-
Expert Opinion on Therapeutic Targets 2023Prostaglandin E (PGE) is produced by cyclooxygenases (COX-1/2) and the microsomal prostaglandin E synthase 1 (mPGES-1). PGE is pro-inflammatory in diseases such as... (Review)
Review
INTRODUCTION
Prostaglandin E (PGE) is produced by cyclooxygenases (COX-1/2) and the microsomal prostaglandin E synthase 1 (mPGES-1). PGE is pro-inflammatory in diseases such as rheumatoid arthritis, cardiovascular disorders, and cancer. While Nonsteroidal anti-inflammatory drugs (NSAIDs) targeting COX can effectively reduce inflammation, their use is limited by gastrointestinal and cardiovascular side effects resulting from the blockade of all prostanoids. To overcome this limitation, selective inhibition of mPGES-1 is being explored as an alternative therapeutic strategy to inhibit PGE production while sparing or even upregulating other prostaglandins. However, the exact timing and location of PGH conversion to PGD, PGI, TXB or PGF, and whether it hinders or supports the therapeutic effect of mPGES-1 inhibition, is not fully understood.
AREAS COVERED
The article briefly describes prostanoid history and metabolism with a strong focus on the vascular effects of prostanoids. Recent advances in mPGES-1 inhibitor development and results from pre-clinical and clinical studies are presented. Prostanoid shunting after mPGES-1 inhibition is highlighted and particularly discussed in the context of cardiovascular diseases.
EXPERT OPINION
The newest research demonstrates that inhibition of mPGES-1 is a potent anti-inflammatory treatment strategy and beneficial and safer regarding cardiovascular side effects compared to NSAIDs. Inhibitors of mPGES-1 hold great potential to advance to the clinic and there are ongoing phase-II trials in endometriosis.
Topics: Female; Humans; Prostaglandin-E Synthases; Prostaglandins; Anti-Inflammatory Agents; Dinoprostone; Anti-Inflammatory Agents, Non-Steroidal; Cyclooxygenase 2
PubMed: 38015194
DOI: 10.1080/14728222.2023.2285785 -
The FEBS Journal Jan 2023Prostaglandin E2 (PGE2) is one of the most abundant prostaglandins and has been implicated in various diseases. Here, we aimed to explore the role of the PGE2 pathway in...
Prostaglandin E2 (PGE2) is one of the most abundant prostaglandins and has been implicated in various diseases. Here, we aimed to explore the role of the PGE2 pathway in mediating ferroptosis during acute kidney injury. When renal tubular epithelial cells stimulated by H O , the contents of glutathione (GSH) and glutathione peroxidase 4 (GPX4) decreased, whereas the level of lipid peroxide increased. Ferrostatin-1 can effectively attenuate these changes. In this process, the expression levels of cyclooxygenase (COX)-1 and COX-2 were up-regulated. Meanwhile, the expression of microsomal prostaglandin E synthase-2 was elevated, whereas the expression of microsomal prostaglandin E synthase-1 and cytosolic prostaglandin E synthase were down-regulated. Furthermore, the expression of 15-hydroxyprostaglandin dehydrogenase decreased. An excessive accumulation of PGE2 promoted ferroptosis, whereas the PGE2 inhibitor pranoprofen minimized the changes for COX-2, GSH, GPX4 and lipid peroxides. A decrease in the levels of the PGE2 receptor E-series of prostaglandin 1/3 partially restored the decline of GSH and GPX4 levels and inhibited the aggravation of lipid peroxide. Consistent with the in vitro results, increased PGE2 levels led to increased levels of 3,4-methylenedioxyamphetamine, Fe accumulation and decreased GSH and GPX4 levels during renal ischaemia/reperfusion injury injury in mice. Our results indicate that the PGE2 pathway mediated oxidative stress-induced ferroptosis in renal tubular epithelial cells.
Topics: Mice; Animals; Dinoprostone; Ferroptosis; Cyclooxygenase 2; Prostaglandin-E Synthases; Lipid Peroxides; Oxidative Stress; Epithelial Cells
PubMed: 36031392
DOI: 10.1111/febs.16609 -
Advances in Experimental Medicine and... 2019The Cyclooxygenase enzymes (COX-1 and COX-2) incorporate 2 molecules of O into arachidonic acid (AA), resulting in an array of bioactive prostaglandins. However, much... (Review)
Review
The Cyclooxygenase enzymes (COX-1 and COX-2) incorporate 2 molecules of O into arachidonic acid (AA), resulting in an array of bioactive prostaglandins. However, much work has been done showing that COX-2 will perform this reaction on several different AA-containing molecules, most importantly, the endocannabinoid 2-arachidonoylglycerol (2-AG). The products of 2-AG oxygenation, prostaglandin glycerol esters (PG-Gs), are analogous to canonical prostaglandins. This chapter reviews the literature detailing the production, metabolism, and bioactivity of these compounds, as well as their detection in intact animals.
Topics: Animals; Arachidonic Acids; Cyclooxygenase 2; Endocannabinoids; Glycerides; Glyceryl Ethers; Prostaglandins
PubMed: 31562623
DOI: 10.1007/978-3-030-21735-8_8 -
Antioxidants & Redox Signaling Jun 2015A diverse family of lipid-derived levulinaldehydes, isolevuglandins (isoLGs), is produced by rearrangement of endoperoxide intermediates generated through both... (Review)
Review
SIGNIFICANCE
A diverse family of lipid-derived levulinaldehydes, isolevuglandins (isoLGs), is produced by rearrangement of endoperoxide intermediates generated through both cyclooxygenase (COX) and free radical-induced cyclooxygenation of polyunsaturated fatty acids and their phospholipid esters. The formation and reactions of isoLGs with other biomolecules has been linked to alcoholic liver disease, Alzheimer's disease, age-related macular degeneration, atherosclerosis, cardiac arythmias, cancer, end-stage renal disease, glaucoma, inflammation of allergies and infection, mitochondrial dysfunction, multiple sclerosis, and thrombosis. This review chronicles progress in understanding the chemistry of isoLGs, detecting their production in vivo and understanding their biological consequences.
CRITICAL ISSUES
IsoLGs have never been isolated from biological sources, because they form adducts with primary amino groups of other biomolecules within seconds. Chemical synthesis enabled investigation of isoLG chemistry and detection of isoLG adducts present in vivo.
RECENT ADVANCES
The first peptide mapping and sequencing of an isoLG-modified protein present in human retina identified the modification of a specific lysyl residue of the sterol C27-hydroxylase Cyp27A1. This residue is preferentially modified by iso[4]LGE2 in vitro, causing loss of function. Adduction of less than one equivalent of isoLG can induce COX-associated oligomerization of the amyloid peptide Aβ1-42. Adduction of isoLGE2 to phosphatidylethanolamines causes gain of function, converting them into proinflammatory isoLGE2-PE agonists that foster monocyte adhesion to endothelial cells.
FUTURE DIRECTIONS
Among the remaining questions on the biochemistry of isoLGs are the dependence of biological activity on isoLG isomer structure, the structures and mechanism of isoLG-derived protein-protein and DNA-protein cross-link formation, and its biological consequences.
Topics: Amyloid; Animals; Blood-Brain Barrier; DNA-Binding Proteins; Fatty Acids, Unsaturated; Humans; Inflammation; Mitochondria; Oxidative Stress; Phosphatidylethanolamines; Prostaglandin-Endoperoxide Synthases; Prostaglandins E; Protein Binding; Pyrrolidines; Tubulin
PubMed: 25557218
DOI: 10.1089/ars.2014.6154 -
Progress in Lipid Research Apr 2017Prostaglandins (PGs) belong to a subclass of eicosanoids and are classified based on the structures of the cyclopentane ring and their number of double bonds in their... (Review)
Review
Prostaglandins (PGs) belong to a subclass of eicosanoids and are classified based on the structures of the cyclopentane ring and their number of double bonds in their hydrocarbon structures. PGs are important lipid mediators that are involved in inflammatory response. The biosynthesis of diverse PGs from unsaturated C20 fatty acids containing at least three double bonds such as dihomo-γ-linoleic acid (20:3), arachidonic acid (20:4), and eicosapentaenoic acid (20:5) is enables by various PG synthases, including prostaglandin H synthase (PGHS), 15-hydroxyprostaglandin dehydrogenase (15-HPGD), PGES, PGDS, PGFS, PGIS, and thromboxane A synthase (TXAS). This review summarizes the biochemical properties, reaction mechanism, and active site details of PG synthases. Because PGs are involved in the immune system, an understanding of PG synthases is important in the design of new anti-inflammatory drugs. The biosynthesis of PGs in various organisms, such as mammals, corals, florideae (a class of red algae), yeast, and fungi, is also introduced. The expression of PG synthases in the microbial systems for the synthesis of PGs is discussed. Now, the biosynthesis of PGs from glucose or glycerol is possible using metabolically engineered cells expressing both unsaturated fatty acid-producing enzymes and PG synthases.
Topics: Animals; Humans; Prostaglandin-Endoperoxide Synthases; Prostaglandins; Species Specificity
PubMed: 28392405
DOI: 10.1016/j.plipres.2017.04.003 -
Current Opinion in Pharmacology Jun 2018Bisphosphonates target and bind avidly to the mineral (hydroxyapatite) found in bone. This targeting ability has been exploited to design and prepare bisphosphonate... (Review)
Review
Bisphosphonates target and bind avidly to the mineral (hydroxyapatite) found in bone. This targeting ability has been exploited to design and prepare bisphosphonate conjugate prodrugs to deliver a wide variety of drug molecules selectively to bones. It is important that conjugates be stable in the blood stream and that conjugate that is not taken up by bone is eliminated rapidly. The prodrugs should release active drug at a rate appropriate so as to provide efficacy. Radiolabelling is the best method to quantify and evaluate pharmacokinetics, tissue distribution, bone uptake and release of the active drug(s). Recent reports have described bisphosphonate conjugates derived from the antiresorptive drug, alendronic acid and anabolic prostanoid drugs that effectively deliver prostaglandins and prostaglandin EP4 receptor agonists to bone and show enhanced anabolic efficacy and tolerability compared to the drugs alone. These conjugate drugs can be dosed infrequently (weekly or bimonthly) whereas the free drugs must be dosed daily.
Topics: Alendronate; Animals; Bone Diseases; Bone and Bones; Delayed-Action Preparations; Diphosphonates; Drug Carriers; Drug Compounding; Durapatite; Humans; Prodrugs; Prostaglandins; Receptors, Prostaglandin E, EP4 Subtype
PubMed: 29626715
DOI: 10.1016/j.coph.2018.03.010 -
Expert Opinion on Pharmacotherapy Dec 2017Glaucoma is the second leading cause of blindness in the world and current pharmacotherapies for glaucoma have remained relatively unchanged (with the exception of fixed... (Review)
Review
Glaucoma is the second leading cause of blindness in the world and current pharmacotherapies for glaucoma have remained relatively unchanged (with the exception of fixed combinations of previously available medications) since the mid-1990s with the development of prostaglandin analogues. Now, with both new formulations and new classes of medications with novel mechanisms of action, the medical therapy of glaucoma may be heralding a new dawn in medical management. Areas covered: This review outlines new topical therapies for intraocular pressure (IOP) lowering treatment, in addition to new formulations, preservative-free options, and advances in glaucoma medical therapy delivery. We performed a comprehensive search for published studies for glaucoma medical therapy using the electronic database PubMed. A manual search for each therapy or delivery system was also performed. Expert commentary: These advances in glaucoma therapy have the potential to overcome many barriers to glaucoma's medical care, particularly in terms of adherence. However, both time and research are needed to prove the relative efficacy and safety of these new pharmacotherapies and products, helping us decide their role in the treatment of elevated intraocular pressure. We are hopeful that these new developments in therapy may bring more options for glaucoma medical therapy.
Topics: Databases, Factual; Glaucoma; Humans; Intraocular Pressure; Prostaglandins; Protein Kinase Inhibitors; Purinergic P1 Receptor Agonists; RNA, Small Interfering; rho-Associated Kinases
PubMed: 29172818
DOI: 10.1080/14656566.2017.1408791 -
Ophthalmic Genetics 2017Prostaglandins are small pro-inflammatory molecules derived from arachidonic acid that play roles in a multitude of biological processes including, but not limited to,... (Review)
Review
Prostaglandins are small pro-inflammatory molecules derived from arachidonic acid that play roles in a multitude of biological processes including, but not limited to, inflammation, pain modulation, allergies, and bone formation. Prostaglandin analogues are the front-line medications for the treatment of glaucoma, a condition resulting in blindness due to the death of retinal ganglion cells. These drugs act by lowering intraocular pressure (IOP), a major risk factor for glaucoma. The currently used prostaglandin analogues (latanoprost, bimatoprost, tafluprost, and travoprost) mimic PGF2 and target one of the prostaglandin receptors (FP), though research into harnessing the other receptors using compounds like Sulprostone (EP3 receptor), or Iloprost (IP receptor) are currently ongoing. In this review, we summarize the research into each of the prostaglandin molecules (PGD2, PGE2, PGF2, PGI2, TXA2) and their respective receptors (DP, EP1, 2, 3, 4, FP, IP). We examine the modes of action of each of these receptors, their expression, their role in aqueous humour production and outflow within the eye, as well as their roles as medications for the treatment of glaucoma.
Topics: Eye; Glaucoma; Humans; Intraocular Pressure; Prostaglandins; Prostaglandins, Synthetic; Receptors, Prostaglandin
PubMed: 27070211
DOI: 10.3109/13816810.2016.1164193 -
Proceedings of the Japan Academy.... 2017Non-steroidal anti-inflammatory drugs (NSAIDs) exert their anti-inflammatory and anti-tumor effects by reducing prostaglandin (PG) production via the inhibition of... (Review)
Review
Non-steroidal anti-inflammatory drugs (NSAIDs) exert their anti-inflammatory and anti-tumor effects by reducing prostaglandin (PG) production via the inhibition of cyclooxygenase (COX). However, the gastrointestinal, renal and cardiovascular side effects associated with the pharmacological inhibition of the COX enzymes have focused renewed attention onto other potential targets for NSAIDs. PGH, a COX metabolite, is converted to each PG species by species-specific PG terminal synthases. Because of their potential for more selective modulation of PG production, PG terminal synthases are now being investigated as a novel target for NSAIDs. In this review, I summarize the current understanding of PG terminal synthases, with a focus on microsomal PGE synthase-1 (mPGES-1) and PGI synthase (PGIS). mPGES-1 and PGIS cooperatively exacerbate inflammatory reactions but have opposing effects on carcinogenesis. mPGES-1 and PGIS are expected to be attractive alternatives to COX as therapeutic targets for several diseases, including inflammatory diseases and cancer.
Topics: Amino Acid Sequence; Animals; Disease; Drug Discovery; Humans; Ligases; Molecular Targeted Therapy; Prostaglandins
PubMed: 29129850
DOI: 10.2183/pjab.93.044 -
Yakugaku Zasshi : Journal of the... 2017Mast cells originate from hematopoietic stem cells and undergo terminal maturation in the extravascular tissues, in which they are ultimately resident. Mast maturation,... (Review)
Review
Mast cells originate from hematopoietic stem cells and undergo terminal maturation in the extravascular tissues, in which they are ultimately resident. Mast maturation, phenotype, and function are dictated by the local microenvironment, which has a significant influence on the ability of mast cells to recognize and respond to stimuli. Activation of mast cells can lead to the release of three distinct classes of mediators, including preformed mediators stored in secretory granules, newly transcribed cytokines and chemokines, and de novo-synthesized bioactive lipid mediators. It is currently recognized that bioactive lipids such as arachidonic acid metabolites (prostaglandins and leukotrienes) released from mast cells modulate innate and adaptive immune responses both directly and indirectly through communication with other microenvironmental immune cells or stroma cells. Moreover, mast cells express a variety of lipid receptors and, if activated by bioactive lipids such as arachidonic acid, ω3 fatty acids, lysophospholipids, and their metabolites, can alter the release and production of other mediators including histamine, cytokines, and chemokines, and thereby alter homeostatic or pathophysiological responses. This review focuses on newly identified functional aspects of bioactive lipids with regard to their immune regulation and functional outcomes in both homeostasis and allergic disease.
Topics: Adaptive Immunity; Animals; Arachidonic Acids; Cellular Microenvironment; Histamine Release; Homeostasis; Humans; Hypersensitivity; Immunity, Innate; Leukotrienes; Lipid Metabolism; Lipids; Mast Cells; Mice; Prostaglandins
PubMed: 28458280
DOI: 10.1248/yakushi.16-00239-2