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International Journal of Molecular... Nov 2021Arachidonic acid (AA) is an essential fatty acid that is released by phospholipids in cell membranes and metabolized by cyclooxygenase (COX), cytochrome P450 (CYP)... (Review)
Review
Arachidonic acid (AA) is an essential fatty acid that is released by phospholipids in cell membranes and metabolized by cyclooxygenase (COX), cytochrome P450 (CYP) enzymes, and lipid oxygenase (LOX) pathways to regulate complex cardiovascular function under physiological and pathological conditions. Various AA metabolites include prostaglandins, prostacyclin, thromboxanes, hydroxyeicosatetraenoic acids, leukotrienes, lipoxins, and epoxyeicosatrienoic acids. The AA metabolites play important and differential roles in the modulation of vascular tone, and cardiovascular complications including atherosclerosis, hypertension, and myocardial infarction upon actions to different receptors and vascular beds. This article reviews the roles of AA metabolism in cardiovascular health and disease as well as their potential therapeutic implication.
Topics: Animals; Arachidonic Acid; Cardiovascular Diseases; Cardiovascular System; Humans; Lipid Metabolism; Prostaglandins
PubMed: 34769460
DOI: 10.3390/ijms222112029 -
Acta Biochimica Polonica 2014This review compiles the current knowledge on the effects of prostanoids - arachidonic acid metabolites - on their own synthesis, activity and degradation. Interaction... (Review)
Review
This review compiles the current knowledge on the effects of prostanoids - arachidonic acid metabolites - on their own synthesis, activity and degradation. Interaction mechanisms between the receptors for the relevant compounds are presented, in particular with regard to the cooperation between a thromboxane A₂ and prostaglandin I₂ receptors. The questions of desensitization and internalization of receptors are discussed. The stages of the inflammatory response and tumor progression are analyzed against the background of the disruption of the synthesis of prostanoids. Special attention is given to the significance of 15-deoxy-Δ(12,14)-prostaglandin J₂ in the regulation of the synthesis of prostanoids and its role as an anti-inflammatory agent. Ultimately, therapeutic approaches as used in various treatments are discussed in the light of the available knowledge.
Topics: Animals; Humans; Prostaglandin D2; Prostaglandin-Endoperoxide Synthases; Prostaglandins; Receptors, Epoprostenol; Receptors, Thromboxane A2, Prostaglandin H2
PubMed: 25343148
DOI: No ID Found -
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 -
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 -
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 -
Biological & Pharmaceutical Bulletin 2022Prostanoids are a group of typical lipid mediators that are biosynthesized from arachidonic acid by the actions of cyclooxygenases and their subsequent terminal... (Review)
Review
Prostanoids are a group of typical lipid mediators that are biosynthesized from arachidonic acid by the actions of cyclooxygenases and their subsequent terminal synthases. Prostanoids exert a wide variety of actions through their specific membrane receptors on target cells. In addition to their classical actions, including fever, pain, and inflammation, prostanoids have been shown to play pivotal roles in various biological processes, such as female reproduction and the maintenance of vascular and gut homeostasis. Moreover, recent research using mice deficient in each of the prostanoid receptors, or using agonists/antagonists specific for each receptor clarified novel actions of prostanoids that had long been unknown, and the mechanisms therein. In this review, we introduce recent advances in the fields of metabolic control by prostanoid receptors such as in adipocyte differentiation, lipolysis, and adipocyte browning in adipose tissues, and discuss the potential of prostanoid receptors as a treatment target for metabolic disorders.
Topics: Adipocytes; Animals; Female; Inflammation; Lipolysis; Mice; Prostaglandins; Receptors, Prostaglandin
PubMed: 35908909
DOI: 10.1248/bpb.b22-00270 -
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 -
World Journal of Gastroenterology Dec 2018The biosynthesis of prostanoids is involved in both physiological and pathological processes. The expression of prostaglandin-endoperoxide synthase 2 (PTGS2; also known... (Review)
Review
The biosynthesis of prostanoids is involved in both physiological and pathological processes. The expression of prostaglandin-endoperoxide synthase 2 (PTGS2; also known as COX-2) has been traditionally associated to the onset of several pathologies, from inflammation to cardiovascular, gastrointestinal and oncologic events. For this reason, the search of selective PTGS2 inhibitors has been a focus for therapeutic interventions. In addition to the classic non-steroidal anti-inflammatory drugs, selective and specific PTGS2 inhibitors, termed coxibs, have been generated and widely used. PTGS2 activity is less restrictive in terms of substrate specificity than the homeostatic counterpart PTGS1, and it accounts for the elevated prostanoid synthesis that accompanies several pathologies. The main regulation of PTGS2 occurs at the transcription level. In addition to this, the stability of the mRNA is finely regulated through the interaction with several cytoplasmic elements, ranging from specific microRNAs to proteins that control mRNA degradation. Moreover, the protein has been recognized to be the substrate for several post-translational modifications that affect both the enzyme activity and the targeting for degradation proteasomal and non-proteasomal mechanisms. Among these modifications, phosphorylation, glycosylation and covalent modifications by reactive lipidic intermediates and by free radicals associated to the pro-inflammatory condition appear to be the main changes. Identification of these post-translational modifications is relevant to better understand the role of PTGS2 in several pathologies and to establish a correct analysis of the potential function of this protein in diseases progress. Finally, these modifications can be used as biomarkers to establish correlations with other parameters, including the immunomodulation dependent on molecular pathological epidemiology determinants, which may provide a better frame for potential therapeutic interventions.
Topics: Biomarkers, Tumor; Colorectal Neoplasms; Cyclooxygenase 2; Cyclooxygenase 2 Inhibitors; Glycosylation; Humans; Phosphorylation; Prostaglandins; Protein Processing, Post-Translational; RNA, Messenger
PubMed: 30622375
DOI: 10.3748/wjg.v24.i48.5454 -
American Journal of Respiratory and... Sep 2022
Topics: Biomarkers; F2-Isoprostanes; Fibroblasts; Humans; Oxidative Stress; Prostaglandins; Pulmonary Fibrosis; Receptors, Prostaglandin; Receptors, Thromboxane; Thromboxanes
PubMed: 35763804
DOI: 10.1164/rccm.202205-0914ED -
Journal of Physiology and Pharmacology... Aug 2013Reactive oxygen species (ROS), such as hydrogen peroxide, superoxide anion radical or hydroxyl radical, play an important role in inflammation processes as well as in... (Review)
Review
Reactive oxygen species (ROS), such as hydrogen peroxide, superoxide anion radical or hydroxyl radical, play an important role in inflammation processes as well as in transduction of signals from receptors to interleukin -1β (IL-1β), tumor necrosis factor α (TNF-α) or lipopolysaccharides (LPS). NADPH oxidase increases the ROS levels, leading to inactivation of protein phosphatase 1 (PP1), protein phosphatase 2A (PP2A) and protein tyrosine phosphatase (PTP): MAPK phosphatase 1 (MKP-1). Inactivation of phosphatases results in activation of mitogen-activated protein kinase (MAPK) cascades: c-Jun N-terminal kinase (JNK), p38 and extracellular signal-regulated kinase (Erk), which, in turn, activate cytosolic phospholipase A₂ (cPLA₂). ROS cause cytoplasmic calcium influx by activation of phospholipase C (PLC) and phosphorylation of IP₃-sensitive calcium channels. ROS activate nuclear factor κB (NF-κB) via IκB kinase (IKK) through phosphoinositide 3-kinase (PI3K), tumor suppressor phosphatase and tensin homolog (PTEN) and protein kinase B (Akt/PKB) or NF-κB-inducing kinase (NIK). IKK phosphorylates NF-κB α subunit (IκBα) at Ser³². Oxidative stress inactivates NIK and IκB kinase γ subunit/NF-κB essential modulator (IKKγ/NEMO), which might cause activation of NF-κB that is independent on IKK and inhibitor of IκBα degradation, including phosphorylation of Tyr⁴² at IκBα by c-Src and spleen tyrosine kinase (Syk), phosphorylation of the domain rich in proline, glutamic acid, serine and threonine (PEST) sequence by casein kinase II and inactivation of protein tyrosine phosphatase 1B (PTP1B). NF-κB and MAPK cascades-activated transcription factor activator protein 1 (AP-1) and CREB-binding protein (CBP/p300) lead to expression of cytosolic phospholipase A₂ (cPLA₂), cyclooxygenase-2 (COX-2) and membrane-bound prostaglandin E synthase 1 (mPGES-1), and thus to increased release of arachidonic acid and production of prostaglandins, particularly prostaglandin E₂ (PGE₂). ROS increase the activity of hematopoietic-type PGD synthase (H-PGDS), and, as a result, the production of prostaglandin D₂ (PGD₂). However, the superoxide radical reacts with nitric oxide forming peroxynitrite that inactivates prostaglandin I synthase (PGIS), suppressing the production of prostaglandin I₂ (PGI₂). ROS do not affect thromboxane synthesis in a direct manner; this is achieved by an increase in cPLA₂ activity and COX-2 expression. The aim of this review was to summarize knowledge of influence of ROS on the synthesis of prostanoids from arachidonic acid.
Topics: Animals; Arachidonic Acid; Humans; NF-kappa B; Oxidative Stress; Phospholipases A2; Prostaglandin-Endoperoxide Synthases; Prostaglandins; Reactive Oxygen Species
PubMed: 24101387
DOI: No ID Found