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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...
October 21, 2016: FASEB Journal: Official Publication of the Federation of American Societies for Experimental Biology
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
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
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
Mahesha N Nadugala, Prasad H Premaratne, Charitha L Goonasekara
B-cell epitopes on the envelope (E) and premembrane (prM) proteins of dengue virus (DENV) were predicted using bioinformatics tools, BepiPred, Ellipro, and SVMTriP. Predicted epitopes, 32 and 17 for E and prM proteins, respectively, were then characterized for their level of conservations. The epitopes, EP4/E (48-55), epitope number 4 of E protein at amino acids 48-55, EP9/E (165-182), EP11/E (218-233), EP20/E (322-349), EP21/E (326-353), EP23/E (356-365), and EP25/E (380-386), showed a high intraserotype conservancy with very low pan-serotype conservancy, demonstrating a potential target as serotype specific diagnostic markers...
2016: Advances in Bioinformatics
Theiler Anna, Konya Viktoria, Pasterk Lisa, Maric Jovana, Bärnthaler Thomas, Lanz Ilse, Platzer Wolfgang, Schuligoi Rufina, Heinemann Akos
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...
September 21, 2016: Vascular Pharmacology
Eydie Miller Ellis, Michael S Berlin, Caroline L Ward, John A Sharpe, Alam Jamil, Alon Harris
BACKGROUND/AIMS: ONO-9054 is being developed for the reduction of intraocular pressure (IOP) in patients with ocular hypertension (OHT) and open-angle glaucoma (OAG). This study compared the novel dual EP3/FP agonist ONO-9054 with the FP agonist Xalatan. METHODS: Adults (n=123) with bilateral mild/moderate OAG or OHT, with unmedicated IOP of ≥24 mm Hg at 8:00 hours, ≥21 mm Hg at 10:00 hours and ≤36 mm Hg, were randomised 1:1 to receive ONO-9054 (0...
September 20, 2016: British Journal of Ophthalmology
Nunzia Caporarello, Mario Salmeri, Marina Scalia, Carla Motta, Cristina Parrino, Lucia Frittitta, Melania Olivieri, Martina Cristaldi, Roberto Avola, Vincenzo Bramanti, Maria Antonietta Toscano, Carmelina Daniela Anfuso, Gabriella Lupo
It is suspected that microbial infections take part in the pathogenesis of diabetes mellitus type 1 (T1DM). Glucose-induced insulin secretion is accompanied by the release of free arachidonic acid (AA) mainly by cytosolic- and calcium independent phospholipases A2 (cPLA2 and iPLA2). Insulinoma cell line (INS-1E) was infected with E. coli isolated from the blood culture of a patient with sepsis. Invasion assay, Scanning Electron Microscopy and Transmission Electron Microscopy demonstrated the capacity of E. coli to enter cells, which was reduced by PLA2 inhibitors...
2016: PloS One
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
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
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
Jens Muff, Leah MacKinnon, Neal D Durant, Lars Frausing Bennedsen, Kirsten Rügge, Morten Bondgaard, Kurt Pennell
The presented research concerned the compatibility of cosolvents with in situ alkaline hydrolysis (ISAH) for treatment of organophosphorous (OPP) pesticide contaminated sites. In addition, the influence of moderate temperature heat increments was studied as a possible enhancement method. A complex dense non-aqueous phase liquid (DNAPL) of primarily parathion (~50 %) and methyl parathion (~15 %) obtained from the Danish Groyne 42 site was used as a contaminant source, and ethanol and propan-2-ol (0, 25, and 50 v/v%) was used as cosolvents in tap water and 0...
August 24, 2016: Environmental Science and Pollution Research International
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
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
Pei Li, Yuming Zhao, Lihong Ge
BACKGROUND: The immunomodulatory and anti-inflammatory functions of human gingiva-derived mesenchymal stromal cells (GMSCs) have been demonstrated in contact hypersensitivity (CHS) models; however, their therapeutic effect during the late phase of CHS has been poor. METHODS: The murine CHS model was induced by applying oxazolone to the ears of mice. Mesenchymal stromal cells were applied via two methods (intravenous or local injection) at three time points: 1 day before sensitization, 1 day before challenge, or 1 h after challenge...
2016: Stem Cell Research & Therapy
Tingting Fang, Jiayun Hou, Mingyan He, Lingyan Wang, Minghuan Zheng, Xiangdong Wang, Jinglin Xia
A wide range of studies has demonstrated the potent anticancer activity of Chinese herbs. Here, we evaluated the anticancer activity and molecular mechanisms of Actinidia chinensis root extract (acRoots) on hepatocellular carcinoma (HCC). HepG2 HCC cells were treated with various concentrations of acRoots for 72 h and examined by mRNA expression profiling, revealing alterations in cellular immunity, inflammation, proliferation, cell cycle, and metabolic signaling responses. Further analysis of the altered genes in cellular immunity and inflammation gene clusters identified prostaglandin E receptor 3 (EP3) as a key regulator of gene expression in response to acRoots...
July 30, 2016: Cell Biology and Toxicology
Tomasz Maślanka, Małgorzata Chrostowska, Iwona Otrocka-Domagała, Anna Snarska, Mateusz Mikiewicz, Monika Zuśka-Prot, Agnieszka Jasiecka, Hubert Ziółkowski, Włodzimierz Markiewicz, Jerzy J Jaroszewski
The aim of this research was to determine whether prostaglandin E2 (PGE2) affects bovine NK cells in respect of their counts, apoptosis and proliferation, and if it does, then which of the PGE2 receptor (EP) subtype(s) mediate(s) these effects. We here report that long-term, but not short-term, exposure of bovine peripheral blood mononuclear cells to PGE2 at 10(-5)M, 10(-6)M and 10(-7)M, but not at 10(-8)M, caused a significant increase in the percentage of early apoptotic cells among NK cell subset. Moreover, PGE2 at 10(-5)M and 10(-6)M, but not at 10(-7)M and 10(-8)M, induced a considerable decrease in the absolute count of NK cells...
August 2016: Research in Veterinary Science
Shoujin Hao, AnnMarie DelliPizzi, Mariana Quiroz-Munoz, Houli Jiang, Nicholas R Ferreri
The mechanisms by which prostanoids contribute to the maintenance of whole body water homeostasis are complex and not fully understood. The present study demonstrates that an EP3-dependent feedback mechanism contributes to the regulation of water homeostasis under high-salt conditions. Rats on a normal diet and tap water were placed in metabolic cages and given either sulprostone (20 μg·kg(-1)·day(-1)) or vehicle for 3 days to activate EP3 receptors in the thick ascending limb (TAL). Treatment was continued for another 3 days in rats given either 1% NaCl in the drinking water or tap water...
October 1, 2016: American Journal of Physiology. Renal Physiology
Kouki Hidaka, Chihiro Miyamoto, Akira Kawata, Makiko Saita, Ryota Kawamata, Yojiro Maehata, Masato Minabe, Satoko W Takahashi, Shun-Suke Takahashi, Yuko Mikuni-Takagaki
OBJECTIVE: We reported at the previous annual meeting that LIPUS treatment of the molar tooth sockets of retired breeder rats accelerated alveolar bone healing, and that associated humoral effects were seen with elevated blood flow. Namely, LIPUS induced VEGF/angiogenesis along with elevated baseline blood flow rate, which was further associated with a sudden depression of blood flow rate in the socket immediately after cessation of LIPUS treatment. Prior injection with EP4 PGE2 receptor antagonist, but not EP3 antagonist, abolished this LIPUS-induced depression, and topical application of PGE2 to the socket epithelium mimicked the LIPUS-induced depression...
August 2016: Journal of Orthopaedic Trauma
Renjun Wang, Wen Zhang, Zengxiang Dong, Yunfeng Qi, Michael Hultström, Xiaofu Zhou, En Yin Lai
AIM: Prostaglandin E2 mediates sympathoexcitation in chronic heart failure (CHF) through EP3 receptors (PTGER3) in the paraventricular nucleus (PVN). The aim of the present study was investigate the role of c-Jun N-terminal kinase (JNK) in expressional regulation of gamma-aminobutyric acid signaling in PVN of CHF rats. METHODS: CHF was induced by left coronary ligation in wistar rats. Renal sympathetic nerve activity and mean arterial pressure responses to the PVN infusion were determined in anesthetized rats...
July 20, 2016: Acta Physiologica
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