-
Science Translational Medicine Oct 2023To date, there are no approved treatments for the diminished strength and paralysis that result from the loss of peripheral nerve function due to trauma, heritable...
To date, there are no approved treatments for the diminished strength and paralysis that result from the loss of peripheral nerve function due to trauma, heritable neuromuscular diseases, or aging. Here, we showed that denervation resulting from transection of the sciatic nerve triggered a marked increase in the prostaglandin-degrading enzyme 15-hydroxyprostaglandin dehydrogenase (15-PGDH) in skeletal muscle in mice, providing evidence that injury drives early expression of this aging-associated enzyme or gerozyme. Treating mice with a small-molecule inhibitor of 15-PGDH promoted regeneration of motor axons and formation of neuromuscular synapses leading to an acceleration in recovery of force after an acute nerve crush injury. In aged mice with chronic denervation of muscles, treatment with the 15-PGDH inhibitor increased motor neuron viability and restored neuromuscular junctions and function. These presynaptic changes synergized with previously reported muscle tissue remodeling to result in a marked increase in the strength of aged muscles. We further found that 15-PGDH aggregates defined the target fibers that are histopathologic hallmarks of human neurogenic myopathies, suggesting that the gerozyme may be involved in their etiology. Our data suggest that inhibition of 15-PGDH may constitute a therapeutic strategy to physiologically boost prostaglandin E2, restore neuromuscular connectivity, and promote recovery of strength after acute or chronic denervation due to injury, disease, or aging.
Topics: Mice; Animals; Humans; Aged; Synapses; Hydroxyprostaglandin Dehydrogenases; Prostaglandins; Muscle, Skeletal; Denervation; Nerve Regeneration
PubMed: 37820010
DOI: 10.1126/scitranslmed.adg1485 -
Pharmacology & Therapeutics Jan 2019Prostaglandins are synthesized through the metabolism of arachidonic acid via the cyclooxygenase pathway. There are five primary prostaglandins, PGD, PGE, PGF, PGI, and... (Review)
Review
Prostaglandins are synthesized through the metabolism of arachidonic acid via the cyclooxygenase pathway. There are five primary prostaglandins, PGD, PGE, PGF, PGI, and thromboxane B, that all signal through distinct seven transmembrane, G-protein coupled receptors. The receptors through which the prostaglandins signal determines their immunologic or physiologic effects. For instance, the same prostaglandin may have opposing properties, dependent upon the signaling pathways activated. In this article, we will detail how inhibition of cyclooxygenase metabolism and regulation of prostaglandin signaling regulates allergic airway inflammation and asthma physiology. Possible prostaglandin therapeutic targets for allergic lung inflammation and asthma will also be reviewed, as informed by human studies, basic science, and animal models.
Topics: Animals; Humans; Hypersensitivity; Phospholipases A2; Prostaglandin-Endoperoxide Synthases; Prostaglandins; Signal Transduction
PubMed: 30081047
DOI: 10.1016/j.pharmthera.2018.08.001 -
The Journal of Physiology Oct 2019
Topics: Cardiovascular Physiological Phenomena; Estrogens; Exercise; Female; Hormone Replacement Therapy; Humans; Male; Prostaglandins
PubMed: 31571227
DOI: 10.1113/JP278605 -
Cancer Metastasis Reviews Sep 2018Many epidemiological studies revealed an association of dietary consumption of fatty acids and prostate cancer. Linoleic acid and alpha-linolenic acid and their... (Review)
Review
Many epidemiological studies revealed an association of dietary consumption of fatty acids and prostate cancer. Linoleic acid and alpha-linolenic acid and their derivatives such as arachidonic acid and eicosapentanoic acid are important polyunsaturated fatty acids in animal fats and in many vegetable oils. Their metabolism at the cellular level by enzymes such as lipoxygenases and cycloxygenases produces the group of eicosanoids molecules with many biological roles and activities in a variety of human diseases including cancer. In this review, we describe the biological activities of lipids with focus in eicosanoids and prostate cancer.
Topics: Animals; Arachidonic Acid; Eicosanoids; Fatty Acids, Unsaturated; Humans; Lipid Metabolism; Lipoxygenases; Male; Metabolic Networks and Pathways; Prostaglandins; Prostatic Neoplasms
PubMed: 30078159
DOI: 10.1007/s10555-018-9750-0 -
Trends in Molecular Medicine Oct 2019Interfering with endocannabinoid (eCB) metabolism to increase their levels is a proven anti-nociception strategy. However, because the eCB and prostanoid systems are... (Review)
Review
Interfering with endocannabinoid (eCB) metabolism to increase their levels is a proven anti-nociception strategy. However, because the eCB and prostanoid systems are intertwined, interfering with eCB metabolism will affect the prostanoid system and inversely. Key to this connection is the production of the cyclooxygenase (COX) substrate arachidonic acid upon eCB hydrolysis as well as the ability of COX to metabolize the eCBs anandamide (AEA) and 2-arachidonoylglycerol (2-AG) into prostaglandin-ethanolamides (PG-EA) and prostaglandin-glycerol esters (PG-G), respectively. Recent studies shed light on the role of PG-Gs and PG-EAs in nociception and inflammation. Here, we discuss the role of these complex systems in nociception and new opportunities to alleviate pain by interacting with them.
Topics: Animals; Endocannabinoids; Humans; Pain; Prostaglandin-Endoperoxide Synthases; Prostaglandins
PubMed: 31160168
DOI: 10.1016/j.molmed.2019.04.009 -
Handbook of Experimental Pharmacology 2020Prostaglandins (PGs) are highly bioactive fatty acids. PGs, especially prostaglandin E (PGE), are abundantly produced by cells of both the bone-forming (osteoblast)...
Prostaglandins (PGs) are highly bioactive fatty acids. PGs, especially prostaglandin E (PGE), are abundantly produced by cells of both the bone-forming (osteoblast) lineage and the bone-resorbing (osteoclast) lineage. The inducible cyclooxygenase, COX-2, is largely responsible for most PGE production in bone, and once released, PGE is rapidly degraded in vivo. COX-2 is induced by multiple agonists - hormones, growth factors, and proinflammatory factors - and the resulting PGE may mediate, amplify, or, as we have recently shown for parathyroid hormone (PTH), inhibit responses to these agonists. In vitro, PGE can directly stimulate osteoblast differentiation and, indirectly via stimulation of RANKL in osteoblastic cells, stimulate the differentiation of osteoclasts. The net balance of these two effects of PGE in vivo on bone formation and bone resorption has been hard to predict and, as expected for such a widespread local factor, hard to study. Some of the complexity of PGE actions on bone can be explained by the fact that there are four receptors for PGE (EP1-4). Some of the major actions of PGE in vitro occur via EP2 and EP4, both of which can stimulate cAMP signaling, but there are other distinct signaling pathways, important in other tissues, which have not yet been fully elucidated in bone cells. Giving PGE or agonists of EP2 and EP4 to accelerate bone repair has been examined with positive results. Further studies to clarify the pathways of PGE action in bone may allow us to identify new and more effective ways to deliver the therapeutic benefits of PGE in skeletal disorders.
Topics: Bone Resorption; Humans; Osteoclasts; Prostaglandins; Receptors, Prostaglandin E, EP4 Subtype
PubMed: 31820176
DOI: 10.1007/164_2019_332 -
Biomolecules May 2021Organ fibrosis is a common pathological result of various chronic diseases with multiple causes. Fibrosis is characterized by the excessive deposition of extracellular... (Review)
Review
Organ fibrosis is a common pathological result of various chronic diseases with multiple causes. Fibrosis is characterized by the excessive deposition of extracellular matrix and eventually leads to the destruction of the tissue structure and impaired organ function. Prostaglandins are produced by arachidonic acid through cyclooxygenases and various prostaglandin-specific synthases. Prostaglandins bind to homologous receptors on adjacent tissue cells in an autocrine or paracrine manner and participate in the regulation of a series of physiological or pathological processes, including fibrosis. This review summarizes the properties, synthesis, and degradation of various prostaglandins, as well as the roles of these prostaglandins and their receptors in fibrosis in multiple models to reveal the clinical significance of prostaglandins and their receptors in the treatment of fibrosis.
Topics: Animals; Autocrine Communication; Chronic Disease; Fibrosis; Humans; Paracrine Communication; Prostaglandin-Endoperoxide Synthases; Prostaglandins
PubMed: 34073892
DOI: 10.3390/biom11060789 -
CNS & Neurological Disorders Drug... 2022Neuroinflammation is characterized by dysregulated inflammatory responses localized within the brain and spinal cord. Neuroinflammation plays a pivotal role in the onset... (Review)
Review
Neuroinflammation is characterized by dysregulated inflammatory responses localized within the brain and spinal cord. Neuroinflammation plays a pivotal role in the onset of several neurodegenerative disorders and is considered a typical feature of these disorders. Microglia perform primary immune surveillance and macrophage-like activities within the central nervous system. Activated microglia are predominant players in the central nervous system response to damage related to stroke, trauma, and infection. Moreover, microglial activation per se leads to a proinflammatory response and oxidative stress. During the release of cytokines and chemokines, cyclooxygenases and phospholipase A2 are stimulated. Elevated levels of these compounds play a significant role in immune cell recruitment into the brain. Cyclic phospholipase A2 plays a fundamental role in the production of prostaglandins by releasing arachidonic acid. In turn, arachidonic acid is biotransformed through different routes into several mediators that are endowed with pivotal roles in the regulation of inflammatory processes. Some experimental models of neuroinflammation exhibit an increase in cyclic phospholipase A2, leukotrienes, and prostaglandins such as prostaglandin E2, prostaglandin D2, or prostacyclin. However, findings on the role of the prostacyclin receptors have revealed that their signalling suppresses Th2-mediated inflammatory responses. In addition, other in vitro evidence suggests that prostaglandin E2 may inhibit the production of some inflammatory cytokines, attenuating inflammatory events such as mast cell degranulation or inflammatory leukotriene production. Based on these conflicting experimental data, the role of arachidonic acid derivatives in neuroinflammation remains a challenging issue.
Topics: Animals; Arachidonic Acid; Brain; Humans; Inflammation; Macrophage Activation; Microglia; Neuroinflammatory Diseases; Prostaglandins; Signal Transduction
PubMed: 33557740
DOI: 10.2174/1871527320666210208130412 -
Journal of Ocular Pharmacology and... May 2020Matrix metalloproteinases (MMPs) are a family of proteolytic enzymes that degrade extracellular matrix (ECM) components such as collagen and have important roles in... (Review)
Review
Matrix metalloproteinases (MMPs) are a family of proteolytic enzymes that degrade extracellular matrix (ECM) components such as collagen and have important roles in multiple biological processes, including development and tissue remodeling, both in health and disease. The activity of MMPs is influenced by the expression of MMPs and tissue inhibitors of metalloproteinase (TIMPs). In the eye, MMP-mediated ECM turnover in the juxtacanalicular region of the trabecular meshwork (TM) reduces outflow resistance in the conventional outflow pathway and helps maintain intraocular pressure (IOP) homeostasis. An imbalance in the MMP/TIMP ratio may be involved in the elevated IOP often associated with glaucoma. The prostaglandin analog/prostamide (PGA) class of topical ocular hypotensive medications used in glaucoma treatment reduces IOP by increasing outflow through both conventional and unconventional (uveoscleral) outflow pathways. Evidence from and studies using animal models and anterior segment explant and cell cultures indicates that the mechanism of IOP lowering by PGAs involves increased MMP expression in the TM and ciliary body, leading to tissue remodeling that enhances conventional and unconventional outflow. PGA effects on MMP expression are dependent on the identity and concentration of the PGA. An intracameral sustained-release PGA implant (Bimatoprost SR) in development for glaucoma treatment can reduce IOP for many months after expected intraocular drug bioavailability. We hypothesize that the higher concentrations of bimatoprost achieved in ocular outflow tissues with the implant produce greater MMP upregulation and more extensive, sustained MMP-mediated target tissue remodeling, providing an extended duration of effect.
Topics: Administration, Topical; Animals; Antihypertensive Agents; Bimatoprost; Ciliary Body; Collagen; Drug Implants; Extracellular Matrix; Glaucoma; Homeostasis; Humans; Intraocular Pressure; Matrix Metalloproteinases; Models, Animal; Prostaglandins, Synthetic; Tissue Inhibitor of Metalloproteinases; Trabecular Meshwork
PubMed: 32233938
DOI: 10.1089/jop.2019.0146 -
British Journal of Pharmacology Apr 2019This article is part of a themed section on Eicosanoids 35 years from the 1982 Nobel: where are we now? To view the other articles in this section visit...
This article is part of a themed section on Eicosanoids 35 years from the 1982 Nobel: where are we now? To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v176.8/issuetoc.
Topics: Animals; History, 20th Century; Humans; Nobel Prize; Physiology; Prostaglandin-Endoperoxide Synthases; Prostaglandins
PubMed: 30953367
DOI: 10.1111/bph.14588