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https://www.readbyqxmd.com/read/28193789/enriching-islet-phospholipids-with-eicosapentaenoic-acid-reduces-prostaglandin-e2-signaling-and-enhances-diabetic-%C3%AE-cell-function
#1
Joshua C Neuman, Michael D Schaid, Allison L Brill, Rachel J Fenske, Carly R Kibbe, Danielle A Fontaine, Sophia M Sdao, Harpreet K Brar, Kelsey M Connors, Haley N Wienkes, Kevin W Eliceiri, Matthew J Merrins, Dawn B Davis, Michelle E Kimple
Prostaglandin E2 (PGE2) is derived from arachidonic acid, while PGE3 is derived from eicosapentaenoic acid (EPA) using the same downstream metabolic enzymes. Little is known about the impact of EPA and PGE3 on β-cell function, particularly in the diabetic state. In this work, we determined PGE3 elicits a 10-fold weaker reduction in glucose-stimulated insulin secretion through the EP3 receptor as compared to PGE2 We tested the hypothesis that enriching pancreatic islet cell membranes with EPA, thereby reducing arachidonic acid abundance, would positively impact β-cell function in the diabetic state...
February 13, 2017: Diabetes
https://www.readbyqxmd.com/read/28165064/role-of-e-type-prostaglandin-receptor-ep3-in-the-vasoconstrictor-activity-evoked-by-prostacyclin-in-thromboxane-prostanoid-receptor-deficient-mice
#2
Zhenhua Li, Yingzhan Zhang, Bin Liu, Wenhong Luo, Hui Li, Yingbi Zhou
Prostacyclin, also termed as prostaglandin I2 (PGI2), evokes contraction in vessels with limited expression of the prostacyclin receptor. Although the thromboxane-prostanoid receptor (TP) is proposed to mediate such a response of PGI2, other unknown receptor(s) might also be involved. TP knockout (TP(-/-)) mice were thus designed and used to test the hypothesis. Vessels, which normally show contraction to PGI2, were isolated for functional and biochemical analyses. Here, we showed that the contractile response evoked by PGI2 was indeed only partially abolished in the abdominal aorta of TP(-/-) mice...
February 6, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28132118/regulation-of-pancreatic-%C3%AE-cell-function-and-mass-dynamics-by-prostaglandin-signaling
#3
REVIEW
Bethany A Carboneau, Richard M Breyer, Maureen Gannon
Prostaglandins (PGs) are signaling lipids derived from arachidonic acid (AA), which is metabolized by cyclooxygenase (COX)-1 or 2 and class-specific synthases to generate PGD2, PGE2, PGF2α, PGI2 (prostacyclin), and thromboxane A2. PGs signal through G-protein coupled receptors (GPCRs) and are important modulators of an array of physiological functions, including systemic inflammation and insulin secretion from pancreatic islets. The role of PGs in β-cell function has been an active area of interest, beginning in the 1970s...
January 28, 2017: Journal of Cell Communication and Signaling
https://www.readbyqxmd.com/read/28131828/ep3-activation-facilitates-bladder-excitability-via-hcn-channels-on-iccs
#4
Chao Wu, Xingyou Dong, Qian Liu, Jingzhen Zhu, Teng Zhang, Qingqing Wang, Xiaoyang Hu Zhenxing Yang, Longkun Li
EP3 is a receptor for prostaglandin E2 (PGE2), and although its effect on bladder excitability has attracted considerable attention, the underlying mechanism remains unclear. To investigate whether the hyperpolarization-activated cyclic nucleotide-gated (HCN) channels in the interstitial cells of Cajal (ICCs) of the bladder are involved in the effect of EP3 activation on bladder excitability, wild-type mice, HCN1 knockout (HCN1(-/-)) mice and rats were used in our study. Double immunofluorescence staining and immunoprecipitation assays demonstrated the interaction between EP3 and the HCN channels...
January 25, 2017: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/28105284/discovery-of-novel-seven-membered-prostacyclin-analogues-as-potent-and-selective-prostaglandin-fp-and-ep3-dual-agonists
#5
Isamu Sugimoto, Tohru Kambe, Tomotaka Okino, Tetsuo Obitsu, Nobukazu Ohta, Taihei Nishiyama, Akihiro Kinoshita, Taku Fujimoto, Hiromu Egashira, Shinsaku Yamane, Satoshi Shuto, Kousuke Tani, Toru Maruyama
A novel series of prostaglandin analogues with a seven-membered ring scaffold was designed, synthesized, and evaluated for the functional activation of prostaglandin receptors to identify potent and subtype-selective FP and EP3 dual agonists. Starting from the prostacyclin derivative 5b, a nonselective agonist for prostaglandin receptors, replacement of the core structure with an octahydro-2H-cyclopenta[b]oxepine scaffold led to the discovery of the potent and selective FP and EP3 dual agonist 11b as a lead compound for the development of an antiglaucoma agent...
January 12, 2017: ACS Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28072531/discovery-of-2-1r-4r-4-4-chlorophenyl-phenyl-carbamoyl-oxy-methyl-cyclohexyl-methoxy-acetate-ralinepag-an-orally-active-prostacyclin-receptor-agonist-for-the-treatment-of-pulmonary-arterial-hypertension
#6
Thuy-Anh Tran, Bryan Kramer, Young-Jun Shin, Pureza Vallar, P Douglas Boatman, Ning Zou, Carleton R Sage, Tawfik Gharbaoui, Ashwin Krishnan, Biman Pal, Sagar R Shakya, Antonio Garrido Montalban, John W Adams, Juan Ramirez, Dominic P Behan, Anna Shifrina, Anthony Blackburn, Tina Leakakos, Yunqing Shi, Michael Morgan, Abu Sadeque, Weichao Chen, David J Unett, Ibragim Gaidarov, Xiaohua Chen, Steve Chang, Hsin-Hui Shu, Shiu-Feng Tung, Graeme Semple
The design and synthesis of a new series of potent non-prostanoid IP receptor agonists that showed oral efficacy in the rat monocrotaline model of pulmonary arterial hypertension (PAH) are described. Detailed profiling of a number of analogues resulted in the identification of 5c (ralinepag) that has good selectivity in both binding and functional assays with respect to most members of the prostanoid receptor family and a more modest 30- to 50-fold selectivity over the EP3 receptor. In our hands, its potency and efficacy are comparable or superior to MRE269 (the active metabolite of the clinical compound NS-304) with respect to in vitro IP receptor dependent cAMP accumulation assays...
February 9, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28065721/the-key-residue-within-the-second-extracellular-loop-of-human-ep3-involved-in-selectively-turning-down-pge2-and-retaining-pge1-mediated-signaling-in-live-cells
#7
Hironari Akasaka, Natasha Thaliachery, Xianghai Zheng, Marissa Blumenthal, Sameer Nikhar, Emma E Murdoch, Qinglan Ling, Ke-He Ruan
Key residues and binding mechanisms of PGE1 and PGE2 on prostanoid receptors are poorly understood due to the lack of X-ray structures for the receptors. We constructed a human EP3 (hEP3) model through integrative homology modeling using the X-ray structure of the β2-adrenergic receptor transmembrane domain and NMR structures of the thromboxane A2 receptor extracellular loops. PGE1 and PGE2 docking into the hEP3 model showed differing configurations within the extracellular ligand recognition site. While PGE2 could form possible binding contact with S211, PGE1 is unable to form similar contacts...
January 5, 2017: Archives of Biochemistry and Biophysics
https://www.readbyqxmd.com/read/28058438/copper-b2pin2-catalyzed-c-h-difluoroacetylation-cycloamidation-of-anilines-leading-to-the-formation-of-3-3-difluoro-2-oxindoles
#8
Miaolin Ke, Qiuling Song
An original and efficient synthesis of 3,3-difluoro-2-oxindole derivatives has been developed via copper/B2pin2-catalyzed difluoroacetylation of aniline via C-H activation followed by intramolecular amidation. In this method, amino groups in primary, secondary or tertiary anilines act as directing groups, providing ortho-difluoroacetylated products regioselectively. And in the first two cases, further intramolecular amidation affords 3,3-difluoro-2-oxindole derivatives via a one-pot strategy. This method facilitates the synthesis of compound A as a potent and selective EP3 receptor antagonist in only five steps in 13% yield instead of the previously reported nine steps in overall 4% yield...
January 6, 2017: Chemical Communications: Chem Comm
https://www.readbyqxmd.com/read/28039934/prostaglandin-e2-promotes-hepatic-bile-acid-synthesis-by-an-e-prostanoid-receptor-3-mediated-hepatocyte-nuclear-receptor-4%C3%AE-cholesterol-7%C3%AE-hydroxylase-pathway-in-mice
#9
Shuai Yan, Juan Tang, Yuyao Zhang, Yuanyang Wang, Shengkai Zuo, Yujun Shen, Qianqian Zhang, Di Chen, Yu Yu, Kai Wang, Sheng-Zhong Duan, Ying Yu
: Prostaglandin E2 (PGE2 ) is an important lipid mediator of inflammation. However, whether and how PGE2 regulates hepatic cholesterol metabolism remains unknown. We found that expression of the PGE2 receptor, E prostanoid receptor 3 (EP3) expression is remarkably increased in hepatocytes in response to hyperlipidemic stress. Hepatocyte-specific deletion of EP3 receptor (EP3(hep-/-) ) results in hypercholesterolemia and augments diet-induced atherosclerosis in low-density lipoprotein receptor knockout (Ldlr(-/-) ) mice...
November 5, 2016: Hepatology: Official Journal of the American Association for the Study of Liver Diseases
https://www.readbyqxmd.com/read/27973680/prostaglandin-e2-potentiates-interferon-%C3%AE-induced-nitric-oxide-production-in-cultured-rat-microglia
#10
Takayuki Nagano, Ryo Nishiyama, Ayaka Sanada, Yukiko Mutaguchi, Anna Ioku, Hirohisa Umeki, Satoshi Kishimoto, Daisuke Yamanaka, Shinya H Kimura, Motohiko Takemura
Prostaglandin E2 (PGE2 ) plays crucial roles in managing microglial activation through the prostanoid EP2 receptor, a PGE2 receptor subtype. In this study, we report that PGE2 enhances interferon-γ (IFN-γ)-induced nitric oxide production in microglia. IFN-γ increased the release of nitrite, a metabolite of nitric oxide, which was augmented by PGE2 , although PGE2 by itself slightly affects nitrite release. The potentiating effect of PGE2 was positively associated with increased expression of inducible nitric oxide synthase...
December 14, 2016: Journal of Neurochemistry
https://www.readbyqxmd.com/read/27770021/in-vivo-studies-validating-multitargeting-of-prostanoid-receptors-for-achieving-superior-anti-inflammatory-effects
#11
David F Woodward, Jenny W Wang, Ming Ni, Alex Bauer, Jose L Martos, Robert W Carling, Neil J Poloso
The purpose of these studies was to test the hypothesis that a selected polypharmacological approach for treating the prostanoid-mediated component of inflammatory diseases would produce a therapeutic effect superior to global inhibition of prostaglandin (PG) biosynthesis by aspirin-like drugs. The compound studied was AGN 211377, which had been previously shown to produce a superior effect on cytokine release from human macrophages compared with cyclooxygenase (COX) inhibitors. AGN 211377 antagonizes prostanoid prostaglandin D2 (DP)1, DP2, prostaglandin E2 (EP)1, EP4, prostaglandin F2α, and thromboxane A2 receptors but not anti-inflammatory EP2, prostaglandin I2, or EP3 receptors...
January 2017: FASEB Journal: Official Publication of the Federation of American Societies for Experimental Biology
https://www.readbyqxmd.com/read/27763812/prostanoid-receptor-antagonist-effects-on-intraocular-pressure-supported-by-ocular-biodisposition-experiments
#12
David F Woodward, Stacey L Wenthur, Tara L Rudebush, Shan Fan, Carol B Toris
PURPOSE: Since all prostanoid receptors affect intraocular pressure (IOP) and endogenous prostanoids are found in ocular tissues, the pressor effects of prostanoid antagonists were comprehensively evaluated. The absence of effects of most of these antagonists was not entirely anticipated. To ensure no false-negative results, ocular biodisposition studies were conducted. METHODS: Monkeys with laser-induced ocular hypertension were used to study antagonist effects on IOP...
October 20, 2016: Journal of Ocular Pharmacology and Therapeutics
https://www.readbyqxmd.com/read/27739618/stimulating-trpv1-externalization-and-synthesis-in-dorsal-root-ganglion-neurons-contributes-to-pge2-potentiation-of-trpv1-activity-and-nociceptor-sensitization
#13
W Ma, B St-Jacques, U Rudakou, Y N Kim
BACKGROUND: Persistent peripheral sensitization contributes to chronic pain. Plasticity of nociceptive dorsal root ganglion (DRG) neurons (nociceptors) induced by pro-inflammatory mediators contributes to sensitization. Prostaglandin E2 (PGE2) enriched in injured tissues is known not only directly to sensitize DRG neurons, but also to potentiate sensitizing effects of other pain mediators such as capsaicin and its receptor transient receptor potential vanilloid-1 (TRPV1). It remains unknown whether PGE2 potentiates TRPV1 activity by stimulating its synthesis, cell surface and axonal trafficking in DRG neurons...
October 14, 2016: European Journal of Pain: EJP
https://www.readbyqxmd.com/read/27711210/signaling-of-prostaglandin-e-receptors-ep3-and-ep4-facilitates-wound-healing-and-lymphangiogenesis-with-enhanced-recruitment-of-m2-macrophages-in-mice
#14
Kanako Hosono, Risa Isonaka, Tadashi Kawakami, Shuh Narumiya, Masataka Majima
Lymphangiogenesis plays an important role in homeostasis, metabolism, and immunity, and also occurs during wound-healing. Here, we examined the roles of prostaglandin E2 (PGE2) receptor (EP) signaling in enhancement of lymphangiogenesis in wound healing processes. The hole-punch was made in the ears of male C57BL/6 mice using a metal ear punch. Healing process and lymphangiogenesis together with macrophage recruitment were analyzed in EP knockout mice. Lymphangiogenesis was up-regulated in the granulation tissues at the margins of punched-hole wounds in mouse ears, and this increase was accompanied by increased expression levels of COX-2 and microsomal prostaglandin E synthase-1...
2016: PloS One
https://www.readbyqxmd.com/read/27664754/the-ep1-ep3-receptor-agonist-17-pt-pge2-acts-as-an-ep4-receptor-agonist-on-endothelial-barrier-function-and-in-a-model-of-lps-induced-pulmonary-inflammation
#15
Anna Theiler, Viktoria Konya, Lisa Pasterk, Jovana Maric, Thomas Bärnthaler, Ilse Lanz, Wolfgang Platzer, Rufina Schuligoi, Akos Heinemann
Endothelial dysfunction is a hallmark of inflammatory conditions. We recently demonstrated that prostaglandin (PG)E2 enhances the resistance of pulmonary endothelium in vitro and counteracts lipopolysaccharide (LPS)-induced pulmonary inflammation in vivo via EP4 receptors. The aim of this study was to investigate the role of the EP1/EP3 receptor agonist 17-phenyl-trinor-(pt)-PGE2 on acute lung inflammation in a mouse model. In LPS-induced pulmonary inflammation in mice, 17-pt-PGE2 reduced neutrophil infiltration and inhibited vascular leakage...
December 2016: Vascular Pharmacology
https://www.readbyqxmd.com/read/27605391/deorphaning-the-macromolecular-targets-of-the-natural-anticancer-compound-doliculide
#16
Gisbert Schneider, Daniel Reker, Tao Chen, Kurt Hauenstein, Petra Schneider, Karl-Heinz Altmann
The cyclodepsipeptide doliculide is a marine natural product with strong actin-polymerizing and anticancer activities. Evidence for doliculide acting as a potent and subtype-selective antagonist of prostanoid E receptor 3 (EP3) is presented. Computational target prediction suggested that this membrane receptor is a likely macromolecular target and enabled immediate in vitro validation. This proof-of-concept study demonstrates the in silico deorphanization of phenotypic screening hits as a viable concept for future natural-product-inspired chemical biology and drug discovery efforts...
September 26, 2016: Angewandte Chemie
https://www.readbyqxmd.com/read/27581447/periaqueductal-grey-ep3-receptors-facilitate-spinal-nociception-in-arthritic-secondary-hypersensitivity
#17
R A R Drake, J L Leith, F Almahasneh, J Martindale, A W Wilson, B Lumb, L F Donaldson
UNLABELLED: Descending controls on spinal nociceptive processing play a pivotal role in shaping the pain experience after tissue injury. Secondary hypersensitivity develops within undamaged tissue adjacent and distant to damaged sites. Spinal neuronal pools innervating regions of secondary hypersensitivity are dominated by descending facilitation that amplifies spinal inputs from unsensitized peripheral nociceptors. Cyclooxygenase-prostaglandin (PG) E2 signaling within the ventrolateral periaqueductal gray (vlPAG) is pronociceptive in naive and acutely inflamed animals, but its contributions in more prolonged inflammation and, importantly, secondary hypersensitivity remain unknown...
August 31, 2016: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
https://www.readbyqxmd.com/read/27572469/rostral-ventrolateral-medulla-ep3-receptor-mediates-the-sympathoexcitatory-and-pressor-effects-of-prostaglandin-e2-in-conscious-rats
#18
Samar Rezq, Abdel A Abdel-Rahman
Whereas few studies have dealt with the central sympathoexcitatory action of the inflammatory prostanoid prostaglandin E2 (PGE2), there is no information on the expression and cardiovascular function of different PGE2 (EP) receptors in one of the major cardiovascular-regulating nuclei, the rostral ventrolateral medulla (RVLM). The current study aimed at filling this knowledge gap as well as elucidating the implicated molecular mechanisms. To achieve these goals, we showed the expression of EP2, EP3, and EP4 receptors in the RVLM and investigated their cardiovascular roles in conscious rats, ex vivo as well as in cultured PC12 cells...
November 2016: Journal of Pharmacology and Experimental Therapeutics
https://www.readbyqxmd.com/read/27512093/role-of-the-prostaglandin-e2-receptor-agonists-in-tgf-%C3%AE-1-induced-mesangial-cell-damage
#19
Pe-Ipei Xi, Yu-Yin Xu, Xiao-Lan Chen, Ya-Ping Fan, Jian-Hua Wu
PGE2 exerts its biological effect through binding to various EP receptors that result inactivation of various signal transduction pathways.It also plays an important role in mice glomerular mesangial cells (MCs) damage induced by transforming growth factor-β1 (TGF-β1); however, the molecular mechanisms remain unknown. In present study, we tested the efficacy of four selective agonists of PGE2  receptor, EP1A (17-phenyl trinor prostaglandin E 2:  ethyl amid), EP2A (butaprost), EP3A (sulprostone) and EP4A (cay10580), on mice MCs...
August 10, 2016: Bioscience Reports
https://www.readbyqxmd.com/read/27502370/prostaglandin-e2-reduces-cardiac-contractility-via-ep3-receptor
#20
Xiaosong Gu, Jiang Xu, Liping Zhu, Timothy Bryson, Xiao-Ping Yang, Edward Peterson, Pamela Harding
BACKGROUND: Prostaglandin E2 (PGE2) EP receptors EP3 and EP4 signal via decreased and increased cAMP production, respectively. Previously, we reported that cardiomyocyte-specific EP4 knockout mice develop dilated cardiomyopathy with reduced ejection fraction. Thus, we hypothesized that PGE2 increases contractility via EP4 but decreases contractility via EP3. METHODS AND RESULTS: The effects of PGE2 and the EP1/EP3 agonist sulprostone on contractility were examined in the mouse Langendorff preparation and in adult mouse cardiomyocytes...
August 2016: Circulation. Heart Failure
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