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Scientific Reports Mar 2023There is increasing evidence of sex differences in underlying mechanisms causing pain in preclinical models, and in clinical populations. There are also important... (Review)
Review
There is increasing evidence of sex differences in underlying mechanisms causing pain in preclinical models, and in clinical populations. There are also important disconnects between clinical pain populations and the way preclinical pain studies are conducted. For instance, osteoarthritis pain more frequently affects women, but most preclinical studies have been conducted using males in animal models. The most widely used painkillers, nonsteroidal anti-inflammatory drugs (NSAIDs), act on the prostaglandin pathway by inhibiting cyclooxygenase (COX) enzymes. The purpose of this study was to analyze the preclinical and clinical literature on the role of prostaglandins and COX in inflammation and pain. We aimed to specifically identify studies that used both sexes and investigate whether any sex-differences in the action of prostaglandins and COX inhibition had been reported, either in clinical or preclinical studies. We conducted a PubMed search and identified 369 preclinical studies and 100 clinical studies that matched our inclusion/exclusion criteria. Our analysis shows that only 17% of preclinical studies on prostaglandins used both sexes and, out of those, only 19% analyzed or reported data separated by sex. In contrast, 79% of the clinical studies analyzed used both sexes. However, only 6% of those reported data separated by sex. Interestingly, 14 out of 15 preclinical studies and 5 out of 6 clinical studies that analyzed data separated by sex have identified sex-differences. This builds on the increasing evidence of sex-differences in prostaglandin signaling and the importance of sex as a biological variable in data analysis. The preclinical literature identifies a sex difference in prostaglandin D synthase (PTGDS) expression where it is higher in female than in male rodents in the nervous system. We experimentally validated that PTGDS expression is higher in female human dorsal root ganglia (DRG) neurons recovered from organ donors. Our semi-systematic literature review reveals a need for continued inclusivity of both male and female animals in prostaglandins studies and data analysis separated by sex in preclinical and clinical studies. Our finding of sex-differences in neuronal PTGDS expression in humans exemplifies the need for a more comprehensive understanding of how the prostaglandin system functions in the DRG in rodents and humans.
Topics: Animals; Female; Humans; Male; Cyclooxygenase 2; Pain; Prostaglandins; Sensory Receptor Cells; Sex Characteristics
PubMed: 36949072
DOI: 10.1038/s41598-023-31603-x -
Proceedings of the National Academy of... May 2023Mast cells play pivotal roles in innate host defenses against venom. Activated mast cells release large amounts of prostaglandin D (PGD). However, the role of PGD in...
Mast cells play pivotal roles in innate host defenses against venom. Activated mast cells release large amounts of prostaglandin D (PGD). However, the role of PGD in such host defense remains unclear. We found that c-kit-dependent and c-kit-independent mast cell-specific hematopoietic prostaglandin D synthase () deficiency significantly exacerbated honey bee venom (BV)-induced hypothermia and increased mortality rates in mice. BV absorption via postcapillary venules in the skin was accelerated upon endothelial barrier disruption resulting in increased plasma venom concentrations. These results suggest that mast cell-derived PGD may enhance host defense against BV and save lives by inhibiting BV absorption into circulation.
Topics: Animals; Mice; Prostaglandins; Mast Cells; Prostaglandin D2; Bee Venoms; Subcutaneous Absorption; Intramolecular Oxidoreductases; Allergens
PubMed: 37216530
DOI: 10.1073/pnas.2300284120 -
British Journal of Pharmacology Apr 2019In contrast to the availability of potent and selective antagonists of several prostaglandin receptor types (including DP , DP , EP and TP receptors), there has been a... (Review)
Review
In contrast to the availability of potent and selective antagonists of several prostaglandin receptor types (including DP , DP , EP and TP receptors), there has been a paucity of well-characterized, selective FP receptor antagonists. The earliest ones included dimethyl amide and dimethyl amine derivatives of PGF , but these have failed to gain prominence. The fluorinated PGF analogues, AL-8810 and AL-3138, were subsequently discovered as competitive and non-competitive FP receptor antagonists respectively. Non-prostanoid structures, such as the thiazolidinone AS604872, the D-amino acid-based oligopeptide PDC31 and its peptidomimic analogue PDC113.824 came next, but the latter two are allosteric inhibitors of FP receptor signalling. AL-8810 has a sub-micromolar in vitro potency and ≥2 log unit selectivity against most other PG receptors when tested in several cell- and tissue-based functional assays. Additionally, AL-8810 has demonstrated therapeutic efficacy as an FP receptor antagonist in animal models of stroke, traumatic brain injury, multiple sclerosis, allodynia and endometriosis. Consequently, it appears that AL-8810 has become the FP receptor antagonist of choice. LINKED ARTICLES: 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; Dinoprost; Drug Discovery; Humans; Prostaglandins F, Synthetic; Receptors, Prostaglandin
PubMed: 29679483
DOI: 10.1111/bph.14335 -
Development (Cambridge, England) May 2023Cilia are essential for the ontogeny and function of many tissues, including the kidney. Here, we report that transcription factor ERRγ ortholog estrogen related...
Cilia are essential for the ontogeny and function of many tissues, including the kidney. Here, we report that transcription factor ERRγ ortholog estrogen related receptor gamma a (Esrrγa) is essential for renal cell fate choice and ciliogenesis in zebrafish. esrrγa deficiency altered proximodistal nephron patterning, decreased the multiciliated cell populace and disrupted ciliogenesis in the nephron, Kupffer's vesicle and otic vesicle. These phenotypes were consistent with interruptions in prostaglandin signaling, and we found that ciliogenesis was rescued by PGE2 or the cyclooxygenase enzyme Ptgs1. Genetic interaction revealed that peroxisome proliferator-activated receptor gamma, coactivator 1 alpha (Ppargc1a), which acts upstream of Ptgs1-mediated prostaglandin synthesis, has a synergistic relationship with Esrrγa in the ciliogenic pathway. These ciliopathic phenotypes were also observed in mice lacking renal epithelial cell (REC) ERRγ, where significantly shorter cilia formed on proximal and distal tubule cells. Decreased cilia length preceded cyst formation in REC-ERRγ knockout mice, suggesting that ciliary changes occur early during pathogenesis. These data position Esrrγa as a novel link between ciliogenesis and nephrogenesis through regulation of prostaglandin signaling and cooperation with Ppargc1a.
Topics: Animals; Mice; Zebrafish; Zebrafish Proteins; Nephrons; Kidney; Prostaglandins; Cilia
PubMed: 37232416
DOI: 10.1242/dev.201411 -
International Journal of Molecular... May 2023Arachidonic acid (AA) is a polyunsaturated fatty acid that is involved in male fertility. Human seminal fluid contains different prostaglandins: PGE (PGE and PGE), PGF,... (Review)
Review
Arachidonic acid (AA) is a polyunsaturated fatty acid that is involved in male fertility. Human seminal fluid contains different prostaglandins: PGE (PGE and PGE), PGF, and their specific 19-hydroxy derivatives, 18,19-dehydro derivatives of PGE and PGE. The objective of this study is to synthesize the available literature of in vivo animal studies and human clinical trials on the association between the AA pathway and male fertility. PGE is significantly decreased in the semen of infertile men, suggesting the potential for exploitation of PGE agonists to improve male fertility. Indeed, ibuprofen can affect male fertility by promoting alterations in sperm function and standard semen parameters. The results showed that targeting the AA pathways could be an attractive strategy for the treatment of male fertility.
Topics: Animals; Male; Humans; Semen; Arachidonic Acid; Prostaglandins E; Prostaglandins; Fertility
PubMed: 37175913
DOI: 10.3390/ijms24098207 -
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 -
Prostaglandins & Other Lipid Mediators Jun 2020The cyclopentenone prostaglandins (CyPGs) are a small group compounds that are a subset of the eicosanoid superfamily, which are metabolites of arachidonic acid as well... (Review)
Review
The cyclopentenone prostaglandins (CyPGs) are a small group compounds that are a subset of the eicosanoid superfamily, which are metabolites of arachidonic acid as well as other polyunsaturated fatty acids. The CyPGs are defined by a structural feature, namely, a five-membered carbocyclic ring containing an alfa-beta unsaturated keto group. The two most studied members are PGA and 15d-PGJ (15-deoxy-Δ12,14-prostaglandin J); other less studied members are PGA, Δ-PGJ, and PGJ. They are involved in a number of biological activities including the ability to resolve chronic inflammation and the growth and survival of cells, particularly those of cancerous or neurological origin. Also, they can activate the prostaglandin DP2 receptor as well as the ligand-dependent transcription factor PPAR-gamma. Their ability to promote the resolution of chronic inflammation makes it of particular interest to have a good understanding of their actions. Since their discovery, the literature on the CyPGs has greatly expanded both in size and in scope; these reports are covered in the current review.
Topics: Animals; Humans; Inflammation; Neoplasms; Prostaglandins
PubMed: 31931079
DOI: 10.1016/j.prostaglandins.2020.106408 -
Reproduction (Cambridge, England) Jan 2015Prostaglandins signaling molecules are involved in numerous physiological processes. They are produced by several enzyme-limited reactions upon fatty acids, which are... (Review)
Review
Prostaglandins signaling molecules are involved in numerous physiological processes. They are produced by several enzyme-limited reactions upon fatty acids, which are catalyzed by two cyclooxygenases and prostaglandin synthases. In particular, the prostaglandins E2 (PGE2), D2 (PGD2), and F2 (PGF2 α) have been shown to be involved in female reproductive mechanisms. Furthermore, widespread expression of lipocalin- and hematopoietic-PGD2 synthases in the male reproductive tract supports the purported roles of PGD2 in the development of both embryonic and adult testes, sperm maturation, and spermatogenesis. In this review, we summarize the putative roles of PGD2 signaling and the roles of both PGD2 synthases in testicular formation and function. We review the data reporting the involvement of PGD2 signaling in the differentiation of Sertoli and germ cells of the embryonic testis. Furthermore, we discuss the roles of lipocalin-PGD2 synthase in steroidogenesis and spermatogenesis, in terms of lipid molecule transport and PGD2 production. Finally, we discuss the hypothesis that PGD2 signaling may be affected in certain reproductive diseases, such as infertility, cryptorchidism, and testicular cancer.
Topics: Adult; Female; Humans; Male; Prostaglandin D2; Reproduction; Signal Transduction
PubMed: 25269616
DOI: 10.1530/REP-14-0381 -
Antioxidants & Redox Signaling Apr 2021Endothelial cells lining the lumen of blood vessels play an important role in the regulation of cardiovascular functions through releasing both vasoconstricting and... (Review)
Review
Endothelial cells lining the lumen of blood vessels play an important role in the regulation of cardiovascular functions through releasing both vasoconstricting and vasodilating factors. The production and function of vasoconstricting factors are largely elevated in hypertension, diabetes, atherosclerosis, and ischemia/reperfusion injuries. Cyclooxygenases (COXs) are the major enzymes producing five different prostanoids that act as either contracting or relaxing substances. Under conditions of increased oxidative stress, the expressions and activities of COX isoforms are altered, resulting in changes in production of various prostanoids and thus affecting vascular tone. This review briefly summarizes the relationship between oxidative stress, COXs, and prostanoids, thereby providing new insights into the pathophysiological mechanisms of cardiovascular diseases (CVDs). Many new drugs targeting oxidative stress, COX-2, and prostanoids against common CVDs have been evaluated in recent years and they are summarized in this review. Comprehensive understanding of the complex interplay between oxidative stress, COXs, and prostanoids in CVDs helps develop more effective measures against cardiovascular pathogenesis. Apart from minimizing the undesired effects of harmful prostanoids, future studies shall investigate the restoration of vasoprotective prostanoids as a means to combat CVDs. 34, 784-799.
Topics: Animals; Atherosclerosis; Cardiovascular Diseases; Cardiovascular System; Cyclooxygenase 2; Cyclooxygenase 2 Inhibitors; Endothelial Cells; Humans; Oxidative Stress; Prostaglandin Antagonists; Prostaglandin-Endoperoxide Synthases; Prostaglandins
PubMed: 32323554
DOI: 10.1089/ars.2020.8105 -
Acta Dermato-venereologica Mar 2018Prostanoids, including prostaglandins (PGs) and thromboxane A2 (TXA2), are a family of lipid-derived autacoids that modulate many physiological systems and pathological... (Review)
Review
Prostanoids, including prostaglandins (PGs) and thromboxane A2 (TXA2), are a family of lipid-derived autacoids that modulate many physiological systems and pathological contexts. Prostanoids are generated by sequential metabolism of arachidonic acid, catalysed by cyclo-oxygenase, to PGH2, which is then converted to PGD2, PGE2, PGF2α, PGI2 and TXA2, catalysed by their specific synthases. Recent evidence suggests that prostanoids play a role in regulating hair growth. The PGF2α analogue is Food and Drug Administration-approved in the US and routinely used to enhance the growth of human eyelashes. PGE2 is reported to protect from radiation-induced hair loss in mice. Conversely, PGD2 inhibits hair growth. This paper reviews the metabolism of prostanoids and the expression pattern of prostanoid receptors in hair follicles, focussing on their different and opposing effects on hair growth and the underlying mechanisms. This has potential clinical relevance in the treatment and prevention of hair disorders.
Topics: Animals; Hair Diseases; Hair Follicle; Humans; Prostaglandins; Receptors, Prostaglandin; Regeneration; Signal Transduction
PubMed: 29136266
DOI: 10.2340/00015555-2843