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Human Reproduction Update Nov 2022Obesity has now been recognized as a high-risk factor for reproductive health. Although remarkable advancements have been made in ART, a considerable number of infertile... (Review)
Review
BACKGROUND
Obesity has now been recognized as a high-risk factor for reproductive health. Although remarkable advancements have been made in ART, a considerable number of infertile obese women still suffer from serial implantation failure, despite the high quality of embryos transferred. Although obesity has long been known to exert various deleterious effects on female fertility, the underlying mechanisms, especially the roles of lipid metabolism in endometrial receptivity, remain largely elusive.
OBJECTIVE AND RATIONALE
This review summarizes current evidence on the impacts of several major lipids and lipid-derived mediators on the embryonic implantation process. Emerging methods for evaluating endometrial receptivity, for example transcriptomic and lipidomic analysis, are also discussed.
SEARCH METHODS
The PubMed and Embase databases were searched using the following keywords: (lipid or fatty acid or prostaglandin or phospholipid or sphingolipid or endocannabinoid or lysophosphatidic acid or cholesterol or progesterone or estrogen or transcriptomic or lipidomic or obesity or dyslipidemia or polycystic ovary syndrome) AND (endometrial receptivity or uterine receptivity or embryo implantation or assisted reproductive technology or in vitro fertilization or embryo transfer). A comprehensive literature search was performed on the roles of lipid-related metabolic pathways in embryo implantation published between January 1970 and March 2022. Only studies with original data and reviews published in English were included in this review. Additional information was obtained from references cited in the articles resulting from the literature search.
OUTCOMES
Recent studies have shown that a fatty acids-related pro-inflammatory response in the embryo-endometrium boundary facilitates pregnancy via mediation of prostaglandin signaling. Phospholipid-derived mediators, for example endocannabinoids, lysophosphatidic acid and sphingosine-1-phosphate, are associated with endometrial receptivity, embryo spacing and decidualization based on evidence from both animal and human studies. Progesterone and estrogen are two cholesterol-derived steroid hormones that synergistically mediate the structural and functional alterations in the uterus ready for blastocyst implantation. Variations in serum cholesterol profiles throughout the menstrual cycle imply a demand for steroidogenesis at the time of window of implantation (WOI). Since 2002, endometrial transcriptomic analysis has been serving as a diagnostic tool for WOI dating. Numerous genes that govern lipid homeostasis have been identified and, based on specific alterations of lipidomic signatures differentially expressed in WOI, lipidomic analysis of endometrial fluid provides a possibility for non-invasive diagnosis of lipids alterations during the WOI.
WIDER IMPLICATIONS
Given that lipid metabolic dysregulation potentially plays a role in infertility, a better understanding of lipid metabolism could have significant clinical implications for the diagnosis and treatment of female reproductive disorders.
Topics: Pregnancy; Animals; Female; Humans; Progesterone; Lipid Metabolism; Endometrium; Embryo Implantation; Infertility, Female; Obesity; Lysophospholipids; Estrogens; Prostaglandins; Lipids
PubMed: 35639910
DOI: 10.1093/humupd/dmac026 -
Signal Transduction and Targeted Therapy Feb 2021The arachidonic acid (AA) pathway plays a key role in cardiovascular biology, carcinogenesis, and many inflammatory diseases, such as asthma, arthritis, etc. Esterified... (Review)
Review
The arachidonic acid (AA) pathway plays a key role in cardiovascular biology, carcinogenesis, and many inflammatory diseases, such as asthma, arthritis, etc. Esterified AA on the inner surface of the cell membrane is hydrolyzed to its free form by phospholipase A2 (PLA2), which is in turn further metabolized by cyclooxygenases (COXs) and lipoxygenases (LOXs) and cytochrome P450 (CYP) enzymes to a spectrum of bioactive mediators that includes prostanoids, leukotrienes (LTs), epoxyeicosatrienoic acids (EETs), dihydroxyeicosatetraenoic acid (diHETEs), eicosatetraenoic acids (ETEs), and lipoxins (LXs). Many of the latter mediators are considered to be novel preventive and therapeutic targets for cardiovascular diseases (CVD), cancers, and inflammatory diseases. This review sets out to summarize the physiological and pathophysiological importance of the AA metabolizing pathways and outline the molecular mechanisms underlying the actions of AA related to its three main metabolic pathways in CVD and cancer progression will provide valuable insight for developing new therapeutic drugs for CVD and anti-cancer agents such as inhibitors of EETs or 2J2. Thus, we herein present a synopsis of AA metabolism in human health, cardiovascular and cancer biology, and the signaling pathways involved in these processes. To explore the role of the AA metabolism and potential therapies, we also introduce the current newly clinical studies targeting AA metabolisms in the different disease conditions.
Topics: Arachidonic Acids; Cell Membrane; Cytochrome P-450 Enzyme System; Humans; Leukotrienes; Lipid Metabolism; Lipoxins; Lipoxygenases; Metabolic Networks and Pathways; Phospholipases A2; Prostaglandin-Endoperoxide Synthases; Prostaglandins
PubMed: 33637672
DOI: 10.1038/s41392-020-00443-w -
The Journal of Experimental Medicine Jan 2016Recent studies on intracellular metabolism in dendritic cells (DCs) and macrophages provide new insights on the functioning of these critical controllers of innate and... (Review)
Review
Recent studies on intracellular metabolism in dendritic cells (DCs) and macrophages provide new insights on the functioning of these critical controllers of innate and adaptive immunity. Both cell types undergo profound metabolic reprogramming in response to environmental cues, such as hypoxia or nutrient alterations, but importantly also in response to danger signals and cytokines. Metabolites such as succinate and citrate have a direct impact on the functioning of macrophages. Immunogenicity and tolerogenicity of DCs is also determined by anabolic and catabolic processes, respectively. These findings provide new prospects for therapeutic manipulation in inflammatory diseases and cancer.
Topics: Animals; Cell Differentiation; Dendritic Cells; Energy Metabolism; Extracellular Space; Fatty Acids; Glycolysis; Glycosylation; Humans; Immunity, Innate; Macrophage Activation; Macrophages; Metabolic Networks and Pathways; Nitric Oxide; Prostaglandins; Reactive Oxygen Species; Receptors, Estrogen; Signal Transduction; ERRalpha Estrogen-Related Receptor
PubMed: 26694970
DOI: 10.1084/jem.20151570 -
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 -
Nature Reviews. Neurology Aug 2019Epilepsy is a chronic neurological disease characterized by an enduring propensity for generation of seizures. The pathogenic processes of seizure generation and... (Review)
Review
Epilepsy is a chronic neurological disease characterized by an enduring propensity for generation of seizures. The pathogenic processes of seizure generation and recurrence are the subject of intensive preclinical and clinical investigations as their identification would enable development of novel treatments that prevent epileptic seizures and reduce seizure burden. Such treatments are particularly needed for pharmacoresistant epilepsies, which affect ~30% of patients. Neuroinflammation is commonly activated in epileptogenic brain regions in humans and is clearly involved in animal models of epilepsy. An increased understanding of neuroinflammatory mechanisms in epilepsy has identified cellular and molecular targets for new mechanistic therapies or existing anti-inflammatory drugs that could overcome the limitations of current medications, which provide only symptomatic control of seizures. Moreover, inflammatory mediators in the blood and molecular imaging of neuroinflammation could provide diagnostic, prognostic and predictive biomarkers for epilepsy, which will be instrumental for patient stratification in future clinical studies. In this Review, we focus on our understanding of the IL-1 receptor-Toll-like receptor 4 axis, the arachidonic acid-prostaglandin cascade, oxidative stress and transforming growth factor-β signalling associated with blood-brain barrier dysfunction, all of which are pathways that are activated in pharmacoresistant epilepsy in humans and that can be modulated in animal models to produce therapeutic effects on seizures, neuronal cell loss and neurological comorbidities.
Topics: Animals; Arachidonic Acid; Biomarkers; Encephalitis; Epilepsy; Humans; Oxidative Stress; Prostaglandins; Receptors, Interleukin-1; Signal Transduction; Toll-Like Receptor 4; Transforming Growth Factor beta
PubMed: 31263255
DOI: 10.1038/s41582-019-0217-x -
Journal of the National Cancer Institute Apr 2023Glyphosate is the most widely applied herbicide worldwide, and its use has been associated with increased risks of certain hematopoietic cancers in epidemiologic...
BACKGROUND
Glyphosate is the most widely applied herbicide worldwide, and its use has been associated with increased risks of certain hematopoietic cancers in epidemiologic studies. Animal and in vitro experiments suggest that glyphosate may induce oxidative stress, a key characteristic of carcinogens; however, evidence in human populations remains scarce. We investigated associations between glyphosate exposure and urinary oxidative stress biomarkers in the Biomarkers of Exposure and Effect in Agriculture study, a molecular epidemiologic subcohort in the Agricultural Health Study.
METHODS
This analysis included 268 male farmers selected based on self-reported recent and lifetime occupational glyphosate use and 100 age- and geography-matched male nonfarmers. Concentrations of glyphosate and oxidative stress biomarkers (8-hydroxy-2'-deoxyguanosine [8-OHdG], 8-iso-prostaglandin-F2α, and malondialdehyde [MDA]) were quantified in first-morning-void urine. We performed multivariable linear regression to evaluate associations of urinary glyphosate and self-reported glyphosate use with each oxidative stress biomarker.
RESULTS
Urinary glyphosate concentrations were positively associated with levels of 8-OHdG (highest vs lowest glyphosate quartile; geometric mean ratio = 1.15, 95% confidence interval = 1.03 to 1.28; Ptrend = .02) and MDA (geometric mean ratio = 1.20, 95% confidence interval = 1.03 to 1.40; Ptrend = .06) overall. Among farmers reporting recent glyphosate use (last 7 days), use in the previous day was also associated with statistically significantly increased 8-OHdG and MDA levels. Compared with nonfarmers, we observed elevated 8-iso-prostaglandin-F2α levels among farmers with recent, high past 12-month, or high lifetime glyphosate use.
CONCLUSIONS
Our findings contribute to the weight of evidence supporting an association between glyphosate exposure and oxidative stress in humans and may inform evaluations of the carcinogenic potential of this herbicide.
Topics: Animals; Humans; Male; 8-Hydroxy-2'-Deoxyguanosine; Herbicides; Oxidative Stress; Biomarkers; Agriculture; Carcinogens; Prostaglandins; Glyphosate
PubMed: 36629488
DOI: 10.1093/jnci/djac242 -
Handbook of Clinical Neurology 2018Fever depends on a complex physiologic response to infectious agents and other conditions. To alleviate fever, many medicinal agents have been developed over a century... (Review)
Review
Fever depends on a complex physiologic response to infectious agents and other conditions. To alleviate fever, many medicinal agents have been developed over a century of trying to improve upon aspirin, which was determined to work by inhibiting prostaglandin synthesis. We present the process of fever induction through prostaglandin synthesis and discuss the development of pharmaceuticals that target enzymes and receptors involved in prostaglandin-mediated signal transduction, including prostaglandin H synthase (also known as cyclooxygenase), phospholipase A, microsomal prostaglandin E synthase-1, EP receptors, and transient potential cation channel subfamily V member 1. Clinical use of established antipyretics will be discussed as well as medicinal agents under clinical trials and future research.
Topics: Animals; Antipyretics; Fever; Humans; Pharmacology, Clinical; Prostaglandins; Signal Transduction
PubMed: 30459046
DOI: 10.1016/B978-0-444-64074-1.00054-9 -
Advances in Experimental Medicine and... 2020Prostanoids (prostaglandins, prostacyclin and thromboxane) belong to the oxylipin family of biologically active lipids generated from arachidonic acid (AA). Protanoids... (Review)
Review
Prostanoids (prostaglandins, prostacyclin and thromboxane) belong to the oxylipin family of biologically active lipids generated from arachidonic acid (AA). Protanoids control numerous physiological and pathological processes. Cyclooxygenase (COX) is a rate-limiting enzyme involved in the conversion of AA into prostanoids. There are two COX isozymes: the constitutive COX-1 and the inducible COX-2. COX-1 and COX-2 have similar structures, catalytic activities, and subcellular localizations but differ in patterns of expression and biological functions. Non-selective COX-1/2 or traditional, non-steroidal anti-inflammatory drugs (tNSAIDs) target both COX isoforms and are widely used to relieve pain, fever and inflammation. However, the use of NSAIDs is associated with various side effects, particularly in the gastrointestinal tract. NSAIDs selective for COX-2 inhibition (coxibs) were purposefully designed to spare gastrointestinal toxicity, but predisposed patients to increased cardiovascular risks. These health complications from NSAIDs prompted interest in the downstream effectors of the COX enzymes as novel drug targets. This chapter describes various safety issues with tNSAIDs and coxibs, and discusses the current development of novel classes of drugs targeting the prostanoid pathway, including nitrogen oxide- and hydrogen sulfide-releasing NSAIDs, inhibitors of prostanoid synthases, dual inhibitors, and prostanoid receptor agonists and antagonists.
Topics: Anti-Inflammatory Agents, Non-Steroidal; Cyclooxygenase 2 Inhibitors; Humans; Prostaglandin Antagonists; Prostaglandin-Endoperoxide Synthases; Prostaglandins; Signal Transduction
PubMed: 32894506
DOI: 10.1007/978-3-030-50621-6_3 -
Journal of Molecular and Cellular... Jun 2022Cardiovascular diseases are the leading cause of death worldwide. A chronic inflammatory response is a common pathological alteration in diverse cardiovascular diseases.... (Review)
Review
Cardiovascular diseases are the leading cause of death worldwide. A chronic inflammatory response is a common pathological alteration in diverse cardiovascular diseases. Prostaglandin (PG) D, a key lipid mediator derived from arachidonic acid metabolism, promotes resolution of inflammation and regulated T cell function through its receptors. Accumulated evidence has shown that dysregulated PGD signaling is involved in the pathogenesis of cardiovascular diseases, including atherosclerosis, hypertension, pulmonary hypertension, abdominal aortic aneurysm, and myocardial ischemia. Here, we summarized the recent progresses on PGD in cardiovascular homeostasis and discussed potential therapeutic translation by targeting PGD signaling.
Topics: Cardiovascular Diseases; Homeostasis; Humans; Inflammation; Prostaglandin D2; Prostaglandins; Receptors, Immunologic; Receptors, Prostaglandin
PubMed: 35367459
DOI: 10.1016/j.yjmcc.2022.03.011 -
International Journal of Molecular... Aug 2021Angioedema is a life-threatening emergency event that is associated with bradykinin and histamine-mediated cascades. Although bradykinin-mediated angioedema currently... (Review)
Review
Angioedema is a life-threatening emergency event that is associated with bradykinin and histamine-mediated cascades. Although bradykinin-mediated angioedema currently has specific therapeutic options, angioedema is sometimes intractable with current treatments, especially histamine-mediated angioedema, suggesting that some other mediators might contribute to the development of angioedema. Fatty acids are an essential fuel and cell component, and act as a mediator in physiological and pathological human diseases. Recent updates of studies revealed that these fatty acids are involved in vascular permeability and vasodilation, in addition to bradykinin and histamine-mediated reactions. This review summarizes each fatty acid's function and the specific receptor signaling responses in blood vessels, and focuses on the possible pathogenetic role of fatty acids in angioedema.
Topics: Angioedema; Bradykinin; Capillary Permeability; Fatty Acids; Histamine; Humans; Prostaglandins
PubMed: 34445711
DOI: 10.3390/ijms22169000