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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 -
Cardiovascular Research Feb 2024
Topics: Moscow; Epoprostenol; Prostaglandins I
PubMed: 38048331
DOI: 10.1093/cvr/cvad160 -
Cellular and Molecular Neurobiology Oct 2022Spinal motor neurons have the longest axons that innervate the skeletal muscles of the central nervous system. Motor neuron diseases caused by spinal motor neuron cell... (Review)
Review
Spinal motor neurons have the longest axons that innervate the skeletal muscles of the central nervous system. Motor neuron diseases caused by spinal motor neuron cell death are incurable due to the unique and irreplaceable nature of their neural circuits. Understanding the mechanisms of neurogenesis, neuritogenesis, and synaptogenesis in motor neurons will allow investigators to develop new in vitro models and regenerative therapies for motor neuron diseases. In particular, small molecules can directly reprogram and convert into neural stem cells and neurons, and promote neuron-like cell differentiation. Prostaglandins are known to have a role in the differentiation and tissue regeneration of several cell types and organs. However, the involvement of prostaglandins in the differentiation of motor neurons from neural stem cells is poorly understood. The general cell line used in research on motor neuron diseases is the mouse neuroblastoma and spinal motor neuron fusion cell line NSC-34. Recently, our laboratory reported that prostaglandin E and prostaglandin D enhanced the conversion of NSC-34 cells into motor neuron-like cells with neurite outgrowth. Moreover, we found that prostaglandin E-differentiated NSC-34 cells had physiological and electrophysiological properties of mature motor neurons. In this review article, we provide contemporary evidence on the effects of prostaglandins, particularly prostaglandin E and prostaglandin D, on differentiation and neural conversion. We also discuss the potential of prostaglandins as candidates for the development of new therapeutic drugs for motor neuron diseases.
Topics: Animals; Cell Differentiation; Mice; Motor Neurons; Neural Stem Cells; Neurogenesis; Oxytocics; Prostaglandins
PubMed: 34032949
DOI: 10.1007/s10571-021-01104-4 -
Arteriosclerosis, Thrombosis, and... Jun 2020Prostanoids are a group of bioactive lipids that are synthesized de novo from membrane phospholipid-released arachidonic acid and have diverse functions in normal... (Review)
Review
Prostanoids are a group of bioactive lipids that are synthesized de novo from membrane phospholipid-released arachidonic acid and have diverse functions in normal physiology and disease. NSAIDs (non-steroidal anti-inflammatory drugs), which are among the most commonly used medications, ameliorate pain, fever, and inflammation by inhibiting COX (cyclooxygenase), which is the rate-limiting enzyme in the biosynthetic cascade of prostanoids. The use of NSAIDs selective for COX-2 inhibition increases the risk of a thrombotic event (eg, myocardial infarction and stroke). All NSAIDs are associated with an increased risk of heart failure. Substantial variation in clinical responses to aspirin exists and is associated with cardiovascular risk. Limited clinical studies suggest the involvement of prostanoids in vascular restenosis in patients who received angioplasty intervention. mPGES (microsomal PG [prostaglandin] E synthase)-1, an alternative target downstream of COX, has the potential to be therapeutically targeted for inflammatory disease, with diminished thrombotic risk relative to selective COX-2 inhibitors. mPGES-1-derived PGE critically regulates microcirculation via its receptor EP (receptor for prostanoid E) 4. This review summarizes the actions and associated mechanisms for modulating the biosynthesis of prostanoids in thrombosis, vascular remodeling, and ischemic heart disease as well as their therapeutic relevance.
Topics: Animals; Anti-Inflammatory Agents; Anti-Inflammatory Agents, Non-Steroidal; Cardiovascular Diseases; Cardiovascular System; Cyclooxygenase 2 Inhibitors; Cyclooxygenase Inhibitors; Drug Discovery; Heart Failure; Humans; Myocardial Infarction; Myocardial Reperfusion Injury; Prostaglandin-E Synthases; Prostaglandins; Risk Factors; Stroke; Vascular Remodeling
PubMed: 32295420
DOI: 10.1161/ATVBAHA.119.313234 -
Blood Nov 2023
Topics: Humans; Epoprostenol; Receptors, Epoprostenol; Oxylipins; Prostaglandins I; Pain; Platelet Activation; Thrombosis
PubMed: 37917084
DOI: 10.1182/blood.2023022227 -
Developmental Cell Sep 2023Early mammalian development occurs during embryo transit of the female reproductive tract. Transport is orchestrated by secreted oviduct fluid, unidirectional beating of...
Early mammalian development occurs during embryo transit of the female reproductive tract. Transport is orchestrated by secreted oviduct fluid, unidirectional beating of epithelial cilia, and smooth muscle contractions. Using gene-edited mice, we document that conditional disruption of a component of the SWI/SNF chromatin remodeling complex in smooth muscle cells prevents transport through the oviduct without perturbing embryogenesis. Analysis with RNA sequencing (RNA-seq), transposase-accessible chromatin with sequencing (ATAC-seq), chromatin immunocleavage sequencing (ChIC-seq), and pharmacologic rescue experiments implicated prostaglandin signaling pathways. In comparison with controls, gene-edited mice had compromised chromatin accessibility at enhancer/promoters of Ptgs2, Pla2g16, Pla2r1, and Ptger3 (EP3) as well as decreased enhancer-promoter interactive looping critical for Ptgs2 (aka Cox-2) expression in a SWI/SNF complex-dependent manner. Treatment of wild-type mice with prostaglandin inhibitors phenocopied the genetically induced defect.
Topics: Female; Animals; Mice; Prostaglandins; Chromatin Assembly and Disassembly; Cyclooxygenase 2; Muscle, Smooth; Chromatin; Mammals
PubMed: 37714160
DOI: 10.1016/j.devcel.2023.08.025 -
Advanced Science (Weinheim,... Jul 2023It is well-known that muscle regeneration declines with aging, and aged muscles undergo degenerative atrophy or sarcopenia. While exercise and acute injury are both...
It is well-known that muscle regeneration declines with aging, and aged muscles undergo degenerative atrophy or sarcopenia. While exercise and acute injury are both known to induce muscle regeneration, the molecular signals that help trigger muscle regeneration have remained unclear. Here, mass spectrometry imaging (MSI) is used to show that injured muscles induce a specific subset of prostanoids during regeneration, including PGG1, PGD2, and the prostacyclin PGI2. The spike in prostacyclin promotes skeletal muscle regeneration via myoblasts, and declines with aging. Mechanistically, the prostacyclin spike promotes a spike in PPARγ/PGC1a signaling, which induces a spike in fatty acid oxidation (FAO) to control myogenesis. LC-MS/MS and MSI further confirm that an early FAO spike is associated with normal regeneration, but muscle FAO became dysregulated during aging. Functional experiments demonstrate that the prostacyclin-PPARγ/PGC1a-FAO spike is necessary and sufficient to promote both young and aged muscle regeneration, and that prostacyclin can synergize with PPARγ/PGC1a-FAO signaling to restore aged muscles' regeneration and physical function. Given that the post-injury prostacyclin-PPARγ-FAO spike can be modulated pharmacologically and via post-exercise nutrition, this work has implications for how prostacyclin-PPARγ-FAO might be fine-tuned to promote regeneration and treat muscle diseases of aging.
Topics: Muscle, Skeletal; PPAR gamma; Epoprostenol; Chromatography, Liquid; Tandem Mass Spectrometry; Prostaglandins I; Regeneration
PubMed: 37140179
DOI: 10.1002/advs.202301519 -
Frontiers in Immunology 2023Allergic inflammation of the airways such as allergic asthma is a major health problem with growing incidence world-wide. One cardinal feature in severe type 2-dominated...
Allergic inflammation of the airways such as allergic asthma is a major health problem with growing incidence world-wide. One cardinal feature in severe type 2-dominated airway inflammation is the release of lipid mediators of the eicosanoid family that can either promote or dampen allergic inflammation. Macrophages are key producers of prostaglandins and leukotrienes which play diverse roles in allergic airway inflammation and thus require tight control. Using RNA- and ATAC-sequencing, liquid chromatography coupled to mass spectrometry (LC-MS/MS), enzyme immunoassays (EIA), gene expression analysis and models, we show that the aryl hydrocarbon receptor (AhR) contributes to this control transcriptional regulation of lipid mediator synthesis enzymes in bone marrow-derived as well as in primary alveolar macrophages. In the absence or inhibition of AhR activity, multiple genes of both the prostaglandin and the leukotriene pathway were downregulated, resulting in lower synthesis of prostanoids, such as prostaglandin E2 (PGE), and cysteinyl leukotrienes, e.g., Leukotriene C4 (LTC). These AhR-dependent genes include encoding for the enzyme cyclooxygenase 1 (COX1) and encoding for the arachidonate 5-lipoxygenase (5-LO) both of which major upstream regulators of the prostanoid and leukotriene pathway, respectively. This regulation is independent of the activation stimulus and partially also detectable in unstimulated macrophages suggesting an important role of basal AhR activity for eicosanoid production in steady state macrophages. Lastly, we demonstrate that AhR deficiency in hematopoietic but not epithelial cells aggravates house dust mite induced allergic airway inflammation. These results suggest an essential role for AhR-dependent eicosanoid regulation in macrophages during homeostasis and inflammation.
Topics: Humans; Chromatography, Liquid; Dinoprostone; Eicosanoids; Inflammation; Leukotrienes; Macrophages, Alveolar; Prostaglandins; Receptors, Aryl Hydrocarbon; Tandem Mass Spectrometry
PubMed: 37081886
DOI: 10.3389/fimmu.2023.1157373 -
Anatomia, Histologia, Embryologia Jan 2024Prostaglandins are synthesized from arachidonic acid through the catalytic activities of cyclooxygenase, while the production of different prostaglandin types,... (Review)
Review
Prostaglandins are synthesized from arachidonic acid through the catalytic activities of cyclooxygenase, while the production of different prostaglandin types, prostaglandin F2 alpha (PGF) and prostaglandin E2 (PGE), are regulated by specific prostaglandin synthases (PGFS and PGES). Prostaglandin ligands (PGF and PGE) bind to specific high-affinity receptors and initiate biologically distinct signalling pathways. In the ovaries, prostaglandins are known to be important endocrine regulators of female reproduction, in addition to maintaining local function through autocrine and/or paracrine effect. Many research groups in different animal species have already identified a variety of factors and molecular mechanisms that are responsible for the regulation of prostaglandin functions. In addition, prostaglandins stimulate their intrafollicular and intraluteal production via the pathway of prostaglandin self-regulation in the ovary. Therefore, the objective of the review article is to discuss recent findings about local regulation patterns of prostaglandin ligands PGF and PGE during different physiological stages of ovarian function in domestic ruminants, especially in bovine. In conclusion, the discussed local regulation mechanisms of prostaglandins in the ovary may stimulate further research activities in different methodological approaches, especially during final follicle maturation and ovulation, as well as corpus luteum formation and function.
Topics: Female; Cattle; Animals; Prostaglandins; Ovary; Prostaglandin-Endoperoxide Synthases; Ruminants; Ovarian Follicle; Corpus Luteum
PubMed: 37788129
DOI: 10.1111/ahe.12980 -
Dermatologic Surgery : Official... May 2021The FDA approved bimatoprost ophthalmic solution 0.03% for treatment of eyelash hypotrichosis in 2008. Consumer concern persists regarding potential side effects of this... (Review)
Review
BACKGROUND
The FDA approved bimatoprost ophthalmic solution 0.03% for treatment of eyelash hypotrichosis in 2008. Consumer concern persists regarding potential side effects of this product.
OBJECTIVE
To identify gaps in the safety information associated with the use of prostaglandin eyelash growth products.
MATERIALS AND METHODS
Literature searches were performed using PubMed, Embase, and Nexis Uni databases without restriction to publication date, language, or study setting.
RESULTS
The literature pertaining to bimatoprost for treatment of eyelash hypotrichosis is dominated by industry-sponsored clinical trials. Study design choices create gaps in our understanding of the clinical safety of these products.
CONCLUSION
Because of study design choice, clinical trials of bimatoprost for eyelash growth may have systematically underreported the incidence of drug application discomfort and prostaglandin-associated periorbitopathy. The risk of increased iris pigmentation remains inadequately investigated. Consequently, there is an ongoing need to educate and monitor patients who choose to use these products.
Topics: Antihypertensive Agents; Bimatoprost; Eyelashes; Humans; Hypotrichosis; Nonprescription Drugs; Ophthalmic Solutions; Prostaglandins, Synthetic
PubMed: 33625141
DOI: 10.1097/DSS.0000000000002928