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Microsomal prostaglandin E synthase-1: the inducible synthase for prostaglandin E2
Annaleise V Sampey, Seetha Monrad, Leslie J Crofford
Arthritis Research & Therapy , 2005, DOI: 10.1186/ar1748
Abstract: Prostaglandin (PG)E2 is the pivotal eicosanoid involved in the development and perpetuation of inflammation seen in diseases such as rheumatoid arthritis. In this disease, local inflammation of synovial tissue is characterized in part by increased local levels of PG, predominantly PGE2 [1]. In the eicosanoid pathway, induction of PGE2 biosynthesis during inflammation requires the enzymatic actions of two cytokine-inducible enzymes: cyclooxygenase (COX) and prostaglandin E synthase (PGES) (Fig. 1). An important role for COX-2 in producing PG in patients with inflammatory arthritis has been clearly shown in clinical trials that demonstrate equal efficacy of specific COX-2 inhibitors and nonspecific nonsteroidal anti-inflammatory drugs (NSAIDs) [2]. Whether a similar essential role exists for the inducible microsomal prostaglandin E synthase-1 (mPGES-1) in the localized increase of PGE2 during inflammatory arthritis in humans is currently unclear.Microsomal prostaglandin E2 synthase-1 belongs to the MAPEG (membrane-associated proteins involved in eicosanoid and glutathione metabolism) superfamily (Table 1). It was initially identified as a homologue to another member (MGST1; see Table 1) and was found to have significant glutathione-dependent PGE2 synthase activity [3]. The human mPGES-1 gene maps to chromosome 9q34.3, contains three exons and two introns, and spans approximately 14.8 kb [4]; the purified recombinant enzyme weighs approximately 17.5 kDa. It has a Vmax of 170 μmol min-1 mg-1 and a kcat/Km of 310 mM-1 s-1 for the conversion of PGH2 to PGE2 at 37°C, which is orders of magnitude higher than other terminal PG synthases and establishes a key role for mPGES-1 in PGE2 synthesis in vivo [5]. There is 80% sequence homology between mouse/rat and human mPGES-1. Mutation of Arg110, but not Tyr117, results in abrogation of the catalytic function of mPGES-1 [6]; these two amino acids are highly conserved in the MAPEG superfamily.In addition to mPGES-1, two other isof
Ascorbic acid enhances the inhibitory effect of aspirin on neuronal cyclooxygenase-2-mediated prostaglandin E2 production  [PDF]
E. Candelario-Jalil,R. S. Akundi,H. S. Bhatia,K. Lieb,K. Appel,E. Munoz,M. Hull,B. L. Fiebich
Quantitative Biology , 2007,
Abstract: In the present study, we show that ascorbic acid dose-dependently inhibited interleukin-1beta (IL-1beta)-mediated PGE2 synthesis in the human neuronal cell line, SK-N-SH. Furthermore, in combination with aspirin, ascorbic acid augmented the inhibitory effect of aspirin on PGE2 synthesis. However, ascorbic acid had no synergistic effect along with other COX inhibitors (SC-58125 and indomethacin). The inhibition of IL-1beta-mediated PGE2 synthesis by ascorbic acid was not due to the inhibition of the expression of COX-2 or microsomal prostaglandin E synthase (mPGES-1). Rather, ascorbic acid dose-dependently (0.1-100 microM) produced a significant reduction in IL-1beta-mediated production of 8-iso-prostaglandin F2alpha (8-iso-PGF2alpha), a reliable indicator of free radical formation, suggesting that the effects of ascorbic acid on COX-2-mediated PGE2 biosynthesis may be the result of the maintenance of the neuronal redox status since COX activity is known to be enhanced by oxidative stress. Our results provide in vitro evidence that the neuroprotective effects of ascorbic acid may depend, at least in part, on its ability to reduce neuronal COX-2 activity and PGE2 synthesis, owing to its antioxidant properties. Further, these experiments suggest that a combination of aspirin with ascorbic acid constitutes a novel approach to render COX-2 more sensitive to inhibition by aspirin, allowing an anti-inflammatory therapy with lower doses of aspirin, thereby avoiding the side effects of the usually high dose aspirin treatment.
In Silico Screening of Nonsteroidal Anti-Inflammatory Drugs and Their Combined Action on Prostaglandin H Synthase-1  [PDF]
Alexey Goltsov,Galina Lebedeva,Ian Humphery-Smith,Gregory Goltsov,Oleg Demin,Igor Goryanin
Pharmaceuticals , 2010, DOI: 10.3390/ph3072059
Abstract: The detailed kinetic model of Prostaglandin H Synthase-1 (PGHS-1) was applied to in silico screening of dose-dependencies for the different types of nonsteroidal anti-inflammatory drugs (NSAIDs), such as: reversible/irreversible, nonselective/selective to PGHS-1/PGHS-2 and time dependent/independent inhibitors (aspirin, ibuprofen, celecoxib, etc.) The computational screening has shown a significant variability in the IC50s of the same drug, depending on different in vitro and in vivo experimental conditions. To study this high heterogeneity in the inhibitory effects of NSAIDs, we have developed an in silico approach to evaluate NSAID action on targets under different PGHS-1 microenvironmental conditions, such as arachidonic acid, reducing cofactor, and peroxide concentrations. The designed technique permits translating the drug IC 50, obtained in one experimental setting to another, and predicts in vivo inhibitory effects based on the relevant in vitro data. For the aspirin case, we elucidated the mechanism underlying the enhancement and reduction (aspirin resistance) of its efficacy, depending on PGHS-1 microenvironment in in vitro/in vivo experimental settings. We also present the results of the in silico screening of the combined action of sets of two NSAIDs (aspirin with ibuprofen, aspirin with celecoxib), and study the mechanism of the experimentally observed effect of the suppression of aspirin-mediated PGHS-1 inhibition by selective and nonselective NSAIDs. Furthermore, we discuss the applications of the obtained results to the problems of standardization of NSAID test assay, dependence of the NSAID efficacy on cellular environment of PGHS-1, drug resistance, and NSAID combination therapy.
Microsomal Prostaglandin E Synthase-1 in Rheumatic Diseases  [PDF]
Marina Korotkova,Per-Johan Jakobsson
Frontiers in Pharmacology , 2011, DOI: 10.3389/fphar.2010.00146
Abstract: Microsomal prostaglandin E synthase-1 (mPGES-1) is a well-recognized target for the development of novel anti-inflammatory drugs that can reduce symptoms of inflammation in rheumatic diseases and other inflammatory conditions. In this review, we focus on mPGES-1 in rheumatic diseases with the aim to cover the most recent advances in the understanding of mPGES-1 in rheumatoid arthritis, osteoarthritis, and inflammatory myopathies. Novel findings regarding regulation of mPGES-1 cell expression as well as enzyme inhibitors are also summarized.
Sulforaphane Inhibits Prostaglandin E2 Synthesis by Suppressing Microsomal Prostaglandin E Synthase 1  [PDF]
Jiping Zhou, Denise G. Joplin, Janet V. Cross, Dennis J. Templeton
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0049744
Abstract: 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.
A novel electron paramagnetic resonance-based assay for prostaglandin H synthase-1 activity
Catriona M Turnbull, Danny McClure, Adriano G Rossi, Ian L Megson
Journal of Inflammation , 2006, DOI: 10.1186/1476-9255-3-12
Abstract: Given the rekindled interest in specific anti-inflammatory PGHS inhibitors with reduced unwanted side effects, it is of paramount importance that there are reliable and efficient techniques to test new inhibitors. Here, we describe a novel in vitro electron paramagnetic resonance (EPR)-based assay for measuring the activity of PGHS-1.We validated a novel in vitro PGHS-1 activity assay based on the oxidation of spin-trap agent, 1-hydroxy-3-carboxy-pyrrolidine (CPH) to 3-carboxy-proxy (CP) under the action of the peroxidase element of PGHS-1. This quantifiable spin-adduct, CP, yields a characteristic 3-line electron paramagnetic (EPR) spectrum.The assay is simple, reproducible and facilitates rapid screening of inhibitors of PGHS-1. Aspirin (100 μM, 1 mM) caused significant inhibition of spin-adduct formation (72 ± 11 and 100 ± 16% inhibition of control respectively; P < 0.05). Indomethacin (100 μM) also abolished the signal (114 ± 10% inhibition of control; P < 0.01). SA and the PGHS-2-selective inhibitor, NS398, failed to significantly inhibit spin-adduct generation (P > 0.05).We have demonstrated and validated a simple, reproducible, quick and specific assay for detecting PGHS-1 activity and inhibition. The EPR-based assay described represents a novel approach to measuring PGHS activity and provides a viable and competitive alternative to existing assays.Prostaglandins are derived from arachidonic acid (AA) in a pathway dependent on the PGHS (EC 1.14.99.1) family of enzymes, which are commonly known as cyclooxygenase (COX), referring to the first step of enzymatic activity. PGHS converts AA to prostaglandin H2 (PGH2), the precursor of all prostanoids. The enzyme contains two active sites: a COX site, where AA is converted into the hydroperoxy endoperoxide, prostaglandin G2 (PGG2), and a haem with peroxidase activity that reduces PGG2 to PGH2 (For review see [1]). The reduction of PGG2 by the peroxidase element generates the corresponding alcohol. This reaction has
Platelet Content of Nitric Oxide Synthase 3 Phosphorylated At Serine1177 Is Associated with the Functional Response of Platelets to Aspirin  [PDF]
Javier Modrego, Luis Azcona, Naiara Martín-Palacios, José J. Zamorano-León, Antonio Segura, Pablo Rodríguez, Reddy Guerra, Juan Tamargo, Carlos Macaya, Antonio J. López-Farré
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0082574
Abstract: Objective To analyse if platelet responsiveness to aspirin (ASA) may be associated with a different ability of platelets to generate nitric oxide (NO). Patients/Methods Platelets were obtained from 50 patients with stable coronary ischemia and were divided into ASA-sensitive (n = 26) and ASA-resistant (n = 24) using a platelet functionality test (PFA-100). Results ASA-sensitive platelets tended to release more NO (determined as nitrite + nitrate) than ASA-resistant platelets but it did not reach statistical significance. Protein expression of nitric oxide synthase 3 (NOS3) was higher in ASA-sensitive than in ASA-resistant platelets but there were no differences in the platelet expression of nitric oxide synthase 2 (NOS2) isoform. The highest NOS3 expression in ASA-sensitive platelets was independent of the presence of T-to-C mutation at nucleotide position ?786 (T?786→C) in the NOS3-coding gene. However, platelet content of phosphorylated NOS3 at Serine (Ser)1177, an active form of NOS3, was higher in ASA-sensitive than in ASA-resistant platelets. The level of platelet NOS3 Ser1177 phosphorylation was positively associated with the closure time in the PFA-100 test. In vitro, collagen failed to stimulate the aggregation of ASA-sensitive platelets, determined by lumiaggregometry, and it was associated with a significant increase (p = 0.018) of NOS3 phosphorylation at Ser1177. On the contrary, collagen stimulated the aggregation of ASA-resistant platelets but did not significantly modify the platelet content of phosphorylated NOS3 Ser1177. During collagen stimulation the release of NO from ASA-sensitive platelets was significantly enhanced but it was not modified in ASA-resistant platelets. Conclusions Functional platelet responsiveness to ASA was associated with the platelet content of phosphorylated NOS3 at Ser1177.
miR-143 Regulation of Prostaglandin-Endoperoxidase Synthase 2 in the Amnion: Implications for Human Parturition at Term  [PDF]
Sun Young Kim, Roberto Romero, Adi L. Tarca, Gaurav Bhatti, JoonHo Lee, Tinnakorn Chaiworapongsa, Sonia S. Hassan, Chong Jai Kim
PLOS ONE , 2011, DOI: 10.1371/journal.pone.0024131
Abstract: Background The human amnion plays a pivotal role in parturition. Two of its compartments, the placental amnion and the reflected amnion, have distinct transcriptome and are functionally coordinated for parturition. This study was conducted to determine the microRNA (miRNA) expression pattern and its significance in the placental amnion and the reflected amnion in association with labor at term. Methodology/Principal Findings MicroRNA microarray, real-time quantitative RT-PCR (qRT-PCR), and miRNA in situ hybridization analyses of the placental amnion and the reflected amnion (n = 20) obtained at term were conducted. Luciferase assay, transfection, and qRT-PCR analyses of primary amnion epithelial cells (AECs) and amnion mesenchymal cells (AMCs) were performed. MicroRNA microarray analysis demonstrated differential expression of 32 miRNAs between the placental amnion and the reflected amnion after labor. Thirty-one (97%) miRNAs, which included miR-143 and miR-145, a cardiovascular-specific miRNA cluster, were down-regulated in the reflected amnion. Analyses of miR-143 and miR-145 by qRT-PCR confirmed microarray results, and further demonstrated their decreased expression in the reflected amnion with labor. Interestingly, expression of miR-143 and miR-145 was higher in AMCs than in AECs (p<0.05). Luciferase assay and transfection confirmed miR-143 binding to 3′ UTR of prostaglandin-endoperoxidase synthase 2 (PTGS2) mRNA and miR-143 regulation of PTGS2 in AMCs. Conclusions We report region-specific amniotic microRNAome and miR-143 regulation of PTGS2 in the context of human labor at term for the first time. The findings indicate that miRNA-mediated post-transcriptional regulation of gene expression machinery in the amnion plays an important role in the compartments (placental amnion vs reflected amnion) and in a cell type-specific manner (AECs vs AMCs) for parturition.
Lipocalin Prostaglandin D Synthase and PPARγ2 Coordinate to Regulate Carbohydrate and Lipid Metabolism In Vivo  [PDF]
Sam Virtue, Mojgan Masoodi, Vidya Velagapudi, Chong Yew Tan, Martin Dale, Tapani Suorti, Marc Slawik, Margaret Blount, Keith Burling, Mark Campbell, Naomi Eguchi, Gema Medina-Gomez, Jaswinder K. Sethi, Matej Ore?i?, Yoshihiro Urade, Julian L. Griffin, Antonio Vidal-Puig
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0039512
Abstract: Mice lacking Peroxisome Proliferator-Activated Receptor γ2 (PPARγ2) have unexpectedly normal glucose tolerance and mild insulin resistance. Mice lacking PPARγ2 were found to have elevated levels of Lipocalin prostaglandin D synthase (L-PGDS) expression in BAT and subcutaneous white adipose tissue (WAT). To determine if induction of L-PGDS was compensating for a lack of PPARγ2, we crossed L-PGDS KO mice to PPARγ2 KO mice to generate Double Knock Out mice (DKO). Using DKO mice we demonstrated a requirement of L-PGDS for maintenance of subcutaneous WAT (scWAT) function. In scWAT, DKO mice had reduced expression of thermogenic genes, the de novo lipogenic program and the lipases ATGL and HSL. Despite the reduction in markers of lipolysis in scWAT, DKO mice had a normal metabolic rate and elevated serum FFA levels compared to L-PGDS KO alone. Analysis of intra-abdominal white adipose tissue (epididymal WAT) showed elevated expression of mRNA and protein markers of lipolysis in DKO mice, suggesting that DKO mice may become more reliant on intra-abdominal WAT to supply lipid for oxidation. This switch in depot utilisation from subcutaneous to epididymal white adipose tissue was associated with a worsening of whole organism metabolic function, with DKO mice being glucose intolerant, and having elevated serum triglyceride levels compared to any other genotype. Overall, L-PGDS and PPARγ2 coordinate to regulate carbohydrate and lipid metabolism.
Effects of prostaglandin F on small intestinal interstitial cells of Cajal  [cached]
Chan Guk Park, Young Dae Kim, Man Yoo Kim, Jae Woong Koh, Jae Yeoul Jun, Cheol Ho Yeum, Insuk So, Seok Choi
World Journal of Gastroenterology , 2011,
Abstract: AIM: To explore the role of prostaglandin F2α (PGF2α)) on pacemaker activity in interstitial cells of Cajal (ICC) from mouse small intestine.METHODS: In this study, effects of PGF2α in the cultured ICC cells were investigated with patch clamp technology combined with Ca2+ image analysis.RESULTS: Externally applied PGF2α (10 μmol/L) produced membrane depolarization in current-clamp mode and increased tonic inward pacemaker currents in voltage-clamp mode. The application of flufenamic acid (a non-selective cation channel inhibitor) or niflumic acid (a Cl- channel inhibitor) abolished the generation of pacemaker currents but only flufenamic acid inhibited the PGF2α-induced tonic inward currents. In addition, the tonic inward currents induced by PGF2α were not inhibited by intracellular application of 5’-[-thio]diphosphate trilithium salt. Pretreatment with Ca2+ free solution, U-73122, an active phospholipase C inhibitor, and thapsigargin, a Ca2+-ATPase inhibitor in endoplasmic reticulum, abolished the generation of pacemaker currents and suppressed the PGF2α-induced tonic inward currents. However, chelerythrine or calphostin C, protein kinase C inhibitors, did not block the PGF2α-induced effects on pacemaker currents. When recording intracellular Ca2+ ([Ca2+]i) concentration using fluo-3/AM, PGF2α broadly increased the spontaneous [Ca2+]i oscillations.CONCLUSION: These results suggest that PGF2α can modulate pacemaker activity of ICC by acting non-selective action channels through phospholipase C-dependent pathway via [Ca2+]i regulation
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