflammatory cytokine, interleukin-1beta, induces the accumulation and retention of myeloid-derived suppressor cells (MDSC), which are commonly found in many patients and experimental animals with cancer and are potent suppressors of adaptive and innate immunity. This finding led us to hypothesize that inflammation leads to cancer through the induction of MDSC, which inhibit immunosurveillance and thereby allow the unchecked persistence and proliferation of premalignant and malignant cells. We now report that host MDSC have receptors for prostaglandin E2 (PGE2) and that E-prostanoid receptor agonists, including PGE2, induce the differentiation of Gr1(+)CD11b(+) MDSC from bone marrow stem cells, whereas receptor antagonists block differentiation. BALB/c EP2 knockout mice inoculated with the spontaneously metastatic BALB/c-derived 4T1 mammary carcinoma have delayed tumor growth and reduced numbers of MDSC relative to wild-type mice, suggesting that PGE2 partially mediates MDSC induction through the EP2 receptor. Treatment of 4T1-tumor-bearing wild-type mice with the cyclooxygenase 2 inhibitor, SC58236, delays primary tumor growth and reduces MDSC accumulation, further showing that PGE2 induces MDSC and providing a therapeutic approach for reducing this tumor-promoting cell population.

  18. Characterization of the promoter of human CRTh2, a prostaglandin D{sub 2} receptor

    SciTech Connect

    Quapp, Russell; Madsen, Norman; Cameron, Lisa

    2007-11-30

    Chemoattractant-receptor homologous molecule expressed on Th2 cells (CRTh2) is a receptor for prostaglandin (PG)D{sub 2}, a lipid mediator involved in allergic inflammation. CRTh2 is expressed by Th2 cells, eosinophils and basophils and PDG{sub 2}-CRTh2 signaling induces calcium mobilization, cell migration and expression of the Th2 cytokines IL-4, IL-5, and IL-13. Despite the role of CRTh2 in allergic inflammation, transcriptional regulation of this gene has not been studied. Here, we demonstrated that a reporter construct of the CRTh2 promoter was induced following T cell stimulation. This activity could be further enhanced by over-expression of GATA-3, but not NFAT2 or STAT6. Electromobility shift assay demonstrated GATA-3 binding to a probe from the CRTh2 promoter. This study provides the first detailed analysis of transcriptional regulation of the human CRTh2 promoter. These findings may help identify strategies to attenuate expression of this gene and influence the maintenance and proliferation of Th2 cells in allergic inflammation.

  19. Effects of prostaglandins and thromboxane analogues on bullock and dog iris sphincter preparations.

    PubMed

    Dong, Y J; Jones, R L

    1982-05-01

    1 The bullock iris sphincter was contracted by low concentrations of prostaglandin E2 (PGE2), 16, 16-dimethyl PGE2 and 17,18,19,20-tetranor-16-p-chlorophenoxy PGE2. Other compounds with thromboxane-like actions, for example 11,9-epoxymethano PGH2, were also potent spasmogens, ZK 36374, a stable carbacyclin, was a partial agonist on the PGE-sensitive system of this tissue. 2 The thromboxane antagonist, EP 045, had little effect on the action of PGE2 and 16,16-dimethyl PGE2 on the bullock iris. 3 The dog iris sphincter was sensitive to PGF2 alpha but not to PGE2 and 11,9-epoxymethano PGH2. 4 16,16-dimethyl PGE2 had very low activity on the dog iris in contrast to its high activity on the bullock iris. The reverse was found with the 17,18,19,20-tetranor-16-m-trifluoromethylphenoxy analogue of PGF2 alpha (ICI 81008). This indicates a considerable selectivity of action of the two analogues. 5 The results are discussed in relation to the existing knowledge of prostanoid receptors.

  20. Effects of prostaglandins and thromboxane analogues on bullock and dog iris sphincter preparations.

    PubMed Central

    Dong, Y. J.; Jones, R. L.

    1982-01-01

    1 The bullock iris sphincter was contracted by low concentrations of prostaglandin E2 (PGE2), 16, 16-dimethyl PGE2 and 17,18,19,20-tetranor-16-p-chlorophenoxy PGE2. Other compounds with thromboxane-like actions, for example 11,9-epoxymethano PGH2, were also potent spasmogens, ZK 36374, a stable carbacyclin, was a partial agonist on the PGE-sensitive system of this tissue. 2 The thromboxane antagonist, EP 045, had little effect on the action of PGE2 and 16,16-dimethyl PGE2 on the bullock iris. 3 The dog iris sphincter was sensitive to PGF2 alpha but not to PGE2 and 11,9-epoxymethano PGH2. 4 16,16-dimethyl PGE2 had very low activity on the dog iris in contrast to its high activity on the bullock iris. The reverse was found with the 17,18,19,20-tetranor-16-m-trifluoromethylphenoxy analogue of PGF2 alpha (ICI 81008). This indicates a considerable selectivity of action of the two analogues. 5 The results are discussed in relation to the existing knowledge of prostanoid receptors. PMID:6177369

  1. Prostaglandin E2 supports growth of chicken embryo intestinal organoids in Matrigel matrix.

    PubMed

    Pierzchalska, Malgorzata; Grabacka, Maja; Michalik, Marta; Zyla, Krzysztof; Pierzchalski, Piotr

    2012-05-01

    Investigating intestinal physiology in vitro remains challenging due to the lack of an effective primary enterocyte culture system. Recently developed protocols for growing organoids containing crypts and villus from adult mouse intestinal epithelium in Matrigel present an attractive alternative to the classical techniques. However, these approaches require the use of sophisticated and expensive serum-free medium supplemented with epithelial growth factor (EGF), Wnt agonist (R-spondin 1), and bone morphogenetic protein inhibitor (Noggin) in high concentrations. Here we demonstrate that is possible to use an isolated chicken embryonic intestinal epithelium to create such an organoid culture. Structures formed in Matrigel matrix in the first two days following isolation survive and enlarge during ensuing weeks. They have the appearance of empty spheres and comprise cells expressing cytokeratin (an epithelial cell marker), villin (a marker of enterocytes), and Sox-9 (a transcription factor characteristic of progenitors and stem cells of intestinal crypts). With chicken embryonic tissue as a source of organoids, prostaglandin E2 is as effective as R-spondin 1 and Noggin in promoting sustained growth and survival of epithelial spheroids.

  2. Effect of eicosapentaenoic acid-derived prostaglandin E3 on intestinal epithelial barrier function.

    PubMed

    Rodríguez-Lagunas, Maria J; Ferrer, Ruth; Moreno, Juan J

    2013-05-01

    Prostaglandins (PG) are inflammatory mediators derived from arachidonic or eicosapentaenoic acid giving rise to the 2-series or the 3-series prostanoids, respectively. Previously, we have observed that PGE2 disrupts epithelial barrier function. Considering the beneficial effect of fish oil consumption in intestinal inflammatory processes, the aim of this study was to assess the role of PGE3 on epithelial barrier function assessed from transepithelial electrical resistance and dextran fluxes in Caco-2 cells. The results indicate that PGE3 increased paracellular permeability (PP) to the same extent as PGE2, through the interaction with EP1 and EP4 receptors and with intracellular Ca(2+) and cAMP as the downstream targets. Moreover, we observed a redistribution of tight junction proteins, occludin and claudin-4. In conclusion, PGE3 is able to increase PP thus leading to reconsider the role of PGE2/PGE3 ratio in the beneficial effects of dietary fish oil supplementation in the disruption of barrier function.

  3. 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.

  4. Neonatal jaundice after labour induced or stimulated by prostaglandin E2 or oxytocin.

    PubMed

    Lange, A P; Secher, N J; Westergaard, J G; Skovgård, I

    1982-05-01

    In a prospective study of neonatal jaundice 739 infants, delivered vaginally, in the vertex presentation, and without major complications, were examined. Labour was induced or stimulated after random allocation of the mothers to one of three oxytocics (prostaglandin E2 orally, oxytocin intravenously, or demoxytocin buccally). Oxytocics were unnecessary after primary amniotomy in 91 women. A linear logistic statistical analysis showed that gestational age has a highly significant influence on the risk of jaundice (defined by maximum serum level of bilirubin greater than or equal to 205 mumol/l). An apparent influence of birthweight could be explained by the correlation between birthweight and gestational age. The influence of the three oxytocic agents was not significant, although they may have had a slight effect; however, any such effect could be a consequence of the infants of mothers given oxytocics being less mature than those whom mothers did not receive oxytocics. The duration of labour and the mother's age also had no effect on risk of jaundice. Thus, neonatal jaundice after induced and stimulated labour seems to be primarily associated with fetal maturity; the pharmacological side-effect, if any, of oxytocics is of no importance.

  5. 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.

  6. Prostaglandin E2 induces chloride secretion through crosstalk between cAMP and calcium signaling in mouse inner medullary collecting duct cells.

    PubMed

    Rajagopal, Madhumitha; Thomas, Sheela V; Kathpalia, Paru P; Chen, Yu; Pao, Alan C

    2014-02-01

    Under conditions of high dietary salt intake, prostaglandin E2 (PGE2) production is increased in the collecting duct and promotes urinary sodium chloride (NaCl) excretion; however, the molecular mechanisms by which PGE2 increases NaCl excretion in this context have not been clearly defined. We used the mouse inner medullary collecting duct (mIMCD)-K2 cell line to characterize mechanisms underlying PGE2-regulated NaCl transport. When epithelial Na(+) channels were inhibited, PGE2 exclusively stimulated basolateral EP4 receptors to increase short-circuit current (Isc(PGE2)). We found that Isc(PGE2) was sensitive to inhibition by H-89 and CFTR-172, indicating that EP4 receptors signal through protein kinase A to induce Cl(-) secretion via cystic fibrosis transmembrane conductance regulator (CFTR). Unexpectedly, we also found that Isc(PGE2) was sensitive to inhibition by BAPTA-AM (Ca(2+) chelator), 2-aminoethoxydiphenyl borate (2-APB) (inositol triphosphate receptor blocker), and flufenamic acid (FFA) [Ca(2+)-activated Cl(-) channel (CACC) inhibitor], suggesting that EP4 receptors also signal through Ca(2+) to induce Cl(-) secretion via CACC. Additionally, we observed that PGE2 stimulated an increase in Isc through crosstalk between cAMP and Ca(2+) signaling; BAPTA-AM or 2-APB inhibited a component of Isc(PGE2) that was sensitive to CFTR-172 inhibition; H-89 inhibited a component of Isc(PGE2) that was sensitive to FFA inhibition. Together, our findings indicate that PGE2 activates basolateral EP4 receptors and signals through both cAMP and Ca(2+) to stimulate Cl(-) secretion in IMCD-K2 cells. We propose that these signaling pathways, and the crosstalk between them, may provide a concerted mechanism for enhancing urinary NaCl excretion under conditions of high dietary NaCl intake.

  7. Prostaglandin E2 induces chloride secretion through crosstalk between cAMP and calcium signaling in mouse inner medullary collecting duct cells

    PubMed Central

    Rajagopal, Madhumitha; Thomas, Sheela V.; Kathpalia, Paru P.; Chen, Yu

    2013-01-01

    Under conditions of high dietary salt intake, prostaglandin E2 (PGE2) production is increased in the collecting duct and promotes urinary sodium chloride (NaCl) excretion; however, the molecular mechanisms by which PGE2 increases NaCl excretion in this context have not been clearly defined. We used the mouse inner medullary collecting duct (mIMCD)-K2 cell line to characterize mechanisms underlying PGE2-regulated NaCl transport. When epithelial Na+ channels were inhibited, PGE2 exclusively stimulated basolateral EP4 receptors to increase short-circuit current (IscPGE2). We found that IscPGE2 was sensitive to inhibition by H-89 and CFTR-172, indicating that EP4 receptors signal through protein kinase A to induce Cl− secretion via cystic fibrosis transmembrane conductance regulator (CFTR). Unexpectedly, we also found that IscPGE2 was sensitive to inhibition by BAPTA-AM (Ca2+ chelator), 2-aminoethoxydiphenyl borate (2-APB) (inositol triphosphate receptor blocker), and flufenamic acid (FFA) [Ca2+-activated Cl− channel (CACC) inhibitor], suggesting that EP4 receptors also signal through Ca2+ to induce Cl− secretion via CACC. Additionally, we observed that PGE2 stimulated an increase in Isc through crosstalk between cAMP and Ca2+ signaling; BAPTA-AM or 2-APB inhibited a component of IscPGE2 that was sensitive to CFTR-172 inhibition; H-89 inhibited a component of IscPGE2 that was sensitive to FFA inhibition. Together, our findings indicate that PGE2 activates basolateral EP4 receptors and signals through both cAMP and Ca2+ to stimulate Cl− secretion in IMCD-K2 cells. We propose that these signaling pathways, and the crosstalk between them, may provide a concerted mechanism for enhancing urinary NaCl excretion under conditions of high dietary NaCl intake. PMID:24284792

  8. Quantum Transport.

    DTIC Science & Technology

    1994-08-15

    Notre Dame was concerned with a variety of quantum transport in mesoscopic structures. This research was funded by the Air Force Office of Scientific...Research under Grant No. AFOSR-91-0211. The major issues examined included quantum transport in high magnetic fields and modulated channels, Coulomb...lifetimes in quasi-1D structures, quantum transport experiments in metals, the mesoscopic photovoltaic effect, and new techniques for fabricating quantum structures in semiconductors.

  9. 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.

  10. Effects of forskolin analogs, phosphodiesterase inhibitors and 8-bromo cyclic AMP on plasma exudations induced with bradykinin and prostaglandin E/sub 1/ in rat skin

    SciTech Connect

    Sugio, K.; Daly, J.W.

    1984-01-09

    The effects of forskolin analogs, phosphodiesterase inhibitors and 8-bromo cyclic AMP on plasma exudations induced with bradykinin and prostaglandin E/sub 1/ in rat skin were investigated using (/sup 125/I) bovine serum albumin (/sup 125/I-BSA). Forskolin, forskolin 7-ethyl carbonate and 7-desacetylforskolin, which are potent activators of adenylate cyclase, greatly potentiated the bradykinin-induced plasma exudation and inhibited the prostaglandin E/sub 1/-induced response. The phosphodiesterase inhibitors, ZK 627ll, dipyridamole, HL 725, and 3-isobutyl-1-methylxanthine potentiated the bradykinin-induced plasma exudation and inhibited and prostaglandin E/sub 1/-induced response. 8-Bromo cyclic AMP in the doses of 0.01 to 1 ..mu..g potentiated the bradykinin-induced plasma exudation, but had no effect at doses of 10 and 100 ..mu..g. 8-bromo cyclic AMP at all doses significantly inhibited the prostaglandin E/sub 1/-induced response. The results suggest that the effects of forskolin and its analogs on plasma exudations induced with bradykinin and prostaglandin E/sub 1/ in rat skin derive from activation of cyclic AMP-generating systems.

  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. Effect of inhibition of prostaglandin E2 production on pancreatic infection in experimental acute pancreatitis

    PubMed Central

    Coelho, Ana Maria M.; Sampietre, Sandra; Patzina, Rosely; Jukemura, Jose; Cunha, Jose Eduardo M.; Machado, Marcel C.C.

    2007-01-01

    Objective. Acute pancreatitis is one the important causes of systemic inflammatory response syndrome (SIRS). SIRS results in gut barrier dysfunction that allows bacterial translocation and pancreatic infection to occur. Indomethacin has been used to reduce inflammatory process and bacterial translocation in experimental models. The purpose of this study was to determine the effect of inhibition of prostaglandin E2 (PGE2) production on pancreatic infection. Materials and methods. An experimental model of severe acute pancreatitis (AP) was utilized. The animals were divided into three groups: sham (surgical procedure without AP induction); pancreatitis (AP induction); and indomethacin (AP induction plus administration of 3 mg/kg of indomethacin). Serum levels of interleukin (IL)-6 and IL-10, PGE2, and tumor necrosis factor (TNF)-α were measured 2 h after the induction of AP. We analyzed the occurrence of pancreatic infection with bacterial cultures performed 24 h after the induction of AP. The occurrence of pancreatic infection (considered positive when the CFU/g was >105), pancreatic histologic analysis, and mortality rate were studied. Results. In spite of the reduction of IL-6, IL-10, and PGE2 levels in the indomethacin group, TNF-α level, bacterial translocation, and pancreatic infection were not influenced by administration of indomethacin. The inhibition of PGE2 production did not reduce pancreatic infection, histologic score, or mortality rate. Conclusion. The inhibition of PGE2 production was not able to reduce the occurrence of pancreatic infection and does not have any beneficial effect in this experimental model. Further investigations will be necessary to discover a specific inhibitor that would make it possible to develop an anti-inflammatory therapy. PMID:18345325

  13. Naturally occurring conjugated octadecatrienoic acids are strong inhibitors of prostaglandin biosynthesis.

    PubMed

    Nugteren, D H; Christ-Hazelhof, E

    1987-03-01

    Fatty acids from natural sources (mostly seed oils) were isolated and assayed for their effect on the bioconversion of arachidonic acid into prostaglandin E2, using sheep vesicular gland microsomes. Homologues and isomers of the naturally occurring fatty acids, obtained by chemical modification and/or organic synthetic methods, were also tested. Two very active cyclooxygenase inhibitors were discovered, namely jacarandic acid (8Z, 10E, 12Z-octadecatrienoic acid), isolated from Jacaranda mimosifolia, the concentration which gives 50% inhibition ([I]50) being 2.4 microM and the synthetic 8Z, 10E, 12E-octadecatrienoic acid, having an [I]50 of 1.0 microM. Under the conditions of the assay (75 microM substrate), earlier described potent inhibitors showed the following [I]50's: indomethacin: 1.3 microM; 9,12-octadecadiynoic acid: 1.3 microM, 8Z, 12E, 14Z-eicosatrienoic acid: 2.7 microM; 5,8,11,14-eicosatetraynoic acid: 4.4 microM. At a concentration of about half that of the substrate, the following naturally occurring fatty acids revealed inhibition ([I]50): columbinic acid (29 microM), calendulic acid (31 microM), liagoric acid (31 microM), ximenynic acid (39 microM), crepenynic acid (40 microM) and timnodonic acid (43 microM). Other fatty acids, and some of the above acids, were converted themselves more or less rapidly, mostly into conjugated monohydroxy fatty acids.

  14. Synthesis and reception of prostaglandins in corpora lutea of domestic cat and lynx.

    PubMed

    Zschockelt, Lina; Amelkina, Olga; Siemieniuch, Marta J; Kowalewski, Mariusz P; Dehnhard, Martin; Jewgenow, Katarina; Braun, Beate C

    2016-08-01

    Felids show different reproductive strategies related to the luteal phase. Domestic cats exhibit a seasonal polyoestrus and ovulation is followed by formation of corpora lutea (CL). Pregnant and non-pregnant cycles are reflected by diverging plasma progesterone (P4) profiles. Eurasian and Iberian lynxes show a seasonal monooestrus, in which physiologically persistent CL (perCL) support constantly elevated plasma P4 levels. Prostaglandins (PGs) represent key regulators of reproduction, and we aimed to characterise PG synthesis in feline CL to identify their contribution to the luteal lifespan. We assessed mRNA and protein expression of PG synthases (PTGS2/COX2, PTGES, PGFS/AKR1C3) and PG receptors (PTGER2, PTGER4, PTGFR), and intra-luteal levels of PGE2 and PGF2α Therefore, CL of pregnant (pre-implantation, post-implantation, regression stages) and non-pregnant (formation, development/maintenance, early regression, late regression stages) domestic cats, and prooestrous Eurasian (perCL, pre-mating) and metoestrous Iberian (perCL, freshCL, post-mating) lynxes were investigated. Expression of PTGS2/COX2, PTGES and PTGER4 was independent of the luteal stage in the investigated species. High levels of luteotrophic PGE2 in perCL might be associated with persistence of luteal function in lynxes. Signals for PGFS/AKR1C3 expression were weak in mid and late luteal stages of cats but were absent in lynxes, concomitant with low PGF2α levels in these species. Thus, regulation of CL regression by luteal PGF2α seems negligible. In contrast, expression of PTGFR was evident in nearly all investigated CL of cat and lynxes, implying that luteal regression, e.g. at the end of pregnancy, is triggered by extra-luteal PGF2α.

  15. Overexpression of the prostaglandin E2 receptor EP2 results in enhanced skin tumor development.

    PubMed

    Sung, Y M; He, G; Hwang, D H; Fischer, S M

    2006-09-07

    We previously showed that the EP2 knockout mice were resistant to chemically induced skin carcinogenesis. The purpose of this study was to investigate the role of the overexpression of the EP2 receptor in mouse skin carcinogenesis. To determine the effect of overexpression of EP2, we used EP2 transgenic (TG) mice and wild-type (WT) mice in a DMBA (7,12-dimethylbenz[alpha]anthracene)/TPA (12-O-tetradecanoylphorbol-13-acetate) two-stage carcinogenesis protocol. EP2 TG mice developed significantly more tumors compared with WT mice. Overexpression of the EP2 receptor increased TPA-induced keratinocyte proliferation both in vivo and in vitro. In addition, the epidermis of EP2 TG mice 48 h after topical TPA treatment was significantly thicker compared to that of WT mice. EP2 TG mice showed significantly increased cyclic adenosine monophosphate levels in the epidermis after prostaglandin E2 (PGE2) treatment. The inflammatory response to TPA was increased in EP2 TG mice, as demonstrated by an increased number of macrophages in the dermis. Tumors and 7 x TPA-treated and DMBA-TPA-treated (6 weeks) skins from EP2 TG mice produced more blood vessels than those of WT mice as determined by CD-31 immunostaining. Vascular endothelial growth factor (VEGF) protein expression was significantly increased in squamous cell carcinoma (SCC) samples from EP2 TG mice compared that of WT mice. There was, however, no difference in the number of apoptotic cells in tumors from WT and EP2 TG mice. Together, our results suggest that the overexpression of the EP2 receptor plays a significant role in the protumorigenic action of PGE2 in mouse skin.

  16. The prostaglandin E2 receptor EP2 is required for cyclooxygenase 2-mediated mammary hyperplasia.

    PubMed

    Chang, Sung-Hee; Ai, Youxi; Breyer, Richard M; Lane, Timothy F; Hla, Timothy

    2005-06-01

    Expression of cyclooxygenase 2 (COX-2) in breast cancer correlates with poor prognosis, and COX-2 enzyme inhibitors reduce breast cancer incidence in humans. We recently showed that COX-2 overexpression in the mammary gland of transgenic mice induced mammary cancer. Because prostaglandin E2 (PGE2) is the major eicosanoid and because the EP2 subtype of the PGE2 receptor is highly expressed in the mammary tumors, we tested if this G protein-coupled receptor is required for tumorigenesis. We crossed the MMTV-COX-2 transgenic mice with Ep2-/- mice and studied tumor development in bigenic mice. Lack of EP2 receptor strongly suppressed COX-2-induced effects such as precocious development of the mammary gland in virgins and the development of mammary hyperplasia in multiparous female mice. Interestingly, the expression of amphiregulin, a potent mammary epithelial cell growth factor was down regulated in mammary glands of Ep2-/- mice. Total cyclic AMP (cAMP) levels were reduced in Ep2-/- mammary glands suggesting that PGE2 signaling via the EP2 receptor activates the Gs/cAMP/protein kinase A pathway. In mammary tumor cell lines, expression of the EP2 receptor followed by treatment with CAY10399, an EP2-specific agonist, strongly induced amphiregulin mRNA levels in a protein kinase A-dependent manner. These data suggest that PGE2 signaling via the EP2 receptor in mammary epithelial cells regulate mammary gland hyperplasia by the cAMP-dependent induction of amphiregulin. Inhibition of the EP2 pathway in the mammary gland may be a novel approach in the prevention and/or treatment of mammary cancer.

  17. Prostaglandin receptor EP2 protects dopaminergic neurons against 6-OHDA-mediated low oxidative stress

    PubMed Central

    Carrasco, Emilce; Werner, Peter; Casper, Diana

    2008-01-01

    Dopaminergic neurons in the substantia nigra (SN) selectively die in Parkinson’s disease (PD), but it is unclear how and why this occurs. Recent findings implicate prostaglandin E2 (PGE2) and two of its four receptors, namely EP1 and EP2, as mediators of degenerative and protective events in situations of acute and chronic neuronal death. EP1 activation can exacerbate excitotoxic damage in stroke models and our recent study showed that EP1 activation may explain the selective sensitivity of dopaminergic neurons to oxidative stress. Conversely, EP2 activation may be neuroprotective, although toxic effects have also been demonstrated. Here we investigated if and how EP2 activation might alter the survival of dopaminergic neurons following selective low-level oxidative injury evoked by the neurotoxin 6-hydroxydopamine (6-OHDA) in primary neuronal cultures prepared from embryonic rat midbrain. We found that cultured dopaminergic neurons displayed EP2 receptors. Butaprost, a selective EP2 agonist, significantly reduced 6-OHDA neurotoxicity. EP2 receptors are coupled to stimulatory G-proteins (Gs), which activate adenylate cyclase, increasing cAMP synthesis, which then activates protein kinase A (PKA). Both dibutyryl cAMP and forskolin reduced dopaminergic cell loss after 6-OHDA exposure. Conversely, KT5720 and H-89, two structurally distinct high-affinity PKA inhibitors, abolished the protective effect of butaprost, implicating cAMP-dependent PKA activity in the neuroprotection by EP2 activation. Finally, we show that melanized dopaminergic neurons in the human SN express EP2. This pathway warrants consideration as a neuroprotective strategy for PD. PMID:18597941

  18. Prostaglandin receptor EP2 protects dopaminergic neurons against 6-OHDA-mediated low oxidative stress.

    PubMed

    Carrasco, Emilce; Werner, Peter; Casper, Diana

    2008-08-15

    Dopaminergic neurons in the substantia nigra (SN) selectively die in Parkinson's disease (PD), but it is unclear how and why this occurs. Recent findings implicate prostaglandin E(2) (PGE(2)) and two of its four receptors, namely EP1 and EP2, as mediators of degenerative and protective events in situations of acute and chronic neuronal death. EP1 activation can exacerbate excitotoxic damage in stroke models and our recent study showed that EP1 activation may explain the selective sensitivity of dopaminergic neurons to oxidative stress. Conversely, EP2 activation may be neuroprotective, although toxic effects have also been demonstrated. Here we investigated if and how EP2 activation might alter the survival of dopaminergic neurons following selective low-level oxidative injury evoked by the neurotoxin 6-hydroxydopamine (6-OHDA) in primary neuronal cultures prepared from embryonic rat midbrain. We found that cultured dopaminergic neurons displayed EP2 receptors. Butaprost, a selective EP2 agonist, significantly reduced 6-OHDA neurotoxicity. EP2 receptors are coupled to stimulatory G-proteins (Gs), which activate adenylate cyclase, increasing cAMP synthesis, which then activates protein kinase A (PKA). Both dibutyryl cAMP and forskolin reduced dopaminergic cell loss after 6-OHDA exposure. Conversely, KT5720 and H-89, two structurally distinct high-affinity PKA inhibitors, abolished the protective effect of butaprost, implicating cAMP-dependent PKA activity in the neuroprotection by EP2 activation. Finally, we show that melanized dopaminergic neurons in the human SN express EP2. This pathway warrants consideration as a neuroprotective strategy for PD.

  19. [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.

  20. Involvement of central microsomal prostaglandin E synthase-1 in IL-1beta-induced anorexia.

    PubMed

    Pecchi, E; Dallaporta, M; Thirion, S; Salvat, C; Berenbaum, F; Jean, A; Troadec, J-D

    2006-05-16

    In response to infection or inflammation, individuals develop a set of symptoms referred to as sickness behavior, which includes a decrease in food intake. The characterization of the molecular mechanisms underlying this hypophagia remains critical, because chronic anorexia may represent a significant health risk. Prostaglandins (PGs) constitute an important inflammatory mediator family whose levels increase in the brain during inflammatory states, and their involvement in inflammatory-induced anorexia has been proposed. The microsomal PGE synthase (mPGES)-1 enzyme is involved in the last step of PGE2 biosynthesis, and its expression is stimulated by proinflammatory agents. The present study attempted to determine whether an upregulation of mPGES-1 gene expression may account for the immune-induced anorexic behavior. We focused our study on mPGES-1 expression in the hypothalamus and dorsal vagal complex, two structures strongly activated during peripheral inflammation and involved in the regulation of food intake. We showed that mPGES-1 gene expression was robustly upregulated in these structures after intraperitoneal and intracerebroventricular injections of anorexigenic doses of IL-1beta. This increase was correlated with the onset of anorexia. The concomitant reduction in food intake and central mPGES-1 gene upregulation led us to test the feeding behavior of mice lacking mPGES-1 during inflammation. Interestingly, IL-1beta failed to decrease food intake in mPGES-1(-/-) mice, although these animals developed anorexia in response to a PGE2 injection. Taken together, our results demonstrate that mPGES-1, which is strongly upregulated during inflammation in central structures involved in feeding control, is essential for immune anorexic behavior and thus may constitute a potential therapeutic target.

  1. The protective effects of prostaglandin E1 on sinusoidal endothelial cells in xenogeneic pig liver perfusion.

    PubMed

    Yagi, T; Ikai, I; Terajima, H; Satoh, S; Kanazawa, A; Shinohara, H; Uesugi, T; Yoneyama, T; Gomi, T; Takahashi, R; Yamamoto, M; Inamoto, T; Yamaoka, Y

    1997-11-01

    The effects of prostaglandin E1 (PGE1) on hepatic sinusoidal endothelial cells (SEC) in the xenogeneic immunoreaction were investigated. Porcine livers were perfused with fresh human blood via the portal vein (PV) and the hepatic artery (HA) either with the administration of PGE1 (Group PG) or without PGE1 (Group C). The creatine kinase-BB component (CK-BB) in the perfusate was measured to assess SEC damage. SEC activation and complement activation were evaluated immunohistochemically by the expression of von Willebrand factor (vWF) and by the deposition of membrane attack complex (MAC), respectively. Xenoperfusion in Group C was discontinued between 4 and 6 hr due to the rapid elevation of HA pressures and the massive loss of perfusate. In Group PG, both PV and HA pressures were kept stable for up to 9 hr. In Group C, severe interlobular bleeding and diffuse extrasinusoidal hemorrhage were observed at 4 hr histologically, while in Group PG, the hepatic architecture was maintained without hemorrhage at 6 hr. MAC was markedly deposited on SEC and parenchymal cells at 3 hr in both groups. The amount of vWF, however, was expressed on SEC in large amounts at 1 hr in Group C, while small amounts were expressed at 1 hr in Group PG. In Group PG, CK-BB release was significantly lower than in Group C (P < 0.01). These results suggest that PGE1 suppressed SEC activation and protected the impairment of hepatic SEC during xenoperfusion without suppressing complement activation, resulting in the prolongation of xenogeneic liver perfusion.

  2. 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.

  3. Dissimilar effects of chronic treatment with aspirin, flubiprofen and indomethacin on renal prostaglandins

    SciTech Connect

    Quilley, C.P.; McGiff, J.C.; Quilley, J.

    1986-03-01

    Inhibition of prostaglandin (PG) excretion is not sustained during long-term aspirin administration. The authors compared the effects of 9d treatment of SHR rats with aspirin (A), 200 mg/kg/d s.c., flubiprofen (F), 2.5 mg/kg/12h s.c., and indomethacin (I), 2.5 mg/kg/12 s.c. on excretion of radioimmunoassayable PGE/sub 2/ and PGF/sub 2..cap alpha../. Conversion of 1-(/sup 14/C) arachidonic acid (AA) by renal papillae was also examined. In vehicle-treated control rats (C) PGF/sub 2..cap alpha../ excretion varied from 32.2 +/- 6.2 (mean +/- SEM) to 41.6 +.- 7.3 ng/6h, 3-fold higher than that of PGE/sub 2/. Within 6h of administration all 3 drugs reduced excretion of PGF/sub 2..cap alpha../ and PGE/sub 2/ to less than 20% and 35% of C rats. Although urinary concentrations of PGF/sub 2..cap alpha../ and PGE/sub 2/ in A-treated rats remained depressed, a 2-fold increase in urine volume resulted in excretion rates similar to C rats. In contrast, urine volume in I- and F-treated rats was unaffected while PGF/sub 2..cap alpha../ and PGE/sub 2/ excretion rates in I-treated rats were 50''% of C rats and were also lower than control in F-treated rats. Paradoxically, metabolism of AA to PGs by by renal papillae dissected on day 10, 2-4h after the last drug dose, was markedly inhibited by A (PGF/sub 2..cap alpha../ by 62% and PGE/sub 2/ by 82%), but unaffected by I and F. As the effects of cyclooxygenase inhibitors differ on in vivo and indices of PG production, their intended action should be verified by measuring PG levels in biological fluids.

  4. Lanreotide inhibits human jejunal secretion induced by prostaglandin E1 in healthy volunteers.

    PubMed

    Sobhani, I; René, E; Ramdani, A; Bayod, F; Sabbagh, L C; Thomas, F; Mignon, M

    1996-02-01

    1. Somatostatin inhibits hormonal secretions in the gastrointestinal tract. Somatostatin analogues are used in the treatment of VIPome-related watery diarrhoea. In addition, more than 10% of patients with AIDS suffer from diarrhoea likely due to the increased intestinal secretion of water and ions. However, the direct effect of somatostatin on the flux of water and ions in the intestine has not been, so far, analyzed in vivo. The aim of the present study was to evaluate the effect of lanreotide, a somatostatin analogue, on the movements of water and ions in the jejunum in man. 2. Accordingly, 10 healthy volunteers (age 18-35 years, mean 27) and two patients with AIDS (26 and 33 years) suffering from water diarrhoea (> 800 ml day-1) underwent intestinal perfusion using a four lumen tube with proximal occluding balloon. The segment tested was 25 cm long. The jejunum was infused by an isotonic control saline solution containing polyethylene glycol (PEG) as nonabsorbable marker. Basal jejunal secretions were measured in all subjects. Prostaglandin E1 (PGE1) was administered intraluminally to stimulate jejunal secretion in healthy volunteers. The effect of intravenous lanreotide on the jejunal PGE1-induced secretions of water and electrolytes was analysed in healthy subjects and on the basal secretions in AIDS patients. Each period was analyzed on the basis of three (10 min) successive intestinal juice collections after 20-30 min equilibration time. The antisecretory effect of lanreotide was evaluated in each subject as the difference between fluxes compared to the control period. 3. In healthy volunteers, PGE1 induced secretion of H2O, Na+, K+ and Cl- in the jejunum and lanreotide reduced significantly PGE1-induced response. In both AIDS patients basal fluxes of water and ions were reduced by lanreotide in a dose-dependent manner. 4. Somatostatin can reduce stimulated-jejunal secretion of ions and water in normal subjects and may improve water diarrhoea in AIDS

  5. 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

  6. Assessment of oxidative stress markers and prostaglandins after chronic training of triathletes.

    PubMed

    Medina, Sonia; Domínguez-Perles, Raul; Cejuela-Anta, Roberto; Villaño, Débora; Martínez-Sanz, José M; Gil, Pilar; García-Viguera, Cristina; Ferreres, Federico; Gil, José I; Gil-Izquierdo, Angel

    2012-12-01

    The present study established the pattern of isoprostanes (IsoPs) and prostaglandins metabolites (PGMs) in urine after triathlon training. Fifteen Caucasian triathletes - 5 women and 10 men - performed 793 and 1603 Objective Load Scales, respectively. The optimization of urine hydrolysis conditions, concerning to the type of buffer, the units of hydrolytic enzyme added, and the pH, allowed precise quantification of these metabolites by UPLC-MS/MS, avoiding the under-estimation of their concentrations that occurred in previous studies. Their rate of conjugation ranged between 36% and 100%. This implies significant importance since it supposes non-detection of some IsoPs and PGMs totally conjugated with glucuronic acid developed by other previous methodologies. Among the 13 compounds analyzed, this assay detected and characterized 4 IsoPs and 3 PGMs in the triathletes' urine. The PGMs tetranor-PGEM and 11β-PGF(2α) and the IsoP 8-iso-PGF(2α), showed lower concentrations after the training program, whereas the PGMs 6-keto-PGF(1α) increased (vascular PGI(2) metabolite). In fact, their pattern in the triathletes' urine indicated that their variation may have been related with the physical activity. Due to its high variation, 6-keto PGF(1α) stood out as a useful marker of the vasodilation and inhibition of the platelet aggregation of the PGI(2) linked to the physical exercise. The data obtained provided a global picture of changes in lipid peroxidation and vascular events as a consequence of chronic exercise.

  7. Seminal plasma affects prostaglandin synthesis and angiogenesis in the porcine uterus.

    PubMed

    Kaczmarek, Monika M; Krawczynski, Kamil; Filant, Justyna

    2013-03-01

    Introduction of semen into the female reproductive tract may induce molecular and cellular changes facilitating conception and pregnancy. Because prostaglandins (PGs) and appropriate vascularization of the endometrium are crucial for pregnancy success, the effect of seminal plasma (SP) on PG synthesis and angiogenesis was investigated. Gilts at estrus received an infusion of 100 ml of either SP or PBS (control). Uterine horns were collected on Days 1, 3, 5, and 10 after each treatment. Concentrations of PGE2, PGF2alpha , and PGFM were measured in the uterine lumen and endometrial tissue. Expression of PG synthesis pathway enzymes and angiogenic factors, infiltration of immune cells, and vascular bed development were assessed. One day after SP infusion, the PGE2:PGF2alpha ratio in the uterine lumen was lower than in controls. In endometrial tissue, however, PGE2 levels and the PGE2:PGF2alpha ratio were elevated on Day 10. PG-endoperoxide synthase expression in the endometrium was up-regulated on Day 1 and decreased on Day 5 after SP treatment compared to that in controls. PGF2alpha synthase levels were decreased on Day 5 and 10 in SP-treated animals when compared to controls. SP-induced vascular bed development was apparent shortly before the time corresponding to maternal recognition of pregnancy in the pig. Together, these data indicate that the porcine uterus can be sensitized shortly after SP exposure to evoke prolonged effects on PG synthesis and angiogenesis in the endometrium, persisting over the course of the prereceptive phase. Thus, SP can affect uterine receptivity and embryo-maternal interactions in pigs through locally direct and/or indirect mechanisms.

  8. Prostaglandin E2 released from activated microglia enhances astrocyte proliferation in vitro

    SciTech Connect

    Zhang Dan; Hu Xiaoming; Qian Li; Wilson, Belinda; Lee, Christopher; Flood, Patrick; Langenbach, Robert; Hong, J.-S.

    2009-07-01

    Microglial activation has been implicated in many astrogliosis-related pathological conditions including astroglioma; however, the detailed mechanism is not clear. In this study, we used primary enriched microglia and astrocyte cultures to determine the role of microglial prostaglandin E{sub 2} (PGE{sub 2}) in the proliferation of astrocytes. The proliferation of astrocytes was measured by BrdU incorporation. The level of PGE{sub 2} was measured by ELISA method. Pharmacological inhibition or genetic ablation of COX-2 in microglia were also applied in this study. We found that proliferation of astrocytes increased following lipopolysaccharide (LPS) treatment in the presence of microglia. Furthermore, increased proliferation of astrocytes was observed in the presence of conditioned media from LPS-treated microglia. The potential involvement of microglial PGE{sub 2} in enhanced astrocyte proliferation was suggested by the findings that PGE{sub 2} production and COX-2 expression in microglia were increased by LPS treatment. In addition, activated microglia-induced increases in astrocyte proliferation were blocked by the PGE{sub 2} antagonist AH6809, COX-2 selective inhibitor DuP-697 or by genetic knockout of microglial COX-2. These findings were further supported by the finding that addition of PGE{sub 2} to the media significantly induced astrocyte proliferation. These results indicate that microglial PGE{sub 2} plays an important role in astrocyte proliferation, identifying PGE{sub 2} as a key neuroinflammatory molecule that triggers the pathological response related to uncontrollable astrocyte proliferation. These findings are important in elucidating the role of activated microglia and PGE{sub 2} in astrocyte proliferation and in suggesting a potential avenue in the use of anti-inflammatory agents for the therapy of astroglioma.

  9. Distribution of microsomal prostaglandin E synthase-1 in the mouse brain.

    PubMed

    Eskilsson, Anna; Tachikawa, Masanori; Hosoya, Ken-Ichi; Blomqvist, Anders

    2014-10-01

    Previous studies in rats have demonstrated that microsomal prostaglandin E synthase-1 (mPGES-1) is induced in brain vascular cells that also express inducible cyclooxygenase-2, suggesting that such cells are the source of the increased PGE2 levels that are seen in the brain following peripheral immune stimulation, and that are associated with sickness responses such as fever, anorexia, and stress hormone release. However, while most of what is known about the functional role of mPGES-1 for these centrally evoked symptoms is based on studies on genetically modified mice, the cellular localization of mPGES-1 in the mouse brain has not been thoroughly determined. Here, using a newly developed antibody that specifically recognizes mouse mPGES-1 and dual-labeling for cell-specific markers, we report that mPGES-1 is constitutively expressed in the mouse brain, being present not only in brain endothelial cells, but also in several other cell types and structures, such as capillary-associated pericytes, astroglial cells, leptomeninges, and the choroid plexus. Regional differences were seen with particularly prominent labeling in autonomic relay structures such as the area postrema, the subfornical organ, the paraventricular hypothalamic nucleus, the arcuate nucleus, and the preoptic area. Following immune stimulation, mPGES-1 in brain endothelial cells, but not in other mPGES-1-positive cells, was coexpressed with cyclooxygenase-2, whereas there was no coexpression between mPGES-1 and cyclooxygenase-1. These data imply a widespread synthesis of PGE2 or other mPGES-1-dependent products in the mouse brain that may be related to inflammation-induced sickness symptom as well as other functions, such as blood flow regulation.

  10. Intrauterine Group A Streptococcal Infections are Exacerbated by Prostaglandin E2

    PubMed Central

    Mason, Katie L.; Rogers, Lisa M.; Soares, Elyara M.; Bani-Hashemi, Tara; Downward, John Erb; Agnew, Dalen; Peters-Golden, Marc; Weinberg, Jason B.; Crofford, Leslie J.; Aronoff, David M.

    2013-01-01

    Streptococcus pyogenes(Group A Streptococcus; GAS) is a major cause of severe postpartum sepsis, a reemerging cause of maternal morbidity and mortality worldwide. Immunological alterations occur during pregnancy to promote maternofetal tolerance, which may increase the risk for puerperal infection. Prostaglandin E2 (PGE2) is an immunomodulatory lipid that regulates maternofetal tolerance, parturition, and innate immunity. The extent to which PGE2 regulates host immune responses to GAS infections in the context of endometritis is unknown. To address this, both an in vivo mouse intrauterine (i.u.) GAS infection model and an in vitro human macrophage-GAS interaction model were utilized. In C57BL/6 mice, i.u. GAS inoculation resulted in local and systemic inflammatory responses and triggered extensive changes in the expression of eicosanoid pathway genes. The i.u. administration of PGE2 increased the mortality of infected mice, suppressed local IL-6 and IL-17A levels, enhanced neutrophilic inflammation, reduced uterine macrophage populations, and increased bacterial dissemination. A role for endogenous PGE2 in modulating anti-streptococcal host defense was suggested because mice lacking the genes encoding the microsomal PGE2 synthase-1 or the EP2 receptor were protected from death, as were mice treated with the EP4 receptor antagonist GW627368X. PGE2 also regulated GAS-macrophage interactions. In GAS-infected human THP-1 (macrophage-like) cells, PGE2 inhibited the production of MCP-1 and TNF-α while augmenting IL-10 expression. PGE2 also impaired the phagocytic ability of human placental macrophages, THP-1 cells, and mouse peritoneal macrophages in vitro. Exploring the targeted disruption of PGE2 synthesis and signaling to optimize existing antimicrobial therapies against GAS may be warranted. PMID:23913961

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

    PubMed

    Koeberle, Andreas; Werz, Oliver

    2015-11-01

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

  12. Prostaglandin E2 promotes MYCN non-amplified neuroblastoma cell survival via β-catenin stabilization

    PubMed Central

    Jansen, Sepp R; Holman, Rian; Hedemann, Ilja; Frankes, Ewoud; Elzinga, Carolina R S; Timens, Wim; Gosens, Reinoud; de Bont, Eveline S; Schmidt, Martina

    2015-01-01

    Amplification of MYCN is the most well-known prognostic marker of neuroblastoma risk classification, but still is only observed in 25% of cases. Recent evidence points to the cyclic adenosine monophosphate (cAMP) elevating ligand prostaglandin E2 (PGE2) and β-catenin as two novel players in neuroblastoma. Here, we aimed to define the potential role of PGE2 and cAMP and its potential interplay with β-catenin, both of which may converge on neuroblastoma cell behaviour. Gain and loss of β-catenin function, PGE2, the adenylyl cyclase activator forskolin and pharmacological inhibition of cyclooxygenase-2 (COX-2) were studied in two human neuroblastoma cell lines without MYCN amplification. Our findings show that PGE2 enhanced cell viability through the EP4 receptor and cAMP elevation, whereas COX-2 inhibitors attenuated cell viability. Interestingly, PGE2 and forskolin promoted glycogen synthase kinase 3β inhibition, β-catenin phosphorylation at the protein kinase A target residue ser675, β-catenin nuclear translocation and TCF-dependent gene transcription. Ectopic expression of a degradation-resistant β-catenin mutant enhances neuroblastoma cell viability and inhibition of β-catenin with XAV939 prevented PGE2-induced cell viability. Finally, we show increased β-catenin expression in human high-risk neuroblastoma tissue without MYCN amplification. Our data indicate that PGE2 enhances neuroblastoma cell viability, a process which may involve cAMP-mediated β-catenin stabilization, and suggest that this pathway is of relevance to high-risk neuroblastoma without MYCN amplification. PMID:25266063

  13. Impaired inflammatory and pain responses in mice lacking an inducible prostaglandin E synthase

    PubMed Central

    Trebino, Catherine E.; Stock, Jeffrey L.; Gibbons, Colleen P.; Naiman, Brian M.; Wachtmann, Timothy S.; Umland, John P.; Pandher, Karamjeet; Lapointe, Jean-Martin; Saha, Sipra; Roach, Marsha L.; Carter, Demetrius; Thomas, Nathalie A.; Durtschi, Becky A.; McNeish, John D.; Hambor, John E.; Jakobsson, Per-Johan; Carty, Thomas J.; Perez, Jose R.; Audoly, Laurent P.

    2003-01-01

    Prostaglandin (PG)E2 is a potent mediator of pain and inflammation, and high levels of this lipid mediator are observed in numerous disease states. The inhibition of PGE2 production to control pain and to treat diseases such as rheumatoid arthritis to date has depended on nonsteroidal antiinflammatory agents such as aspirin. However, these agents inhibit the synthesis of all prostanoids. To produce biologically active PGE2, PGE synthases catalyze the isomerization of PGH2 into PGE2. Recently, several PGE synthases have been identified and cloned, but their role in inflammation is not clear. To study the physiological role of the individual PGE synthases, we have generated by targeted homologous recombination a mouse line deficient in microsomal PGE synthase 1 (mPGES1) on the inbred DBA/1lacJ background. mPGES1-deficient (mPGES1-/-) mice are viable and fertile and develop normally compared with wild-type controls. However, mPGES1-/- mice displayed a marked reduction in inflammatory responses compared with mPGES1+/+ mice in multiple assays. Here, we identify mPGES1 as the PGE synthase that contributes to the pathogenesis of collagen-induced arthritis, a disease model of human rheumatoid arthritis. We also show that mPGES1 is responsible for the production of PGE2 that mediates acute pain during an inflammatory response. These findings suggest that mPGES1 provides a target for the treatment of inflammatory diseases and pain associated with inflammatory states. PMID:12835414

  14. Prostaglandin E2 exerts the proapoptotic and antiproliferative effects on bovine NK cells.

    PubMed

    Maślanka, Tomasz; Chrostowska, Małgorzata; Otrocka-Domagała, Iwona; Snarska, Anna; Mikiewicz, Mateusz; Zuśka-Prot, Monika; Jasiecka, Agnieszka; Ziółkowski, Hubert; Markiewicz, Włodzimierz; Jaroszewski, Jerzy J

    2016-08-01

    The aim of this research was to determine whether prostaglandin E2 (PGE2) affects bovine NK cells in respect of their counts, apoptosis and proliferation, and if it does, then which of the PGE2 receptor (EP) subtype(s) mediate(s) these effects. We here report that long-term, but not short-term, exposure of bovine peripheral blood mononuclear cells to PGE2 at 10(-5)M, 10(-6)M and 10(-7)M, but not at 10(-8)M, caused a significant increase in the percentage of early apoptotic cells among NK cell subset. Moreover, PGE2 at 10(-5)M and 10(-6)M, but not at 10(-7)M and 10(-8)M, induced a considerable decrease in the absolute count of NK cells. The magnitude of these effects increased with an increasing concentration of PGE2. The blockade of EP1, EP2, EP3 and EP4 receptors did not prevent the PGE2-induced apoptosis and depletion of NK cells. The results suggest that the proapoptotic effect of PGE2 is secondary in character and the induction of this effect is not mediated through EP receptors. Furthermore, the studies demonstrated that PGE2 at 10(-5)M and 10(-6)M, but not at 10(-7)M and 10(-8)M, highly significantly reduced the percentage of proliferating NK cells. The EP1, EP1/2 and EP3 receptor antagonists were unable to block this effect significantly, whereas the selective blockade of EP4 receptors prevented the PGE2-induced inhibition of NK cells proliferation. These results indicate that PGE2 at certain concentrations may impair the proliferation of NK cells and this effect is mediated via the EP4 receptor.

  15. Prostaglandin E1 inhibits collagenase gene expression in rabbit synoviocytes and human fibroblasts.

    PubMed

    Salvatori, R; Guidon, P T; Rapuano, B E; Bockman, R S

    1992-07-01

    Cartilage breakdown, as seen in inflammatory and degenerative joint diseases, can be mediated by proteolytic enzymes, such as the metalloproteinase collagenase, the only enzyme able to digest collagen at neutral pH. In vitro collagenase gene expression can be stimulated by the phorbol ester tumor promoter 12-O-tetradecanoyl-phorbol-13-acetate. We have investigated the effect of prostaglandin E1 (PGE1) on 12-O-tetradecanoyl-phorbol-13-acetate-stimulated collagenase mRNA levels in the rabbit synoviocyte cell line HIG-82. PGE1, but not PGE2 or PGF2 alpha, was able to selectively reduce collagenase mRNA levels in a dose-dependent fashion. PGE1 markedly increased intracellular levels of cAMP, while PGE2 and PGF2 alpha had little or no effect on cAMP production in the HIG-82 synoviocytes. Agents known to increase intracellular cAMP levels, such as the adenyl cyclase activator forskolin and the phosphodiesterase inhibitor 3-isobutyl-1-methylxanthine (IBMX), mimicked the effect of PGE1, on collagenase mRNA levels. PGE1, forskolin, and IBMX also decreased collagenase mRNA levels in human skin fibroblasts, demonstrating that this observation was not unique to the HIG-82 cell line. Transient transfection experiments carried out in HIG-82 cells using a 1.2-kilobase portion of the 5'-flanking region of the human collagenase gene linked to the reporter gene luciferase demonstrated that PGE1, forskolin, and IBMX exert their inhibitory effect on the promoter region of the collagenase gene.

  16. 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.

  17. [How should we treat intestinal ischemia?--II: Effects of pentoxifylline, glucagon and prostaglandin E1].

    PubMed

    Sakio, H; Tanaka, Y; Ueno, K; Oishi, S; Ohtsu, S; Okuda, C

    1995-02-01

    It is important to repair or ameliorate the intestinal ischemia in critically ill patients. Recent study of our suggests the superiority of dobutamine, but not dopamine, in improving the intestinal oxygenation. In this study we examined the effects of pentoxifylline (PF), glucagon (GL) and prostaglandin E1 (PGE1) during reduced blood flow of the superior mesenteric artery (SMA) in 20 anesthetized dogs. As an index of the intestinal oxygenation, tonometrically measured intestinal intramural pH (pHi) was used. A tonometer was inserted into the midjejunum through enterotomy. The SMA blood flow was measured by a transit-time flow meter. A vascular screw clamp for blood flow reduction was placed around the origin of the SMA, proximal to the flow probe. The SMA blood flow was adjusted to 70% of baseline for three hours. After two hours of decreased blood flow, pHi dropped significantly from baseline. Then, either PF (20 mg.kg-1.min-1 over 10 min, followed by 0.1 mg.kg-1.min-1), GL (1 microgram.kg-1.min-1) or PGE1 (0.05 and 0.5 microgram.kg-1.min-1) was infused intravenously for one hour. With infusions of GL and large dose of PGE1, pHi tended to decrease further, although GL increased the cardiac output. Small dose of PGE1 had no significant effect on pHi. PF treatment showed beneficial effects not only on the cardiac output and the SMA blood flow, but also on pHi. We conclude that PF therapy may restore the intestinal microvascular blood flow. Further study of the effects of PF on tissue oxygenation and blood rheology is warranted.

  18. Uterine prostaglandin concentrations in sheep during late pregnancy and adrenocorticotropin-induced labor

    SciTech Connect

    Evans, C.A.; Kennedy, T.G.; Patrick, J.E.; Challis, J.R.G.

    1981-11-01

    Concentractions of prostaglandin E (PGE), PGF, and 6-oxo-PGF/sub 1..cap alpha../ (the hydrolysis product of PGI/sub 2/) were measured by RIA in different areas of myometrium, endometrium, cotyledons, amnion, and chorioallantoic membrane taken from chronically catheterized sheep. The animals were 130 days pregnant and had been treated for 70 h with continuous intrafetal infusions of either ACTH-(1-24) or saline. Maternal and fetal plasma samples were collected at 8-h intervals beginning 48 h before the start of infusion, and maternal plasma progesterone, estrone, and estradiol and fetal plasma cortisol concentrations were estimated by RIAs. As suggested by a significant fall in maternal plasma progesterone and rises in maternal plasma estrone and fetal plasma cortisol concentrations, sheep receiving intrafetal ACTH were in early labor at the time tissue samples were taken for PG determinations. For myometrium, analysis of variance indicated a significant effect of uterine area of PG concentrations. Concentrations of 6-oxo-PGF/sub 1..cap alpha../ were elevated toward the cervical end of the myometrium in ACTH-treated animals. PGF and PGE concentrations were higher at the tubal and cervical ends of the myometrium in both groups of animals. In the endometrium of treated animals, concentrations of PGE, but not PGF or 6-oxo-PGF/sub 1..cap alpha../, were elevated significantly. For cotyledons and chorioallantois, concentrations of PGF and 6-oxo-PGF/sub 1..cap alpha../, but not PGE, were elevated significantly in ACTH-treated animals. PG concentrations were not elevated in amnion taken from ACTH-treated animals. For both groups, the areas of highest PG concentrations were cotyledons and chorioallantois, suggesting that these may be major sites of synthesis.

  19. Therapy of bovine endometritis with prostaglandin F2α: a meta-analysis.

    PubMed

    Haimerl, P; Heuwieser, W; Arlt, S

    2013-05-01

    The objective of the conducted meta-analysis was to assess the efficacy of the treatment of bovine endometritis with PGF(2α) by statistical means. Postpartum uterine infections have a high prevalence and a very negative effect on reproductive performance in dairy cattle. Because of a wide discordance between research results, a meta-analysis of the efficacy of the treatment of bovine endometritis with PGF(2α) was conducted. A comprehensive literature search was performed using online databases to reveal a total of 2,307 references. In addition, 5 articles were retrieved by reviewing citations. After applying specific exclusion criteria and evaluating specific evidence parameters, 5 publications, comprising 6 trials, were eligible for being analyzed by means of meta-analysis. Data for each trial were extracted and analyzed using meta-analysis software Review Manager (version 5.1; The Nordic Cochrane Centre, Copenhagen, Denmark). Estimated effect sizes of PGF(2α) were calculated on calving to first service and calving to conception interval. Prostaglandin F(2α) treatment of cows with chronic endometritis had a negative effect on both reproductive performance parameters. Heterogeneity was substantial for calving to first service and calving to conception interval [I(2) (measure of variation beyond chance)=100 and 87%, respectively]; therefore, random-effects models were used. Sensitivity analysis as well as subgroup analysis showed that the performance of randomization was influential in modifying effect size of PGF(2α) treatment. The funnel plot illustrated a publication bias toward smaller studies that reported a prolonged calving to conception interval after a PGF(2α) treatment. We conclude that the investigation of this subject by means of meta-analysis did not reveal an improvement of reproductive performance of cows with endometritis after treatment with PGF(2α). Furthermore, there is a shortage of comparable high quality studies investigating

  20. Staphylococcal exopolysaccharides inhibit lymphocyte proliferative responses by activation of monocyte prostaglandin production.

    PubMed Central

    Stout, R D; Ferguson, K P; Li, Y N; Lambe, D W

    1992-01-01

    The glycocalyx (exopolysaccharides) of Staphylococcus epidermidis has been reported to inhibit a variety of host defense mechanisms. We have examined the inhibitory effects of glycocalyx on the proliferation of human peripheral blood mononuclear cells (PBMC) and the mechanism of this inhibition. Glycocalyx isolated and partially purified under endotoxin-free conditions from defined liquid medium cultures of S. epidermidis and Staphylococcus lugdunensis inhibited the proliferative response of PBMC when added to cultures at 10 to 100 micrograms/ml. Glycocalyx-mediated inhibition of phytohemagglutinin-stimulated proliferation of PBMC required the presence of plastic-adherent peripheral blood monocytes. Culture supernatants of monocytes stimulated with glycocalyx contained a soluble factor that inhibited the proliferation of monocyte-depleted PBMC. This soluble inhibitory factor was not produced in the absence of glycocalyx or in the presence of both glycocalyx and indomethacin. Analysis of the supernatants of cultures of adherent monocytes revealed that glycocalyx from S. epidermidis and from S. lugdunensis could activate monocyte production of prostaglandin E2 (PGE2), human interleukin-1, and tumor necrosis factor alpha. The addition of purified PGE2, at the same levels of PGE2 (greater than or equal to 10(-9) M) generated in the monocyte cultures, to PBMC cultures resulted in a similar inhibition of proliferative responses. It is concluded that, contrary to previous suggestions, the bacterial glycocalyx does not have a direct inhibitory effect on T lymphocytes. However, it does appear that glycocalyx from coagulase-negative staphylococci can activate monocyte PGE2 production and that it is this activity that in turn contributes to the inhibition of T-cell proliferation. PMID:1541565

  1. 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.

  2. AH6809, a prostaglandin DP-receptor blocking drug on human platelets.

    PubMed Central

    Keery, R. J.; Lumley, P.

    1988-01-01

    1. The effect of AH6809 (6-isopropoxy-9-oxoxanthene-2-carboxylic acid) has been studied upon the anti-aggregatory and aggregatory actions of various agents on human platelets in whole blood. 2. Prostaglandin D2 (PGD2), BW245C, 9 alpha, 11 beta-PGF2, PGI2 and 5'-N-ethylcarboxamide adenosine (NECA) all inhibited ADP-induced platelet aggregation in whole blood. The anti-aggregatory activity of PGD2, BW245C and 9 alpha, 11 beta-PGF2 but not PGI2 or NECA was antagonized by AH6809. NECA was antagonized by AH6809. 3. The antagonism of the anti-aggregatory activity of PGD2 by AH6809 was concentration-related and could be overcome by increasing the concentration of PGD2. Analysis of the data yielded an apparent pA2 for AH6809 of 5.35. 4. At approximately 10 fold higher concentrations than those required to antagonize the action of PGD2, AH6809 also antagonized the aggregatory effect of U-46619 in whole blood (pA2 = 4.45). However, concentrations of AH6809 up to 300 microM were without effect upon either ADP- or platelet activating factor (Paf)-induced aggregation (pA2 less than 3.5). 5. The potency of AH6809 against PGD2 and U-46619 was increased in a resuspended platelet preparation suggesting that the drug is extensively bound to plasma proteins. However, in resuspended platelets the specificity of AH6809 relative to that seen in whole blood was reduced since aggregation by ADP and Paf was also slightly antagonized. 6. In conclusion, AH6809 appears to be a weak but specific DP-receptor blocking drug on human platelets and should prove to be a useful drug tool for defining the involvement of endogenous PGD2 in platelet aggregation and classifying the mode of action of anti-aggregatory prostanoids. PMID:2460179

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

    PubMed

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

    2014-07-01

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

  4. Overexpressed TRPV3 ion channels in skin keratinocytes modulate pain sensitivity via prostaglandin E2

    PubMed Central

    Huang, Susan M.; Lee, Hyosang; Chung, Man-Kyo; Park, Una; Yu, Yin Yin; Bradshaw, Heather B.; Coulombe, Pierre A.; Walker, J. Michael; Caterina, Michael J.

    2009-01-01

    The ability to sense changes in the environment is essential for survival because it permits responses such as withdrawal from noxious stimuli and regulation of body temperature. Keratinocytes, which occupy much of the skin epidermis, are situated at the interface between the external environment and the body's internal milieu, and have long been appreciated for their barrier function against external insults. The recent discovery of temperature-sensitive TRPV ion channels in keratinocytes has raised the possibility that these cells also actively participate in acute temperature and pain sensation. To address this notion, we generated and characterized transgenic mice that overexpress TRPV3 in epidermal keratinocytes under the control of the keratin 14 promoter. Compared to wild-type controls, keratinocytes overexpressing TRPV3 exhibited larger currents as well as augmented prostaglandin E2 (PGE2) release in response to two TRPV3 agonists, 2-aminoethoxydiphenyl borate (2APB) and heat. Thermal selection behavior and heat-evoked withdrawal behavior of naïve mice overexpressing TRPV3 were not consistently altered. Upon selective pharmacological inhibition of TRPV1 with JNJ-7203212, however, the keratinocyte-specific TRPV3 transgenic mice showed increased escape responses to noxious heat relative to their wild-type littermates. Co-administration of the cyclooxygenase inhibitor, ibuprofen, with the TRPV1 antagonist decreased inflammatory thermal hyperalgesia in transgenic but not wild-type animals. Our results reveal a previously undescribed mechanism for keratinocyte participation in thermal pain transduction through keratinocyte TRPV3 ion channels and the intercellular messenger PGE2. PMID:19091963

  5. Reversal of the Transcriptome by Prostaglandin E2 during Myofibroblast Dedifferentiation

    PubMed Central

    Wettlaufer, Scott H.; Scott, Jacob P.; McEachin, Richard C.; Peters-Golden, Marc

    2016-01-01

    Myofibroblasts, the major effector cells in pathologic fibrosis, derive from the differentiation of fibroblasts driven by mediators such as transforming growth factor-β1 (TGF-β1) and biomechanical signals. Although the myofibroblast has traditionally been considered a terminally differentiated cell, the lipid mediator prostaglandin E2 (PGE2) has been shown to not only prevent but also reverse myofibroblast differentiation, as characterized by the ability of PGE2 to diminish expression of collagen I and α-smooth muscle actin in established myofibroblasts. Here, we use microarrays to examine the extent of transcriptomic changes that occur during TGF-β1–induced differentiation and PGE2-induced dedifferentiation of myofibroblasts. Normal primary human adult lung fibroblasts were cultured for 24 hours with or without TGF-β1 and treated for 48 hours with PGE2. Gene expression levels were assessed from total RNA on the Affymetrix U219 microarray. TGF-β1 up-regulated 588 genes and down-regulated 689 genes compared with control cells. PGE2 reversed the expression of 363 (62%) of the TGF-β1–up-regulated genes and 345 (50%) of the TGF-β1–down-regulated genes. Genes up-regulated by TGF-β1 and reversed by PGE2 were enriched in annotations for Cell Adhesion, Contractile Fiber, and Actin Binding, whereas genes down-regulated by TGF-β1 but subsequently reversed by PGE2 were enriched in annotations for Glycoprotein, Polysaccharide Binding, and Regulation of Cell Migration. Surprisingly, the genes whose expression was affected by PGE2 differed between TGF-β1–induced myofibroblasts and undifferentiated fibroblasts. These data demonstrate the capacity of PGE2 to effect marked global alterations in the transcriptomic program of differentiated myofibroblasts and emphasize the considerable plasticity of these cells. PMID:26098591

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

    PubMed

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

    2012-07-01

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

  7. 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.

  8. 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.

  9. The involvement of prostaglandin E2 in interleukin-1β evoked anorexia is strain dependent.

    PubMed

    Nilsson, Anna; Elander, Louise; Hallbeck, Martin; Örtegren Kugelberg, Unn; Engblom, David; Blomqvist, Anders

    2017-02-01

    From experiments in mice in which the prostaglandin E2 (PGE2) synthesizing enzyme mPGES-1 was genetically deleted, as well as from experiments in which PGE2 was injected directly into the brain, PGE2 has been implicated as a mediator of inflammatory induced anorexia. Here we aimed at examining which PGE2 receptor (EP1-4) that was critical for the anorexic response to peripherally injected interleukin-1β (IL-1β). However, deletion of neither EP receptor in mice, either globally (for EP1, EP2, and EP3) or selectively in the nervous system (EP4), had any effect on the IL-1β induced anorexia. Because these mice were all on a C57BL/6 background, whereas previous observations demonstrating a role for induced PGE2 in IL-1β evoked anorexia had been carried out on mice on a DBA/1 background, we examined the anorexic response to IL-1β in mice with deletion of mPGES-1 on a C57BL/6 background and a DBA/1 background, respectively. We confirmed previous findings that mPGES-1 knock-out mice on a DBA/1 background displayed attenuated anorexia to IL-1β; however, mice on a C57BL/6 background showed the same profound anorexia as wild type mice when carrying deletion of mPGES-1, while displaying almost normal food intake after pretreatment with a cyclooxygenase-2 inhibitor. We conclude that the involvement of induced PGE2 in IL-1β evoked anorexia is strain dependent and we suggest that different routes that probably involve distinct prostanoids exist by which inflammatory stimuli may evoke an anorexic response and that these routes may be of different importance in different strains of mice.

  10. Functional reconstitution of prostaglandin E receptor from bovine adrenal medulla with guanine nucleotide binding proteins

    SciTech Connect

    Negishi, M.; Ito, S.; Yokohama, H.; Hayashi, H.; Katada, T.; Ui, M.; Hayaishi, O.

    1988-05-15

    Prostaglandin E/sub 2/ (PEG/sub 2/) was found to bind specifically to a 100,000 x g pellet prepared from bovine adrenal medulla. The PGE receptor was associated with a GTP-binding protein (G-protein) and could be covalently cross-linked with this G-protein by dithiobis(succinimidyl propionate) in the 100,000 x g pellet. In order to characterize the G-protein associated with the PGE receptor and reconstitute these proteins in phospholipid vesicles, the authors purified the G-protein to apparent homogeneity from the 100,000 x g pellet. The G-protein served as a substrate of pertussis toxin but differed in its ..cap alpha.. subunit from two known pertussis toxin substrate G-proteins (G/sub i/ and G/sub 0/) purified from bovine brain. The molecular weight of the ..cap alpha.. subunit was 40,000, which is between those of G/sub i/ and G/sub 0/. The purified protein was also distinguished immunologically from G/sub i/ and G/sub 0/ and was referred to as G/sub am/. Reconstitution of the PGE receptor with pure C/sub am/, G/sub i/, or G/sub 0/ in phospholipid vesicles resulted in a remarkable restoration of (/sup 3/H)PGE/sub 2/ binding activity in a GTP-dependent manner. The efficiency of these three G-proteins in this capacity was roughly equal. When pertussis toxin- or N-ethylmaleimide-treated G-proteins, instead of the native ones, were reconstituted into vesicles, the restoration of binding activity was no longer observed. These results indicate that the PGE receptor can couple functionally with G/sub am/, G/sub i/, or G/sub 0/ in phospholipid vesicles and suggest that G/sub am/ may be involved in signal transduction of the PGE receptor in bovine adrenal medulla.

  11. Loss of platelet alpha 2-adrenergic receptors during simulated extracorporeal circulation: prevention with prostaglandin E1

    SciTech Connect

    Wachtogel, Y.T.; Musial, J.; Jenkin, B.; Niewiarowski, S.; Edmunds, L.H. Jr.; Colman, R.W.

    1985-05-01

    Cardiopulmonary bypass prolongs bleeding time and increases postoperative blood loss. During in vitro recirculation in an extracorporeal circuit containing a membrane oxygenator and primed with fresh heparinized human blood, the authors previously observed t