Aspects of Prostaglandin Glycerol Ester Biology

Kingsley, Philip J.; Rouzer, Carol A.; Morgan, Amanda; Patel, Sachin; Marnett, Lawrence J.

doi:10.1007/978-3-030-21735-8_8

Cited by 14 publications

(9 citation statements)

References 41 publications

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“…5,17 Thus, chemical compounds that can prevent the degradation of 2-AG and PG-Gs in biological systems by inhibiting the hydrolytic enzymes that catabolize these bioactive lipid mediators could be useful tools to increase their local concentrations, thereby attenuating oxidative and inflammatory stress. 14,18,19 PG-Gs can exert biological activity through their direct interaction with cellular receptors, triggering Ca 2+ mobilization, inositol 1,4,5-trisphosphate synthesis, and activation of protein kinase C. 20,21 However, the study of these lipid mediators is complicated because some of their biological effects are due to the action of their corresponding free prostaglandins. 20,22 These issues increase the importance of better understanding the cellular effects of PG-Gs in various contexts.…”

Section: Introductionmentioning

confidence: 99%

“…14,18,19 PG-Gs can exert biological activity through their direct interaction with cellular receptors, triggering Ca 2+ mobilization, inositol 1,4,5-trisphosphate synthesis, and activation of protein kinase C. 20,21 However, the study of these lipid mediators is complicated because some of their biological effects are due to the action of their corresponding free prostaglandins. 20,22 These issues increase the importance of better understanding the cellular effects of PG-Gs in various contexts. In this vein, prostaglandin D 2 -glyceryl ester (PGD 2 -G) was shown to have pronounced anti-inflammatory effects in mouse macrophages, whereas its regioisomer prostaglandin E 2glyceryl ester (PGE 2 -G) exhibited pro-inflammatory effects.…”

Section: Introductionmentioning

confidence: 99%

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Inactivation of CES1 Blocks Prostaglandin D₂ Glyceryl Ester Catabolism in Monocytes/Macrophages and Enhances Its Anti-inflammatory Effects, Whereas the Pro-inflammatory Effects of Prostaglandin E₂ Glyceryl Ester Are Attenuated

et al. 2020

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Human monocytic cells in blood have important roles in host defense and express the enzyme carboxylesterase 1 (CES1). This metabolic serine hydrolase plays a critical role in the metabolism of many molecules, including lipid mediators called prostaglandin glyceryl esters (PG-Gs), which are formed during cyclooxygenase-mediated oxygenation of the endocannabinoid 2-arachidonoylglycerol. Some PG-Gs have been shown to exhibit anti-inflammatory effects; however, they are unstable compounds, and their hydrolytic breakdown generates pro-inflammatory prostaglandins. We hypothesized that by blocking the ability of CES1 to hydrolyze PG-Gs in monocytes/macrophages, the beneficial effects of anti-inflammatory prostaglandin D2-glyceryl ester (PGD2-G) could be augmented. The goals of this study were to determine whether PGD2-G is catabolized by CES1, evaluate the degree to which this metabolism is blocked by small-molecule inhibitors, and assess the immunomodulatory effects of PGD2-G in macrophages. A human monocytic cell line (THP-1 cells) was pretreated with increasing concentrations of known small-molecule inhibitors that block CES1 activity [chlorpyrifos oxon (CPO), WWL229, or WWL113], followed by incubation with PGD2-G (10 μM). Organic solvent extracts of the treated cells were analyzed by liquid chromatography with tandem mass spectrometry to assess levels of the hydrolysis product PGD2. Further, THP-1 monocytes with normal CES1 expression (control cells) and “knocked-down” CES1 expression (CES1KD cells) were employed to confirm CES1’s role in PGD2-G catabolism. We found that CES1 has a prominent role in PGD2-G hydrolysis in this cell line, accounting for about 50% of its hydrolytic metabolism, and that PGD2-G could be stabilized by the inclusion of CES1 inhibitors. The inhibitor potency followed the rank order: CPO > WWL113 > WWL229. THP-1 macrophages co-treated with WWL113 and PGD2-G prior to stimulation with lipopolysaccharide exhibited a more pronounced attenuation of pro-inflammatory cytokine levels (interleukin-6 and TNFα) than by PGD2-G treatment alone. In contrast, prostaglandin E2-glyceryl ester (PGE2-G) had opposite effects compared to those of PGD2-G, which appeared to be dependent on the hydrolysis of PGE2-G to PGE2. These results suggest that the anti-inflammatory effects induced by PGD2-G can be further augmented by inactivating CES1 activity with specific small-molecule inhibitors, while pro-inflammatory effects of PGE2-G are attenuated. Furthermore, PGD2-G (and/or its downstream metabolites) was shown to activate the lipid-sensing receptor PPARγ, resulting in altered “alternative macrophage activation” response to the Th2 cytokine interleukin-4. These findings suggest that inhibition of CES1 and other enzymes that regulate the levels of pro-resolving mediators such as PGD2-G in specific cellular niches might be a novel anti-inflammatory approach.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Inactivation of CES1 Blocks Prostaglandin D₂ Glyceryl Ester Catabolism in Monocytes/Macrophages and Enhances Its Anti-inflammatory Effects, Whereas the Pro-inflammatory Effects of Prostaglandin E₂ Glyceryl Ester Are Attenuated

et al. 2020

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“…We also did not detect any 2-glycerol ester of PGE 1 even at the first time point after Prostanit injection. Prostaglandin glycerol esters are novel cyclooxygenase 2 (COX2) metabolites of endocannabinoid 2-arachidonoyl glycerol and putatively other closely related glycerol esters of dihomo-γ-linolenic acid or eicosapentaenoic acid with biological properties distinct from those of corresponding natural prostaglandins [ 34 ]. The absence of 2-glycerol ester of PGE 1 in the metabolite profile led us to the conclusion that the mentioned metabolite is not involved in the biological effects of Prostanit, at least in rabbits.…”

Section: Discussionmentioning

confidence: 99%

In Vivo Targeted Metabolomic Profiling of Prostanit, a Novel Anti-PAD NO-Donating Alprostadil-Based Drug

et al. 2020

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Prostanit is a novel drug developed for the treatment of peripheral arterial diseases. It consists of a prostaglandin E1 (PGE1) moiety with two nitric oxide (NO) donor fragments, which provide a combined vasodilation effect on smooth muscles and vascular spastic reaction. Prostanit pharmacokinetics, however, remains poorly investigated. Thus, the object of this study was to investigate the pharmacokinetics of Prostanit-related and -affected metabolites in rabbit plasma using the liquid chromatography-mass spectrometry (LC-MS) approach. Besides, NO generation from Prostanit in isolated rat aorta and human smooth muscle cells was studied using the Griess method. In plasma, Prostanit was rapidly metabolized to 1,3-dinitroglycerol (1,3-DNG), PGE1, and 13,14-dihydro-15-keto-PGE1. Simultaneously, the constant growth of amino acid (proline, 4-hydroxyproline, alanine, phenylalanine, etc.), steroid (androsterone and corticosterone), and purine (adenosine, adenosine-5 monophosphate, and guanosine) levels was observed. Glycine, aspartate, cortisol, and testosterone levels were decreased. Ex vivo Prostanit induced both NO synthase-dependent and -independent NO generation. The observed pharmacokinetic properties suggested some novel beneficial activities (i.e., effect prolongation and anti-inflammation). These properties may provide a basis for future research of the effectiveness and safety of Prostanit, as well as for its characterization from a clinical perspective.

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“…Besides this well‐studied enzymatic function of COX isoenzymes, the inducible COX‐2 selectively oxygenates 2‐arachidonoylglycerol to form prostaglandin glycerol esters (PG‐Gs) [2] . Due to the rapid degradation of PG‐Gs, there is limited knowledge about their biological function [3] . Previous studies suggested that the PG‐Gs PGE 2 ‐G and PGF 2α ‐G may activate GPCRs in the murine macrophage‐like cell line RAW264.7 and the human lung's adenocarcinoma cell line H1819 [4] .…”

Section: Introductionmentioning

confidence: 99%

“…[2] Due to the rapid degradation of PG‐Gs, there is limited knowledge about their biological function. [3] Previous studies suggested that the PG‐Gs PGE 2 ‐G and PGF 2α ‐G may activate GPCRs in the murine macrophage‐like cell line RAW264.7 and the human lung's adenocarcinoma cell line H1819. [4] The fast Ca 2+ response observed with both cell lines indicated specific signal transduction via unknown G q ‐ and/or G i protein‐coupled receptors.…”

Section: Introductionmentioning

confidence: 99%

Mapping the Binding Sites of UDP and Prostaglandin E2 Glyceryl Ester in the Nucleotide Receptor P2Y₆

Zimmermann

Brüser

et al. 2022

ChemMedChem

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Cyclooxygenase-2 catalyzes the biosynthesis of prostaglandins from arachidonic acid and the biosynthesis of prostaglandin glycerol esters (PG-Gs) from 2-arachidonoylglycerol. PG-Gs are mediators of several biological actions such as macrophage activation, hyperalgesia, synaptic plasticity, and intraocular pressure. Recently, the human UDP receptor P2Y 6 was identified as a target for the prostaglandin E2 glycerol ester (PGE 2 -G).Here, we show that UDP and PGE 2 -G are evolutionary conserved endogenous agonists at vertebrate P2Y 6 orthologs. Using sequence comparison of P2Y 6 orthologs, homology modeling, and ligand docking studies, we proposed several receptor positions participating in agonist binding. Site-directed mutagenesis and functional analysis of these P2Y 6 mutants revealed that both UDP and PGE 2 -G share in parts one ligand-binding site. Thus, the convergent signaling of these two chemically very different agonists has already been manifested in the evolutionary design of the ligand-binding pocket.

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Aspects of Prostaglandin Glycerol Ester Biology

Cited by 14 publications

References 41 publications

Inactivation of CES1 Blocks Prostaglandin D₂ Glyceryl Ester Catabolism in Monocytes/Macrophages and Enhances Its Anti-inflammatory Effects, Whereas the Pro-inflammatory Effects of Prostaglandin E₂ Glyceryl Ester Are Attenuated

Inactivation of CES1 Blocks Prostaglandin D₂ Glyceryl Ester Catabolism in Monocytes/Macrophages and Enhances Its Anti-inflammatory Effects, Whereas the Pro-inflammatory Effects of Prostaglandin E₂ Glyceryl Ester Are Attenuated

In Vivo Targeted Metabolomic Profiling of Prostanit, a Novel Anti-PAD NO-Donating Alprostadil-Based Drug

Mapping the Binding Sites of UDP and Prostaglandin E2 Glyceryl Ester in the Nucleotide Receptor P2Y₆

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Aspects of Prostaglandin Glycerol Ester Biology

Cited by 14 publications

References 41 publications

Inactivation of CES1 Blocks Prostaglandin D2 Glyceryl Ester Catabolism in Monocytes/Macrophages and Enhances Its Anti-inflammatory Effects, Whereas the Pro-inflammatory Effects of Prostaglandin E2 Glyceryl Ester Are Attenuated

Inactivation of CES1 Blocks Prostaglandin D2 Glyceryl Ester Catabolism in Monocytes/Macrophages and Enhances Its Anti-inflammatory Effects, Whereas the Pro-inflammatory Effects of Prostaglandin E2 Glyceryl Ester Are Attenuated

In Vivo Targeted Metabolomic Profiling of Prostanit, a Novel Anti-PAD NO-Donating Alprostadil-Based Drug

Mapping the Binding Sites of UDP and Prostaglandin E2 Glyceryl Ester in the Nucleotide Receptor P2Y6

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Inactivation of CES1 Blocks Prostaglandin D₂ Glyceryl Ester Catabolism in Monocytes/Macrophages and Enhances Its Anti-inflammatory Effects, Whereas the Pro-inflammatory Effects of Prostaglandin E₂ Glyceryl Ester Are Attenuated

Inactivation of CES1 Blocks Prostaglandin D₂ Glyceryl Ester Catabolism in Monocytes/Macrophages and Enhances Its Anti-inflammatory Effects, Whereas the Pro-inflammatory Effects of Prostaglandin E₂ Glyceryl Ester Are Attenuated

Mapping the Binding Sites of UDP and Prostaglandin E2 Glyceryl Ester in the Nucleotide Receptor P2Y₆