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Sample records for prostaglandin transporter slco2a1

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

    PubMed Central

    Nakanishi, Takeo; 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. PMID:25923111

  2. A Hereditary Enteropathy Caused by Mutations in the SLCO2A1 Gene, Encoding a Prostaglandin Transporter

    PubMed Central

    Esaki, Motohiro; Hirano, Atsushi; Kubokura, Naoya; Asano, Kouichi; Kochi, Shuji; Yanai, Shunichi; Fuyuno, Yuta; Shimamura, Katsuyoshi; Hosoe, Naoki; Ogata, Haruhiko; Watanabe, Takashi; Aoyagi, Kunihiko; Ooi, Hidehisa; Watanabe, Kenji; Yasukawa, Shigeyoshi; Hirai, Fumihito; Matsui, Toshiyuki; Iida, Mitsuo; Yao, Tsuneyoshi; Hibi, Toshifumi; Kosaki, Kenjiro; Kanai, Takanori; Kitazono, Takanari; Matsumoto, Takayuki

    2015-01-01

    Previously, we proposed a rare autosomal recessive inherited enteropathy characterized by persistent blood and protein loss from the small intestine as chronic nonspecific multiple ulcers of the small intestine (CNSU). By whole-exome sequencing in five Japanese patients with CNSU and one unaffected individual, we found four candidate mutations in the SLCO2A1 gene, encoding a prostaglandin transporter. The pathogenicity of the mutations was supported by segregation analysis and genotyping data in controls. By Sanger sequencing of the coding regions, 11 of 12 other CNSU patients and 2 of 603 patients with a diagnosis of Crohn’s disease were found to have homozygous or compound heterozygous SLCO2A1 mutations. In total, we identified recessive SLCO2A1 mutations located at seven sites. Using RT-PCR, we demonstrated that the identified splice-site mutations altered the RNA splicing, and introduced a premature stop codon. Tracer prostaglandin E2 uptake analysis showed that the mutant SLCO2A1 protein for each mutation exhibited impaired prostaglandin transport. Immunohistochemistry and immunofluorescence analyses revealed that SLCO2A1 protein was expressed on the cellular membrane of vascular endothelial cells in the small intestinal mucosa in control subjects, but was not detected in affected individuals. These findings indicate that loss-of-function mutations in the SLCO2A1 gene encoding a prostaglandin transporter cause the hereditary enteropathy CNSU. We suggest a more appropriate nomenclature of “chronic enteropathy associated with SLCO2A1 gene” (CEAS). PMID:26539716

  3. Prostaglandin transporters ABCC4 and SLCO2A1 in the uterine endometrium and conceptus during pregnancy in pigs.

    PubMed

    Seo, Heewon; Choi, Yohan; Shim, Jangsoo; Yoo, Inkyu; Ka, Hakhyun

    2014-05-01

    Prostaglandins (PGs) are involved in many reproductive activities including luteolysis, maternal recognition of pregnancy, endometrial gene expression, conceptus development, and parturition in domestic animals. However, mechanisms by which PGE2 and PGF2alpha are modulated in the uterine endometrium and expression of ABCC4 and SLCO2A1, responsible for efficient transport of PGs across the cell membrane, in the endometrium during the estrous cycle and pregnancy are not fully understood in pigs. Therefore, we determined expression of ABCC4 and SLCO2A1, genes involved in transport of PGE2 and PGF2alpha in the uterine endometrium during the estrous cycle and pregnancy in pigs. ABCC4 and SLCO2A1 mRNAs were expressed in the uterine endometrium, most abundantly on Day 12 of pregnancy and during late pregnancy. Expression of ABCC4 mRNA and protein was localized mainly to uterine luminal epithelial (LE) and glandular epithelial (GE) cells, and expression of SLCO2A1 mRNA and protein was expressed primarily in uterine LE and blood vessels. Expression of ABCC4 and SLCO2A1 mRNAs was also detected in conceptuses during early pregnancy. In addition, explant culture experiments showed that increasing doses of interleukin 1B (IL1B) with estrogen and progesterone increased levels of ABCC4 and SLCO2A1 mRNAs in the uterine endometrium. These results indicate that expression of genes responsible for transport of PGE2 and PGF2alpha are dynamically regulated in the uterine endometrium during pregnancy and that ABCC4 and SLCO2A1 play critical roles in supporting the establishment and maintenance of pregnancy by regulating PG transport at the maternal-fetal interface in pigs. PMID:24695625

  4. 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

  5. Exome Sequencing Identifies SLCO2A1 Mutations as a Cause of Primary Hypertrophic Osteoarthropathy

    PubMed Central

    Zhang, Zhenlin; Xia, Weibo; He, Jinwei; Zhang, Zeng; Ke, Yaohua; Yue, Hua; Wang, Chun; Zhang, Hao; Gu, Jiemei; Hu, Weiwei; Fu, Wenzhen; Hu, Yunqiu; Li, Miao; Liu, Yujuan

    2012-01-01

    By using whole-exome sequencing, we identified a homozygous guanine-to-adenine transition at the invariant −1 position of the acceptor site of intron 1 (c.97−1G>A) in solute carrier organic anion transporter family member 2A1 (SLCO2A1), which encodes a prostaglandin transporter protein, as the causative mutation in a single individual with primary hypertrophic osteoarthropathy (PHO) from a consanguineous family. In two other affected individuals with PHO from two unrelated nonconsanguineous families, we identified two different compound heterozygous mutations by using Sanger sequencing. These findings confirm that SLCO2A1 mutations inactivate prostaglandin E2 (PGE2) transport, and they indicate that mutations in SLCO2A1 are the pathogenic cause of PHO. Moreover, this study might also help to explain the cause of secondary hypertrophic osteoarthropathy. PMID:22197487

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

    PubMed Central

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

    2015-01-01

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

  7. Interplacental uterine expression of genes involved in prostaglandin synthesis during canine pregnancy and at induced prepartum luteolysis/abortion

    PubMed Central

    2014-01-01

    Background In the non-pregnant dog, ovarian cyclicity is independent of a uterine luteolysin. This is in contrast to pregnant animals where a prepartum increase of luteolytic PGF2α occurs, apparently originating in the pregnant uterus. Recently, the placenta as a source of prepartum prostaglandins (PGs) was investigated, indicating fetal trophoblast cells as the likely main source. However, the possible contribution of uterine interplacental tissues to the production of these hormones has not yet been thoroughly examined in the dog. Methods Several key factors involved in the production and/or actions of PGs were studied: cyclooxygenase 2 (COX2, PTGS2), PGF2α-synthase (PGFS/AKR1C3), PGE2-synthase (PGES), and the respective receptors FP (PTGFR), EP2 (PTGER2) and EP4 (PGTER4), 15-hydroxyprostaglandin dehydrogenase (HPGD), PG-transporter (PGT, SLCO2A1) and progesterone receptor. Their expression and localization patterns were assessed by Real Time PCR and immunohistology in the interplacental uterine sites from pregnant dogs during the pre-implantation period (days 8–12), post-implantation (days 18–25), mid-gestation (days 35–40) and during antigestagen-induced luteolysis/abortion. Results Whereas only low COX2 expression was observed in uterine samples at all the selected time points, expression of PGFS/AKR1C3 strongly increased post-implantation. A gradual increase in PGES-mRNA expression was noted towards mid-gestation. FP-mRNA expression decreased significantly with the progression of pregnancy until mid-gestation. This was associated with clearly detectable expression of HPGD, which did not change significantly over time. The expression of FP and EP2-mRNA decreased significantly over time while EP4-mRNA expression remained unaffected. The antigestagen-treatment led to a significant increase in expression of COX2, PGES, EP2 and PGT (SLCO2A1) mRNA. COX2 was localized predominantly in the myometrium. The expression of PGFS/AKR1C3, which was unchanged, was

  8. Prostaglandin signaling regulates ciliogenesis by modulating intraflagellar transport

    PubMed Central

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

    2014-01-01

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

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

    PubMed

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

    2016-05-11

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

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

    PubMed Central

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

    2015-01-01

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

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

    PubMed Central

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

    2015-01-01

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

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

    PubMed Central

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

    2016-01-01

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

  13. 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

  14. Effect of prostaglandin E2 on multidrug resistance transporters in human placental cells.

    PubMed

    Mason, Clifford W; Lee, Gene T; Dong, Yafeng; Zhou, Helen; He, Lily; Weiner, Carl P

    2014-12-01

    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

  15. The Prostaglandin Transporter: Eicosanoid Reuptake, Control of Signaling, and Development of High-Affinity Inhibitors as Drug Candidates

    PubMed Central

    Schuster, Victor L.; Chi, Yuling; Lu, Run

    2015-01-01

    We discovered the prostaglandin transporter (PGT) and cloned the human cDNA and gene. PGT transports extracellular prostaglandins (PGs) into the cytoplasm for enzymatic inactivation. PGT knockout mice have elevated prostaglandin E2 (PGE2) and neonatal patent ductus arteriosus, which reflects PGT's control over PGE2 signaling at EP1/EP4 cell-surface receptors. Interestingly, rescued PGT knockout pups have a nearly normal phenotype, as do human PGT nulls. Given the benign phenotype of PGT genetic nulls, and because PGs are useful medicines, we have approached PGT as a drug target. Triazine library screening yielded a lead compound of inhibitory constant 50% (IC50) = 3.7 μM, which we developed into a better inhibitor of IC50 378 nM. Further structural improvements have yielded 26 rationally designed derivatives with IC50 < 100 nM. The therapeutic approach of increasing endogenous PGs by inhibiting PGT offers promise in diseases such as pulmonary hypertension and obesity. PMID:26330684

  16. Treatment of obesity and pulmonary arterial hypertension with inhibitors of the prostaglandin transporter: evaluation of patent WO2014/204895A1.

    PubMed

    Dingemanse, Jasper; Bolli, Martin; Iglarz, Marc

    2015-01-01

    Prostaglandins display a wide array of pharmacological effects and prostaglandin analogs are already used in the treatment of pulmonary arterial hypertension (PAH). After synthesis and release from cells, prostaglandins undergo reuptake by the prostaglandin transporter (PGT). WO2014/204895 claims the use of a series of trisubstituted triazine derivatives for the treatment of obesity and PAH. Composition of matter of these triazines has been claimed in WO2011/037610 and the compounds are described as potent inhibitors of the PGT. One compound (nr 146) was shown to improve high fat diet-induced glucose tolerance in a mouse model. In addition, this compound has been explored in the rat monocrotaline model of PAH and reduced characteristic features of the pathology. This class of compounds presents a potential new treatment paradigm in the treatment of obesity-related disorders and PAH. PMID:26099857

  17. 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

  18. Central nervous system influence of prostaglandin E2 on jejunal water and electrolyte transport in conscious dogs.

    PubMed

    Primi, M P; Bueno, L

    1986-12-01

    The effects of intracerebroventricular (i.c.v.) vs. i.v. administration of prostaglandin E2 (PGE2) on net fluxes of water, Na+, and K+ through a jejunal Thiry-Vella loop were investigated before or after previous treatment with adrenergic blockers, indomethacin, and 8-(N,N-diethylamino)octyl-3,4,5-trimethoxybenzoate hydrochloride (TMB8) in conscious dogs. Administered intracerebroventricularly at doses of 20-100 ng/kg, PGE2 significantly reduced (p less than 0.01), in a dose-related manner, the net fluxes of water, Na+, and K+, which were reversed from an absorption to a secretion. Intravenously administered PGE2 at a five times higher dosage failed to significantly alter net water and electrolyte fluxes. Phentolamine (0.2 mg/kg body wt) and tolazoline (2 mg/kg body wt) administered intravenously abolished the secretory effects of centrally administered PGE2 (50 ng/kg). However, 10 times lower dosages of phentolamine and tolazoline administered intracerebroventricularly did not prevent the PGE2-induced secretion of water and electrolytes. Intracerebroventricular administration of indomethacin (10 micrograms/kg body wt) and TMB8 (1 microgram/kg body wt), did not modify the effect of i.c.v.-administered PGE2; however, indomethacin administered intracerebroventricularly alone stimulated water and electrolyte absorption. None of these treatments results in a significant (p greater than 0.05) change in mean transit time through the Thiry-Vella loop. We conclude that centrally administered PGE2 influences jejunal water, Na+, and K+ absorption, through a mechanism related to adrenergic innervation and/or involving at least alpha 2-adrenoceptors. The results also suggest that PGE2 in the central nervous system controls jejunal water and ion transport in the dog. PMID:3464524

  19. Sperm transport through the rete testis in anesthetized rats: role of the testicular capsule and effect of gonadotropins and prostaglandins

    SciTech Connect

    Free, M.J.; Jaffe, R.A.; Morford, D.E.

    1980-01-01

    An intact testicular capsule was not necessary for flow of rete testis fluid in anesthetized rats fitted with efferent duct cannulae. Flow was unaffected by i.v. injections of FSH, LH or prolactin, or by intratesticular injections of prostaglandin E/sub 1/, E/sub 2/ or A/sub 1/. However, small increases in intratesticular pressure resulting from injection of 2 to 20 ..mu..l saline resulted in transient (3 to 7 min) increases in flow rate, while PGF/sub 2..cap alpha../ increased rete testis fluid flow 2 to 3-fold over a 20 to 40 min period. PGF/sub 2..cap alpha../ effect was reduced or eliminated when the testicular capsule was cut open. Sperm concentration in the rete fluid was unaffected by any of the treatments mentioned above, suggesting that spermiation was unaffected. In hypophysectomized rats given replacement androgens for 8 weeks (2.5 to 25 mg testosterone propionate/day), sperm concentration in rete fluid was similar to normal, although rate of fluid flow, and therefore sperm output rates, were significantly reduced. These data suggest a link between testicular fluid production and sperm release in the rat.

  20. Prostaglandins and prostaglandin receptor antagonism in migraine.

    PubMed

    Antonova, Maria

    2013-05-01

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

  1. Prostaglandins: pharmacology and clinical application.

    PubMed

    Karim, S M; Hillier, K

    1974-01-01

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

  2. Misidentification of prostamides as prostaglandins.

    PubMed

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

    2005-07-01

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

  3. Diverse Roles of Prostaglandins in Blastocyst Implantation

    PubMed Central

    2014-01-01

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

  4. Prostaglandins, bioassay and inflammation

    PubMed Central

    Flower, R J

    2006-01-01

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

  5. Atrial natriuretic peptide(31-67) inhibits Na+ transport in rabbit inner medullary collecting duct cells. Role of prostaglandin E2.

    PubMed Central

    Gunning, M E; Brady, H R; Otuechere, G; Brenner, B M; Zeidel, M L

    1992-01-01

    Atrial natriuretic peptide (ANP)(31-67), a portion of the atrial peptide prohormone, circulates in humans, and its plasma level varies with atrial pressure. Like the more widely studied carboxy-terminal fragment ANP(99-126), ANP(31-67) stimulates natriuresis and diuresis. We examined the mechanism of this natriuresis by measuring the effects of ANP(31-67) on Na+ transport in cells of the rabbit inner medullary collecting duct (IMCD). ANP(31-67) (10(-8) M) caused a 26 +/- 4% inhibition of oxygen consumption (QO2); half-maximal inhibition occurred at 10(-11) M, suggesting a physiologic effect. This effect was not additive with either ouabain or amiloride, suggesting that it reflected inhibition of Na+ transport-dependent QO2. ANP(31-67) reduced the amphotericin-induced stimulation of QO2 consistent with inhibition by this peptide of the Na(+)-K(+)-ATPase. In addition, ANP(31-67) reduced ouabain-sensitive 86Rb+ uptake under Vmax conditions. Several lines of evidence indicated that PGE2, a known endogenous IMCD Na(+)-K(+)-ATPase inhibitor, mediates pump inhibition by ANP(31-67). Thus, ANP(31-67) inhibits Na+ transport by inhibiting the Na(+)-K(+)-ATPase of IMCD cells, an effect mediated by the generation of PGE2. PMID:1533229

  6. [Prostaglandins in gynecology and obstetrics].

    PubMed

    Klausch, B; Kyank, H

    1972-06-01

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

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

    PubMed

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

    2010-01-01

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

  8. Anorectic activity of prostaglandin precursors.

    PubMed Central

    Doggett, N S; Jawaharlal, K

    1977-01-01

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

  9. The Enteropathy of Prostaglandin Deficiency

    PubMed Central

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

    2009-01-01

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

  10. The current status of prostaglandins as abortifacients.

    PubMed

    Brenner, W E

    1975-10-01

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

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

    PubMed

    Zwergel, U; Zwergel, T; Ziegler, M

    1991-01-01

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

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

    PubMed Central

    Hawkey, C J

    1986-01-01

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

  13. 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...

  14. Prostaglandins and mechanisms of preterm birth.

    PubMed

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

    2002-07-01

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

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

    PubMed Central

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

    2015-01-01

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

  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. Prostaglandin E1 in hand angiography

    SciTech Connect

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

    1983-11-01

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

  18. Prostaglandin E3 metabolism and cancer

    PubMed Central

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

    2015-01-01

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

  19. Endogenous prostaglandin in guinea pig taenia coli.

    PubMed

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

    1976-01-01

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

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

    PubMed

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

    2006-08-01

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

  1. 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.

  2. Clinical applications of prostaglandins in Obstetrics and Gynaecology.

    PubMed

    Karim, S M

    1982-10-01

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

  3. 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

  4. 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

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

    PubMed

    Bito, L Z; Salvador, E V

    1976-08-01

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

  6. Reversible Conjunctival Pigmentation Associated With Prostaglandin Use.

    PubMed

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

    2016-01-01

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

  7. Prostaglandin dehydrogenase and the initiation of labor.

    PubMed

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

    1999-01-01

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

  8. Prostaglandins: a report on early clinical studies

    PubMed Central

    Hinman, J. W.

    1970-01-01

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

  9. 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

  10. Effects of Prostaglandin Analogues on Aqueous Humor Outflow Pathways

    PubMed Central

    Winkler, Nelson S.

    2014-01-01

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

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

    PubMed

    Sinzinger, H; Oguogho, A; Kaliman, J

    1997-09-01

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

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

    PubMed

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

    1983-08-01

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

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

    PubMed

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

    2012-07-01

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

  14. 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.

  15. Simulated microgravity upregulates an endothelial vasoconstrictor prostaglandin.

    PubMed

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

    2001-08-01

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

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

    PubMed

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

    2008-08-01

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

  17. 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

  18. 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.

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

    PubMed Central

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

    1975-01-01

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

  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. Many Putative Endocrine Disruptors Inhibit Prostaglandin Synthesis

    PubMed Central

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

    2011-01-01

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

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

    PubMed Central

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

    1979-01-01

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

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

    PubMed

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

    1988-01-01

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

  4. 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

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

    PubMed

    Neacsu, Alina Mihaela

    2009-01-01

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

  6. Transportation.

    ERIC Educational Resources Information Center

    Crank, Ron

    This instructional unit is one of 10 developed by students on various energy-related areas that deals specifically with transportation and energy use. Its objective is for the student to be able to discuss the implication of energy usage as it applies to the area of transportation. Some topics covered are efficiencies of various transportation…

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

    PubMed

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

    2012-12-01

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

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

    PubMed

    Binda, Chantal; Parent, Jean-Luc

    2015-01-01

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

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

    PubMed

    Sánchez, T; Moreno, J J

    1999-04-01

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

  10. Reducing prostaglandin E2 production to raise cancer immunogenicity

    PubMed Central

    Zelenay, Santiago; Reis e Sousa, Caetano

    2016-01-01

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

  11. Reducing prostaglandin E2 production to raise cancer immunogenicity.

    PubMed

    Zelenay, Santiago; Reis E Sousa, Caetano

    2016-05-01

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

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

    PubMed

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

    2004-05-01

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

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

    PubMed

    Nordmann, J-P

    2005-06-01

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

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

    PubMed

    Bryman, I; Norström, A; Lindblom, B

    1986-04-01

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

  15. 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

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

    PubMed

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

    2016-07-01

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

  17. 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.

  18. A severe phenotype of Gitelman syndrome with increased prostaglandin excretion and favorable response to indomethacin

    PubMed Central

    Larkins, Nicholas; Wallis, Mathew; McGillivray, Barbara; Mammen, Cherry

    2014-01-01

    Our understanding of Gitelman syndrome (GS) and Bartter syndrome has continued to evolve with the use of genetic testing to more precisely define the tubular defects responsible. GS is caused by mutations in the SLC12A3 gene encoding the Na+–Cl− co-transporter of the distal convoluted tubule (NCCT) and tends to be associated with a milder salt-losing phenotype. We describe two female siblings presenting in infancy with a severe salt-losing tubulopathy and failure to thrive due to compound heterozygous mutations in the SLC12A3 gene encoding the NCCT. Both children were treated with indomethacin resulting in improved linear growth and polyuria. Some atypical biochemical findings in our cases are discussed including raised urinary prostaglandin (PGE2) excretion that normalized with intravenous fluid repletion. PMID:25852896

  19. Prostaglandin uptake and metabolism by the perfused rat liver

    PubMed Central

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

    1970-01-01

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

  20. 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.

  1. 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

  2. Cytoprotective effect of prostaglandin E2 in irradiated rat ileum

    SciTech Connect

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

    1984-01-01

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

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

    SciTech Connect

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

    1986-03-01

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

  4. 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.

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

    PubMed Central

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

    2010-01-01

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

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

    PubMed Central

    Feldberg, W; Saxena, P N

    1975-01-01

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

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

    PubMed

    Bygdeman, M

    1984-12-01

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

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

    SciTech Connect

    Patterson, J.W. )

    1990-09-28

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

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

    PubMed

    Lau, S S; Monks, T J

    1987-01-01

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

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

    PubMed Central

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

    2016-01-01

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

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

    PubMed Central

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

    1990-01-01

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

  12. Human brain prostaglandin D synthase has been evolutionarily differentiated from lipophilic-ligand carrier proteins.

    PubMed Central

    Nagata, A; Suzuki, Y; Igarashi, M; Eguchi, N; Toh, H; Urade, Y; Hayaishi, O

    1991-01-01

    cDNAs for glutathione-independent prostaglandin D synthase were isolated from cDNA libraries of human brain. The longest cDNA insert was 837 base pairs long and contained a coding region of 570 base pairs corresponding to 190 amino acid residues with a calculated Mr of 21,016. Between two cDNA inserts isolated from the two different libraries, nucleotide substitutions were observed at 16 positions, including conservative amino acid substitutions at 2 positions and nonconservative substitutions at 5 positions, indicating genetic heterogeneity of this enzyme in humans. The computer-assisted homology search revealed that the enzyme is a member of the lipocalin superfamily, comprising secretory hydrophobic molecule transporters, showing the greatest homology (28.8-29.4% identity; 51.3-53.1% similarity) to alpha 1-microglobulin among the members of this superfamily. In a phylogenetic tree of the superfamily, this enzyme, alpha 1-microglobulin, and the gamma chain of the complement component C8 form a cluster separate from the other 14 members. The two distinctive characteristics of glutathione-independent prostaglandin D synthase, as compared to the other members of this superfamily, are its enzymatic properties and its association with membranes that were probably acquired after evolutionary divergence of the two lipocalins. Based on the observed sequence homology, the tertiary structure of the enzyme was deduced to consist of an eight-stranded anti-parallel beta-barrel forming a hydrophobic pocket. Furthermore, the Cys-65 residue in the pocket, which is conserved only in the human and rat enzymes but not in other lipocalins, was considered to be a putative active site of the enzyme. Images PMID:1902577

  13. The Distribution of Prostaglandins in Afferent and Efferent Lymph From Inflammatory Sites

    PubMed Central

    Johnston, Miles G.; Hay, John B.; Movat, Henry

    1980-01-01

    Arachidonic acid labeled with 14C was injected directly into lymph nodes that had been stimulated at various times with Escherichia coli. The efferent lymph was collected, and labeled catabolites were extracted and analyzed chromatographically. The pimary conversion product recovered was Prostaglandin E2 (PGE2), with the lesser products thromboxane, prostacyclin and prostaglandin F2α (PGF2α) also detected. When the efferent lymph was analyzed by radioimmunoassay after subcutaneous injectino of E coli into the hock, PGE and PGF levels rapidly increased, reached the highest levels in the first 10 hours, and then returned to normal by 24 hours. When the afferent lymph plasma draining inflammatory sites was compared directly with efferent lymph, PGF levels were similar, but the PGE level was always several times higher in the afferent lymph. To examine the catabolism of PG, either 3,H-PGF2ά of 3H-PGE2 was injected into the node, and the efferent lymph plasma was analyzed. No conversion of PGF2α to other products was found. In contrast, catabolic products of PGE2 were detected. With the use of equilibrium dialysis techniques, the binding of PGE2 and PGF2α to proteins in lymph and to bovine serum albumin (BSA), human serum albumin (HSA), and BSA stripped of its fatty acids was established. The binding to lymph proteins correlated with the albumin concentrations in the lymph. This albumin binging probably facilitated the retention and transport of PG in the lymph. PG appears in the lymph at a time corresponding to the uptake and processing of antigen by the node and near the time when lymphokines are detected in lymph and could modulate several steps in the immune response. The PGE detectable in the lymph draining an inflammatory site may play a role in the modulation of blood flow. PMID:6992593

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

    PubMed

    Kanda, Naoko; Ishikawa, Takeko; Watanabe, Shinichi

    2010-04-01

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

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

    PubMed

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

    1985-01-01

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

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

    SciTech Connect

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

    1984-05-01

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

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

    PubMed

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

    2005-01-01

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

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

    PubMed Central

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

    2009-01-01

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

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

    PubMed

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

    2016-07-01

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

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

    PubMed

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

    1986-01-01

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

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

    PubMed

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

    1984-03-01

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

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

    PubMed

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

    1992-04-01

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

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

    PubMed

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

    1997-03-14

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

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

    PubMed

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

    2015-10-20

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

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

    PubMed Central

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

    2011-01-01

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

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

    PubMed Central

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

    2015-01-01

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

  7. Canine gastric mucosal vasodilation with prostaglandins and histamine analogs

    SciTech Connect

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

    1982-10-01

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

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

    PubMed Central

    Seebacher, Frank; Franklin, Craig E

    2003-01-01

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

  9. Direct evidence of the cyclooxygenase pathway of prostaglandin synthesis in arthropods: genetic and biochemical characterization of two crustacean cyclooxygenases.

    PubMed

    Varvas, Külliki; Kurg, Reet; Hansen, Kristella; Järving, Reet; Järving, Ivar; Valmsen, Karin; Lõhelaid, Helike; Samel, Nigulas

    2009-12-01

    Prostaglandins, well-known lipid mediators in vertebrate animals, have also shown to play certain regulatory roles in insects and other arthropods acting on reproduction, immune system and ion transport. However, knowledge of their biosynthetic pathways in arthropods is lacking. In the present study, we report the cloning and expression of cyclooxygenase (COX) from amphipod crustaceans Gammarus spp and Caprella spp. The amphipod COX proteins contain key residues shown to be important for cyclooxygenase and peroxidase activities. Differently from all other known cyclooxygenases the N-terminal signal sequence of amphipod enzymes is not cleaved during protein expression in mammalian cells. The C-terminus of amphipod COX is shorter than that of mammalian isoforms and lacks the KDEL(STEL)-type endoplasmic reticulum retention/retrieval signal. Despite that, amphipod COX proteins are N-glycosylated and locate similarly to the vertebrate COX on the endoplasmic reticulum and nuclear envelope. Both amphipod COX mRNAs encode functional cyclooxygenases that catalyze the transformation of arachidonic acid into prostaglandins. Using bioinformatic analysis we identified a COX-like gene from the human body louse Pediculus humanus corporis genome that encodes a protein with about 30% sequence identity with human COX-1 and COX-2. Although the COX gene is known to be absent from genomes of Drosophila sp., Aedes aegypti, Bombyx mori, and other insects, our studies establish the existence of the COX gene in certain lineages within the insect world. PMID:19854273

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

    PubMed

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

    2014-09-01

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

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

    PubMed

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

    2013-01-01

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

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

    PubMed

    Takeuchi, K; Kogo, H; Aizawa, Y

    1981-04-01

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

  13. Metabolism of prostaglandin E1 in dog kidneys

    PubMed Central

    Nakano, J.

    1970-01-01

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

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

    SciTech Connect

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

    1986-05-01

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

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

    PubMed Central

    Kim, Sangwon F.

    2011-01-01

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

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

    PubMed Central

    Zhang, Zhenyu; Lou, Jiangyan

    2015-01-01

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

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

    PubMed

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

    1990-12-01

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

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

    PubMed

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

    1977-04-15

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

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

    PubMed

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

    1991-05-01

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

  20. 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.

  1. Activation of prostaglandin EP receptors by lubiprostone in rat and human stomach and colon

    PubMed Central

    Bassil, A K; Borman, R A; Jarvie, E M; McArthur-Wilson, R J; Thangiah, R; Sung, E Z H; Lee, K; Sanger, G J

    2008-01-01

    Background and purpose: Lubiprostone (Amitiza), a possible ClC-2 channel opener derived from prostaglandin E1 and indicated for the treatment of constipation, increases chloride ion transport and fluid secretion into the intestinal lumen. As lubiprostone may also directly modulate gastrointestinal motility, we investigated its actions and the possible involvement of prostaglandin EP receptor activation on rat and human isolated gastrointestinal preparations. Experimental approach: Rat and human isolated preparations were mounted in tissue baths for isometric recording. The effects of lubiprostone on muscle tension and on electrically stimulated, neuronal contractions were investigated in the absence and presence of EP receptor antagonists. Key results: In rat and human stomach longitudinal muscle, lubiprostone induced a contraction (pEC50 of 7.0±0.0, n=4 and 6.4±0.2, n=3, respectively), which was inhibited by pretreatment with the EP1 receptor antagonist, EP1A 300 nM (pEC50 reduced to 6.2±0.2, n=6), but not by the EP3 or EP4 receptor antagonists (L-798106 and GW627368X, respectively, 1 μM, P>0.05). Lubiprostone also reduced electrically stimulated, neuronal contractions in rat and human colon circular muscle preparations (pIC50 of 8.9±0.4, n=7 and 8.7±0.9, n=6, respectively), an effect mediated pre-junctionally. This effect was reduced by the EP4 receptor antagonist (pIC50 of 6.7±1.1, n=7 and 7.7±0.4, n=6, respectively) but not by EP1 or EP3 receptor antagonists. Conclusions and implications: In rats and humans, lubiprostone contracts stomach longitudinal muscle and inhibits neuronally mediated contractions of colon circular muscle. Experiments are now needed to determine if this additional activity of lubiprostone contributes to its clinical efficacy and/or side-effect profile. PMID:18332851

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

    PubMed

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

    1991-05-01

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

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

    PubMed

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

    2014-09-12

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

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

    PubMed Central

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

    1979-01-01

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

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

    PubMed

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

    1998-07-31

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

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

    PubMed Central

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

    2014-01-01

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

  7. Novel concepts on the role of prostaglandins on luteal maintenance and maternal recognition and establishment of pregnancy in ruminants.

    PubMed

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

    2016-07-01

    In ruminants, the corpus luteum (CL) of early pregnancy is resistant to luteolysis. Prostaglandin (PG)E2 is considered a luteoprotective mediator. Early studies indicate that during maternal recognition of pregnancy (MRP) in ruminants, a factor(s) from the conceptus or gravid uterus reaches the ovary locally through the utero-ovarian plexus (UOP) and protects the CL from luteolysis. The local nature of the embryonic antiluteolytic or luteoprotective effect precludes any direct effect of a protein transported or acting between the gravid uterus and CL in ruminants. During MRP, interferon tau (IFNT) secreted by the trophoblast of the conceptus inhibits endometrial pulsatile release of PGF2α and increases endometrial PGE2. Our recent studies indicate that (1) luteal PG biosynthesis is selectively directed toward PGF2α at the time of luteolysis and toward PGE2 at the time of establishment of pregnancy (ESP); (2) the ability of the CL of early pregnancy to resist luteolysis is likely due to increased intraluteal biosynthesis and signaling of PGE2; and (3) endometrial PGE2 is transported from the uterus to the CL through the UOP vascular route during ESP in sheep. Intrauterine co-administration of IFNT and prostaglandin E2 synthase 1 (PGES-1) inhibitor reestablishes endometrial PGF2α pulses and regresses the CL. In contrast, intrauterine co-administration of IFNT and PGES-1 inhibitor along with intraovarian administration of PGE2 rescues the CL. Together, the accumulating information provides compelling evidence that PGE2 produced by the CL in response to endometrial PGE2 induced by pregnancy may counteract the luteolytic effect of PGF2α as an additional luteoprotective mechanism during MRP or ESP in ruminants. Targeting PGE2 biosynthesis and signaling selectively in the endometrium or CL may provide luteoprotective therapy to improve reproductive efficiency in ruminants. PMID:27179861

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

    PubMed

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

    2012-07-01

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

  9. Prostaglandin synthesis by chicken and rat lung microsomes

    SciTech Connect

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

    1986-03-01

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

  10. Developmental changes of prostaglandin processing in rat small intestine

    SciTech Connect

    Koldovsky, O.; Bedrick, A.

    1986-03-01

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

  11. 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.

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

    PubMed

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

    2015-01-01

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

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

    PubMed

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

    1988-05-01

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

  14. 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.

  15. Influence of prostaglandin E2 on parturition in cattle.

    PubMed

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

    2007-09-22

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

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

    PubMed

    Schmidt, R S

    1993-03-01

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

  17. Renal Effects of Prostaglandins and Cyclooxygenase-2 Inhibitors

    PubMed Central

    2008-01-01

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

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

    PubMed

    Fretland, D J; Cammarata, P S

    1984-04-01

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

  19. 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

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

    PubMed

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

    1987-07-20

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

  1. 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.

  2. 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.

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

    PubMed Central

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

    2013-01-01

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

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

    PubMed Central

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

    1989-01-01

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

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

    PubMed Central

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

    1977-01-01

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

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

    PubMed Central

    Coleman, R. A.; Kennedy, I.

    1980-01-01

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

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

    PubMed Central

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

    2014-01-01

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

  8. A Cyclooxygenase-2-dependent Prostaglandin E2 Biosynthetic System in the Golgi Apparatus*

    PubMed Central

    Yuan, Chong; Smith, William L.

    2015-01-01

    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 Ca2+ 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. PMID:25548276

  9. Opposing effects of nitric oxide and prostaglandin inhibition on muscle mitochondrial Vo(2) during exercise.

    PubMed

    Boushel, Robert; Fuentes, Teresa; Hellsten, Ylva; Saltin, Bengt

    2012-07-01

    Nitric oxide (NO) and prostaglandins (PG) together play a role in regulating blood flow during exercise. NO also regulates mitochondrial oxygen consumption through competitive binding to cytochrome-c oxidase. Indomethacin uncouples and inhibits the electron transport chain in a concentration-dependent manner, and thus, inhibition of NO and PG synthesis may regulate both muscle oxygen delivery and utilization. The purpose of this study was to examine the independent and combined effects of NO and PG synthesis blockade (L-NMMA and indomethacin, respectively) on mitochondrial respiration in human muscle following knee extension exercise (KEE). Specifically, this study examined the physiological effect of NO, and the pharmacological effect of indomethacin, on muscle mitochondrial function. Consistent with their mechanism of action, we hypothesized that inhibition of nitric oxide synthase (NOS) and PG synthesis would have opposite effects on muscle mitochondrial respiration. Mitochondrial respiration was measured ex vivo by high-resolution respirometry in saponin-permeabilized fibers following 6 min KEE in control (CON; n = 8), arterial infusion of N(G)-monomethyl-L-arginine (L-NMMA; n = 4) and Indo (n = 4) followed by combined inhibition of NOS and PG synthesis (L-NMMA + Indo, n = 8). ADP-stimulated state 3 respiration (OXPHOS) with substrates for complex I (glutamate, malate) was reduced 50% by Indo. State 3 O(2) flux with complex I and II substrates was reduced less with both Indo (20%) and L-NMMA + Indo (15%) compared with CON. The results indicate that indomethacin reduces state 3 mitochondrial respiration primarily at complex I of the respiratory chain, while blockade of NOS by L-NMMA counteracts the inhibition by Indo. This effect on muscle mitochondria, in concert with a reduction of blood flow accounts for in vivo changes in muscle O(2) consumption during combined blockade of NOS and PG synthesis. PMID:22552792

  10. 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.

  11. Opposing roles of Prostaglandin D2 receptors in ulcerative colitis

    PubMed Central

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

    2014-01-01

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

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

    PubMed

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

    2016-06-01

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

  13. Reversal of Myofibroblast Differentiation by Prostaglandin E2

    PubMed Central

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

    2013-01-01

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

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

    PubMed

    Takahashi, T; Kawashima, M

    2009-08-01

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

  15. Prostaglandin E2 modulation of rheumatoid factor synthesis.

    PubMed

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

    1988-12-01

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

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

    PubMed

    Kellner, R G; Van der Kraak, G

    1992-04-01

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

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

    PubMed

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

    2015-10-12

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

  18. Effects of /sup 60/Co radiation on synthesis of prostaglandins F/sub 2//sub. cap alpha. /, E, and thromboxane B/sub 2/ in lung airways of guinea pigs

    SciTech Connect

    Steel, L.K.; Sweedler, I.K.; Catravas, G.N.

    1983-04-01

    At 1 hr to 14 days after total-body exposure of guinea pigs to 3.0 Gy /sup 60/Co, changes were detected in prostaglandin concentrations in bronchial airway tissues. At 3 hr postexposure, tissue levels of PGE were significantly elevated, while at 48 hr transiently elevated levels of PGF/sub 2//sub ..cap alpha../ were observed. By 72 hr, levels returned to control values. Airway synthesis of thromboxane B/sub 2/ in irradiated animals did not differ from that in controls. Also assessed were the capacities of bronchial airway preparations to respond to H-1 receptor stimulation by the exogenous addition of histamine or transmembrane divalent cation transport stimulation with ionophore. Tissues from irradiated animals demonstrated alterations in the amount and type of prostaglandins generated, varying with time postirradiation.

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

    PubMed

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

    2012-10-01

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

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

    PubMed

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

    1992-01-01

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

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

    SciTech Connect

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

    1988-12-01

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

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

    PubMed

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

    2015-04-01

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

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

    PubMed

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

    2015-07-01

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

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

    NASA Technical Reports Server (NTRS)

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

    1990-01-01

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

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

    PubMed Central

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

    2015-01-01

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

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

    PubMed Central

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

    1991-01-01

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

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

    PubMed

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

    2015-06-15

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

  8. Prostaglandin A2 enhances cellular insulin sensitivity via a mechanism that involves the orphan nuclear receptor NR4A3.

    PubMed

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

    2013-03-01

    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

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

    PubMed

    Lee, Te-Ching; Ho, Han-Chen

    2011-01-01

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

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

    PubMed

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

    2005-03-01

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

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

    PubMed Central

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

    2013-01-01

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

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

    Technology Transfer Automated Retrieval System (TEKTRAN)

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

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

    PubMed Central

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

    1990-01-01

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

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

    PubMed Central

    Sanger, G J; Bennett, A

    1979-01-01

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

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

    PubMed

    Ganesh, Thota

    2015-07-01

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

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

    PubMed Central

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

    2013-01-01

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

  17. 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

  18. Prostaglandin E2 stimulates sodium reabsorption in MDCK C7 cells, a renal collecting duct principal cell model.

    PubMed

    Wegmann, M; Nüsing, R M

    2003-11-01

    We examined the direct epithelial effects of the major product of arachidonic acid metabolism in the kidney, prostaglandin E(2) (PGE(2)), on ion transport and signal transduction in the hormone-sensitive Madin-Darby canine kidney (MDCK) C7 subclone as a model of renal collecting duct principal cells. MDCK C7 cells were grown on microporous permeable filter supports and mounted in Ussing-type chambers. Reverse transcriptase (RT)-PCR and sequencing were used to determine E-prostanoid (EP) receptor expression. Basolateral and, about 14-fold less potent, apical addition of PGE(2) increased short-circuit current (I(sc)) in a concentration-dependent manner. This ion transport was biphasic with a rapid peak not detectable under chloride-free conditions. The remaining, stably elevated current was unaffected by furosemide, hydrochlorothiazide, ethylisopropanol amiloride, and 5-nitro-2-(3-phenyl-propyl-amino)benzoic acid (NPPB). In contrast, apical amiloride (10 microM) significantly decreased I(sc), indicating sodium reabsorption. The effect of PGE(2) was attenuated in the presence of vasopressin. Agonists acting by cAMP elevation like dibutyryl-cAMP and theophylline also induced an amiloride-sensitive ion transport with similar kinetics as PGE(2). Moreover, PGE(2) rapidly increased intracellular cAMP levels. RT-PCR demonstrated mRNA expression of the epithelial sodium channel (ENaC), and of the EP2 receptor in MDCK C7 cells. Accordingly, EP2 receptor agonist butaprost mimicked PGE(2) epithelial action. In conclusion, PGE(2) induces amiloride-sensitive sodium reabsorption in MDCK C7 monolayers. This ion transport is most likely mediated by EP2 receptor activation leading to increased intracellular cAMP levels. Therefore, PGE(2) might also contribute to Na(+) reabsorption in the mammalian collecting duct. PMID:14580365

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

    PubMed

    Miao, Yun-gen; Jiang, Li-jun

    2003-01-01

    The growth of the silkworm is influenced by the outside and inside environment. Among them, the category of various endocrine hormone of inside is the main factors that adjust the characters such as growth and propagate. In this experiment, we applied different dosage of prostaglandin to the fourth and fifth instar silkworm to observe the effects of prostaglandin F2alpha (PGF2alpha) on silk gland growth, mid-gut biochemical constituents and the lipid profiles of silkworm larva, Bombyx mori L. The weight of the posterior silk gland increased significantly (P < 0.001) by 20-24% after treatment with PGF2alpha. The increase in the lipid profiles except lipase activity suggests that the silk gland had more synthetic activity that might reflect in active spinning of silkworm larva. The changes of total proteins, free amino acids and alkaline phosphatase in mid-gut of control and PGF2alpha treated silkworm, B. mori L. indicate that PGF2alpha favored stimulatory effect on physiology of digestion, absorption and transportation of nutrients which might influence on the growth and development of larva. PMID:12611497

  20. 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 ...

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

    PubMed

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

    2015-01-01

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

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

    PubMed Central

    Chen, Enping

    2012-01-01

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

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

    PubMed

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

    2013-06-01

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

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

    PubMed Central

    Kim, Joohwee; Shim, Minsub

    2015-01-01

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

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

    Technology Transfer Automated Retrieval System (TEKTRAN)

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

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

    PubMed Central

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

    2010-01-01

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

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

    PubMed Central

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

    2016-01-01

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

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

    PubMed

    Zimmer, K M; Karmazyn, M

    1997-11-01

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

  9. Localization of a cyclopentenone prostaglandin to the endoplasmic reticulum and induction of BiP mRNA.

    PubMed Central

    Takahashi, S; Odani, N; Tomokiyo, K; Furuta, K; Suzuki, M; Ichikawa, A; Negishi, M

    1998-01-01

    Cyclopentenone prostaglandins (PGs) are transported into cells and stimulate the expression of various stress genes, such as that coding for BiP (an ER luminal protein). To reveal the site of action of the PGs for the induction of stress-gene expression, we introduced a fluorescent probe, pyrene, into two types of PG analogue, GIF0010 (a cyclopentenone type) and GIF0037 (a cyclopentanone type) and examined their intracellular localization in normal rat kidney cells and their ability to induce the BiP gene expression. GIF0010 accumulated around the nuclei and coincided with BiP, a resident protein in the endoplasmic reticulum (ER) and markedly induced BiP gene expression. By contrast, GIF0037 and pyrene neither accumulated in the cell nor induced BiP gene expression. Thus the ER localization of GIF0010 and the induction of gene expression by GIF0010 are ascribed to the cyclopentenone structure. Treatment with cycloheximide inhibited both the accumulation of GIF0010 and the induction of the BiP mRNA, suggesting that the ER localization of the PG and subsequent gene expression require the nascent protein synthesis. These results demonstrate that the cyclopentenone PG is specifically accumulated in the ER, transducing a signal for BiP gene expression in the nuclei. PMID:9742210

  10. Lipocalin-type prostaglandin D synthase scavenges biliverdin in the cerebrospinal fluid of patients with aneurysmal subarachnoid hemorrhage

    PubMed Central

    Inui, Takashi; Mase, Mitsuhito; Shirota, Ryoko; Nagashima, Mariko; Okada, Tetsuya; Urade, Yoshihiro

    2014-01-01

    Lipocalin-type prostaglandin (PG) D synthase (L-PGDS) is the second major protein in human cerebrospinal fluid (CSF) and belongs to the lipocalin superfamily composed of various secretory lipophilic ligand transporter proteins. However, the endogenous ligand of L-PGDS has not yet been elucidated. In this study, we purified L-PGDS from the CSF of aneurysmal subarachnoid hemorrhage (SAH) patients. Lipocalin-type PG D synthase showed absorbance spectra with major peaks at 280 and 392 nm and a minor peak at around 660 nm. The absorbance at 392 nm of L-PGDS increased from 1 to 9 days and almost disappeared at 2 months after SAH, whereas the L-PGDS activity decreased from 1 to 7 days and recovered to normal at 2 months after SAH. These results indicate that some chromophore had accumulated in the CSF after SAH and bound to L-PGDS, thus inactivating it. Matrix assisted laser desorption ionization time-of-flight mass spectrometry of L-PGDS after digestion of it with endoproteinase Lys-C revealed that L-PGDS had covalently bound biliverdin, a by-product of heme breakdown. These results suggest that L-PGDS acted as a scavenger of biliverdin, which is a molecule not found in normal CSF. This is the first report of identification of a pathophysiologically important endogenous ligand for this lipocalin superfamily protein in humans. PMID:25005874

  11. 15-deoxy prostaglandin J2, the nonenzymatic metabolite of prostaglandin D2, induces apoptosis in keratinocytes of human hair follicles: a possible explanation for prostaglandin D2-mediated inhibition of hair growth.

    PubMed

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

    2016-07-01

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

  12. 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

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

    PubMed

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

    2015-10-01

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

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

    PubMed Central

    Flitney, F W; Singh, J

    1980-01-01

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

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

    PubMed

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

    2016-06-01

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

  16. 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

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

    PubMed Central

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

    2011-01-01

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

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

    PubMed

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

    2011-02-01

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

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

    PubMed Central

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

    1990-01-01

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

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

    PubMed Central

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

    1975-01-01

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

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

    PubMed

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

    1980-01-01

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

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

    PubMed

    Chen, J K; Elder, M G

    1983-09-01

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

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

    PubMed

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

    1998-04-20

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

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

    SciTech Connect

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

    1984-04-01

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

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

    PubMed

    Brown, R C; Poole, A

    1984-10-01

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

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

    PubMed

    MacKenzie, I Z; Fry, A

    1988-05-01

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

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

    PubMed

    Larsson, Karin; Jakobsson, Per-Johan

    2015-07-01

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

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

    PubMed

    Ferreira, S H; Nakamura, M

    1979-08-01

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

  9. Antagonist of prostaglandin E2 receptor 4 induces metabolic alterations in liver of mice.

    PubMed

    Li, Ning; Zhang, Limin; An, Yanpeng; Zhang, Lulu; Song, Yipeng; Wang, Yulan; Tang, Huiru

    2015-03-01

    Prostaglandin E2 receptor 4 (EP4) is one of the receptors for prostaglandin E2 and plays important roles in various biological functions. EP4 antagonists have been used as anti-inflammatory drugs. To investigate the effects of an EP4 antagonist (L-161982) on the endogenous metabolism in a holistic manner, we employed a mouse model, and obtained metabolic and transcriptomic profiles of multiple biological matrixes, including serum, liver, and urine of mice with and without EP4 antagonist (L-161982) exposure. We found that this EP4 antagonist caused significant changes in fatty acid metabolism, choline metabolism, and nucleotide metabolism. EP4 antagonist exposure also induced oxidative stress to mice. Our research is the first of its kind to report information on the alteration of metabolism associated with an EP4 antagonist. This information could further our understanding of current and new biological functions of EP4. PMID:25669961

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

    PubMed Central

    Nieves, Ashley; Garza, Luis A.

    2014-01-01

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

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

    PubMed

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

    2016-03-01

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

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

    PubMed

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

    2011-01-01

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

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

    PubMed

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

    2009-08-01

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

  14. 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

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

    PubMed Central

    Özyol, Pelin; Özyol, Erhan; Baldemir, Ercan

    2016-01-01

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

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

    PubMed Central

    Clark, W G; Cumby, H R

    1976-01-01

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

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

    PubMed

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

    2002-01-01

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

  18. 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.

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

    PubMed

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

    1987-12-10

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

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

    PubMed

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

    2013-09-01

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

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

    PubMed Central

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

    2016-01-01

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

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

    PubMed Central

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

    2015-01-01

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

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

    PubMed

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

    1992-01-01

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

  4. 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.

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

    PubMed

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

    2014-05-01

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

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

    PubMed Central

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

    2014-01-01

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

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

    PubMed

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

    1984-11-01

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

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

    PubMed

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

    2016-03-01

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

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

    PubMed

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

    2016-04-01

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

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

    PubMed

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

    2015-01-01

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

  11. 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

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

    SciTech Connect

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

    1983-05-01

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

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

    PubMed

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

    2016-06-25

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

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

    PubMed

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

    2016-06-01

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

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

    PubMed

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

    2014-03-14

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

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

    PubMed Central

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

    1991-01-01

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

  17. 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.

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

    PubMed Central

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

    2014-01-01

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

  19. ABC transporters and neuroblastoma.

    PubMed

    Yu, Denise M T; Huynh, Tony; Truong, Alan M; Haber, Michelle; Norris, Murray D

    2015-01-01

    Neuroblastoma is the most common cancer of infancy and accounts for 15% of all pediatric oncology deaths. Survival rates of high-risk neuroblastoma remain less than 50%, with amplification of the MYCN oncogene the most important aberration associated with poor outcome. Direct transcriptional targets of MYCN include a number of ATP-binding cassette (ABC) transporters, of which ABCC1 (MRP1), ABCC3 (MRP3), and ABCC4 (MRP4) are the best characterized. These three transporter genes have been shown to be strongly prognostic of neuroblastoma outcome in primary untreated neuroblastoma. In addition to their ability to efflux a number of chemotherapeutic drugs, evidence suggests that these transporters also contribute to neuroblastoma outcome independent of any role in cytotoxic drug efflux. Endogenous substrates of ABCC1 and ABCC4 that may be potential candidates affecting neuroblastoma biology include molecules such as prostaglandins and leukotrienes. These bioactive lipid mediators have the ability to influence biological processes contributing to cancer initiation and progression, such as angiogenesis, cell signaling, inflammation, proliferation, and migration and invasion. ABCC1 and ABCC4 are thus potential targets for therapeutic suppression in high-risk neuroblastoma, and recently developed small-molecule inhibitors may be an effective strategy in treating aggressive forms of this cancer, as well as other cancers that express high levels of these transporters. PMID:25640269

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

    PubMed Central

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

    1984-01-01

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

  1. 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

  2. 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

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

    PubMed

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

    2016-08-01

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

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

    PubMed

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

    2013-01-01

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

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

    PubMed

    Siljehav, Veronica; Shvarev, Yuri; Herlenius, Eric

    2014-11-01

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

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

    PubMed

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

    2016-07-01

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

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

    PubMed Central

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

    1987-01-01

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

  8. 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.

  9. Canine placental prostaglandin E2 synthase: expression, localization, and biological functions in providing substrates for prepartum PGF2alpha synthesis.

    PubMed

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

    2014-12-01

    The prepartum output of PGF2alpha in the bitch is associated with increased placental PGE2-synthase (PTGES) mRNA levels. Contrasting with this is a decreased expression of PGF2alpha-synthase (PGFS/AKR1C3) in uteroplacental compartments during prepartum luteolysis, suggesting an involvement of alternative synthetic pathways in PGF2alpha synthesis, for example, conversion of PGE2 to PGF2alpha. However, because the expression and possible functions of the respective PTGES proteins remained unknown, no further conclusion could be drawn. Therefore, a canine-specific PTGES antibody was generated and used to investigate the expression, cellular localization, and biochemical activities of canine uteroplacental PTGES throughout pregnancy and at prepartum luteolysis. Additionally, the biochemical activities of these tissues involved in the conversion of PGE2 to PGF2alpha were investigated. The endometrial PTGES was localized in the uterine surface epithelium at preimplantation and in superficial and deep uterine glands, endothelial cells, and myometrium throughout pregnancy and at parturition. Placental signals were mostly in the trophoblast. The biochemical properties of recombinant PTGES protein were confirmed. Additionally, expression of two PGE2-receptors, PTGER2/EP2 and PTGER4/EP4, revealed their decreasing expression during luteolysis. In contrast, the uteroplacental expression of prostaglandin transporter (PGT) was strongly elevated prior to parturition. These localization patterns resembled that of PTGES. The increased expression of PTGES and PGT at parturition, together with the accompanying decreased levels of PGE2-receptors and the capability of canine uterine and placental homogenates to take part in the conversion of PGE2 to PGF2alpha, as found in this study, suggest that PGE2 could be used locally as a substrate for prepartum PGF2alpha synthesis in the dog. PMID:25297547

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

    PubMed

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

    2015-01-01

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