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Molecules (Basel, Switzerland) Aug 2023Aging increases oxidative and inflammatory stress caused by a reduction in metabolism and clearance, thus leading to the development of age-associated diseases. The... (Review)
Review
Aging increases oxidative and inflammatory stress caused by a reduction in metabolism and clearance, thus leading to the development of age-associated diseases. The quality of our daily diet and exercise is important for the prevention of these diseases. Marine resources contain various valuable nutrients, and unique glycerophospholipid plasmalogens are found abundantly in some marine invertebrates, including ascidians. One of the major classes, the ethanolamine class (PlsEtn), exists in a high ratio to phospholipids in the brain and blood, while decreased levels have been reported in patients with age-associated diseases, including Alzheimer's disease. Animal studies have shown that the administration of marine PlsEtn prepared from marine invertebrates improved PlsEtn levels in the body and alleviated inflammation. Animal and human studies have reported that marine PlsEtn ameliorates cognitive impairment. In this review, we highlight the biological significance, relationships with age-associated diseases, food functions, and healthcare materials of plasmalogens based on recent knowledge and discuss the contribution of marine plasmalogens to health maintenance in aging.
Topics: Animals; Humans; Plasmalogens; Brain; Cognitive Dysfunction; Aging; Alzheimer Disease
PubMed: 37687157
DOI: 10.3390/molecules28176328 -
Current Opinion in Lipidology Oct 2023To explore the multiple roles that lysophosphatidic acid (LPA) plays in vascular disease and atherosclerosis. (Review)
Review
PURPOSE OF REVIEW
To explore the multiple roles that lysophosphatidic acid (LPA) plays in vascular disease and atherosclerosis.
RECENT FINDINGS
A high-fat high-cholesterol diet decreases antimicrobial activity in the small intestine, which leads to increased levels of bacterial lipopolysaccharide in the mucus of the small intestine and in plasma that increase systemic inflammation, and enhance dyslipidemia and aortic atherosclerosis. Decreasing LPA production in enterocytes reduces the impact of the diet. LPA signaling inhibits glucagon-like peptide 1 secretion, promotes atherosclerosis, increases vessel permeability and infarct volume in stroke, but protects against abdominal aortic aneurysm formation and rupture. Acting through the calpain system in lymphatic endothelial cells, LPA reduces the trafficking of anti-inflammatory Treg lymphocytes, which enhances atherosclerosis. Acting through LPA receptor 1 in cardiac lymphatic endothelial cells and fibroblasts, LPA enhances hypertrophic cardiomyopathy.
SUMMARY
LPA plays multiple roles in vascular disease and atherosclerosis that is cell and context dependent. In some settings LPA promotes these disease processes and in others it inhibits the disease process. Because LPA is so ubiquitous, therapeutic approaches targeting LPA must be as specific as possible for the cells and the context in which the disease process occurs.
Topics: Humans; Endothelial Cells; Lysophospholipids; Atherosclerosis; Intestine, Small
PubMed: 37497844
DOI: 10.1097/MOL.0000000000000890 -
Science Signaling Aug 2023TPC2 is a pathophysiologically relevant lysosomal ion channel that is activated directly by the phosphoinositide PI(3,5)P and indirectly by the calcium ion...
TPC2 is a pathophysiologically relevant lysosomal ion channel that is activated directly by the phosphoinositide PI(3,5)P and indirectly by the calcium ion (Ca)-mobilizing molecule NAADP through accessory proteins that associate with the channel. TPC2 toggles between PI(3,5)P-induced, sodium ion (Na)-selective and NAADP-induced, Ca-permeable states in response to these cues. To address the molecular basis of polymodal gating and ion-selectivity switching, we investigated the mechanism by which NAADP and its synthetic functional agonist, TPC2-A1-N, induced Ca release through TPC2 in human cells. Whereas NAADP required the NAADP-binding proteins JPT2 and LSM12 to evoke endogenous calcium ion signals, TPC2-A1-N did not. Residues in TPC2 that bind to PI(3,5)P were required for channel activation by NAADP but not for activation by TPC2-A1-N. The cryptic voltage-sensing region of TPC2 was required for the actions of TPC2-A1-N and PI(3,5)P but not for those of NAADP. These data mechanistically distinguish natural and synthetic agonist action at TPC2 despite convergent effects on Ca permeability and delineate a route for pharmacologically correcting impaired NAADP-evoked Ca signals.
Topics: Humans; Calcium; Permeability; Cues; Phosphatidylinositols; Research Personnel
PubMed: 37607219
DOI: 10.1126/scisignal.adg0661 -
Current Opinion in Cell Biology Jun 2024Phosphoinositides broadly impact membrane dynamics, signal transduction and cellular physiology. The orchestration of signaling complexity by this seemingly simple... (Review)
Review
Phosphoinositides broadly impact membrane dynamics, signal transduction and cellular physiology. The orchestration of signaling complexity by this seemingly simple metabolic pathway remains an open question. It is increasingly evident that comprehending the complexity of the phosphoinositides metabolic network requires a systems view based on nonlinear dynamics, where the products of metabolism can either positively or negatively modulate enzymatic function. These feedback and feedforward loops may be paradoxical, leading to counterintuitive effects. In this review, we introduce the framework of nonlinear dynamics, emphasizing distinct dynamical regimes such as the excitable state, oscillations, and mixed-mode oscillations-all of which have been experimentally observed in phosphoinositide metabolisms. We delve into how these dynamical behaviors arise from one or multiple network motifs, including positive and negative feedback loops, coherent and incoherent feedforward loops. We explore the current understanding of the molecular circuits responsible for these behaviors. While mapping these circuits presents both conceptual and experimental challenges, redefining cellular behavior based on dynamical state, lipid fluxes, time delay, and network topology is likely essential for a comprehensive understanding of this fundamental metabolic network.
Topics: Phosphatidylinositols; Humans; Animals; Nonlinear Dynamics; Signal Transduction; Metabolic Networks and Pathways; Models, Biological
PubMed: 38797149
DOI: 10.1016/j.ceb.2024.102373 -
Pharmacology & Therapeutics Sep 2023MFSD2B has been identified as the exclusive sphingosine-1-phosphate (S1P) transporter in red blood cells (RBC) and platelets. MFSD2B-mediated S1P export from platelets... (Review)
Review
MFSD2B has been identified as the exclusive sphingosine-1-phosphate (S1P) transporter in red blood cells (RBC) and platelets. MFSD2B-mediated S1P export from platelets is required for aggregation and thrombus formation, whereas RBC MFSD2B maintains plasma S1P levels in concert with SPNS2, the vascular and lymphatic endothelial cell S1P exporter, to control endothelial permeability and ensure normal vascular development. However, the physiological function of MFSD2B in RBC remains rather elusive despite mounting evidence that the intracellular S1P pool plays important roles in RBC glycolysis, adaptation to hypoxia and the regulation of cell shape, hydration, and cytoskeletal organisation. The large accumulation of S1P and sphingosine in MFSD2B-deficient RBC coincides with stomatocytosis and membrane abnormalities, the reasons for which have remained obscure. MFS family members transport substrates in a cation-dependent manner along electrochemical gradients, and disturbances in cation permeability are known to alter cell hydration and shape in RBC. Furthermore, the mfsd2 gene is a transcriptional target of GATA together with mylk3, the gene encoding myosin light chain kinase (MYLK). S1P is known to activate MYLK and thereby impact on myosin phosphorylation and cytoskeletal architecture. This suggests that metabolic, transcriptional and functional interactions may exist between MFSD2B-mediated S1P transport and RBC deformability. Here, we review the evidence for such interactions and the implications for RBC homeostasis.
Topics: Humans; Erythrocytes; Homeostasis; Lysophospholipids; Sphingosine
PubMed: 37390971
DOI: 10.1016/j.pharmthera.2023.108483 -
Immunological Reviews Aug 2023In addition to direct activation by pathogens and antigens, immune cell functions are further modulated by factors in their environment. Recent studies have revealed... (Review)
Review
In addition to direct activation by pathogens and antigens, immune cell functions are further modulated by factors in their environment. Recent studies have revealed that lysophospholipids (LPL) derived from membrane glycerophospholipids are such environmental factors. They are produced by the action of various phospholipases and modulate immune responses positively or negatively via G-protein-coupled receptor-type receptors. These include lysophosphatidic acid, lysophosphatidylserine (LysoPS), and lysophosphatidylinositol. Here, we summarize what is known about the synthetic pathways, receptors, and immunomodulatory functions of these LPLs. Particular focus is given to LysoPS, which have recently been identified, and recent findings on their immunomodulatory actions are presented.
Topics: Humans; Signal Transduction; Receptors, G-Protein-Coupled; Lysophospholipids
PubMed: 37036835
DOI: 10.1111/imr.13204 -
ACS Chemical Biology Aug 2023-Acyl-phosphatidylethanolamine hydrolyzing phospholipase D (NAPE-PLD) is a zinc metallohydrolase that hydrolyzes -acyl-phosphatidylethanolamines (NAPEs) to form...
-Acyl-phosphatidylethanolamine hydrolyzing phospholipase D (NAPE-PLD) is a zinc metallohydrolase that hydrolyzes -acyl-phosphatidylethanolamines (NAPEs) to form -acyl-ethanolamines (NAEs) and phosphatidic acid. Several lines of evidence suggest that reduced NAPE-PLD activity could contribute to cardiometabolic diseases. For instance, expression is reduced in human coronary arteries with unstable atherosclerotic lesions, defective efferocytosis is implicated in the enlargement of necrotic cores of these lesions, and NAPE-PLD products such as palmitoylethanolamide and oleoylethanolamide have been shown to enhance efferocytosis. Thus, enzyme activation mediated by a small molecule may serve as a therapeutic treatment for cardiometabolic diseases. As a proof-of-concept study, we sought to identify small molecule activators of NAPE-PLD. High-throughput screening followed by hit validation and primary lead optimization studies identified a series of benzothiazole phenylsulfonyl-piperidine carboxamides that variably increased activity of both mouse and human NAPE-PLD. From this set of small molecules, two NAPE-PLD activators ( and ) were shown to increase efferocytosis by bone-marrow derived macrophages isolated from wild-type mice, while efferocytosis was significantly reduced in BMDM or after Nape-pld inhibition. Together, these studies demonstrate an essential role for NAPE-PLD in the regulation of efferocytosis and the potential value of NAPE-PLD activators as a strategy to treat cardiometabolic diseases.
Topics: Mice; Humans; Animals; Phospholipase D; Phosphatidylethanolamines; Brain; Macrophages; Cardiovascular Diseases
PubMed: 37531659
DOI: 10.1021/acschembio.3c00401 -
Placenta Mar 2024Placental phospholipid synthesis is critical for the expansion of the placental exchange surface area and for production of signaling molecules. Despite their...
INTRODUCTION
Placental phospholipid synthesis is critical for the expansion of the placental exchange surface area and for production of signaling molecules. Despite their importance, it is not yet established which enzymes involved in the de novo synthesis and remodeling of placental phospholipids are expressed and active in the human placenta.
METHODS
We identified phospholipid synthesis enzymes by immunoblotting in placental homogenates and immunofluorescence in placenta tissue sections. Primary human trophoblast (PHT) cells from term healthy placentas (n = 10) were cultured and exposed to C labeled fatty acids (16:0, 18:1 and 18:2 n-6, 22:6 n-3) for 2 and 24 h. Three phospholipid classes; phosphatidic acid, phosphatidylcholine, and lysophosphatidylcholine containing C fatty acids were quantified by Liquid Chromatography with tandem mass spectrometry (LC/MS-MS).
RESULTS
Acyl transferase and phospholipase enzymes were detected in human placenta homogenate and primarily expressed in the syncytiotrophoblast. Three representative C fatty acids (16:0, 18:1 and 18:2 n-6) were incorporated rapidly into phosphatidic acid in trophoblasts, but C labeled docosahexaenoic acid (DHA; 22:6 n-3) incorporation was not detected. C DHA was incorporated into phosphatidylcholine. Lysophosphatidylcholine containing all four C labeled fatty acids were found in high abundance.
CONCLUSIONS
Phospholipid synthesis and remodeling enzymes are present in the syncytiotrophoblast. C labeled fatty acids were rapidly incorporated into cellular phospholipids. C DHA was incorporated into phospholipids through the remodeling pathway rather than by de novo synthesis. These understudied pathways are highly active and critical for structure and function of the placenta.
Topics: Humans; Pregnancy; Female; Placenta; Phospholipids; Lysophosphatidylcholines; Fatty Acids; Phosphatidylcholines
PubMed: 38278000
DOI: 10.1016/j.placenta.2024.01.007 -
Cells Sep 2023Lysophosphatidic acid (LPA) signalling is essential for maintaining germ cell viability during mouse spermatogenesis; however, its role in human spermatozoa is unknown....
Lysophosphatidic acid (LPA) signalling is essential for maintaining germ cell viability during mouse spermatogenesis; however, its role in human spermatozoa is unknown. We previously demonstrated that peroxiredoxin 6 (PRDX6) calcium-independent phospholipase A (iPLA) releases lysophospholipids such as LPA or arachidonic acid (AA) and that inhibiting PRDX6 iPLA activity impairs sperm cell viability. The exogenous addition of LPA bypassed the inhibition of PRDX6 iPLA activity and maintained the active phosphoinositide 3-kinase (PI3K)/AKT pathway. Here, we aimed to study PI3K/AKT pathway regulation via LPA signalling and protein kinases in maintaining sperm viability. The localization of LPARs in human spermatozoa was determined using immunocytochemistry, and P-PI3K and P-AKT substrate phosphorylations via immunoblotting. Sperm viability was determined using the hypo-osmotic swelling test. LPAR1, 3, 5 and 6 were located on the sperm plasma membrane. The inhibition of LPAR1-3 with Ki16425 promoted the impairment of sperm viability and decreased the phosphorylation of PI3K AKT substrates. Inhibitors of PKC, receptor-type PTK and PLC impaired sperm viability and the PI3K/AKT pathway. Adding 1-oleoyl-2-acetyl-snglycerol (OAG), a cell-permeable analog of diacylglycerol (DAG), prevented the loss of sperm viability and maintained the phosphorylation of PI3K. In conclusion, human sperm viability is supported by LPAR signalling and regulated by PLC, PKC and RT-PTK by maintaining phosphorylation levels of PI3K and AKT substrates.
Topics: Humans; Male; Lysophospholipids; Peroxiredoxin VI; Phosphatidylinositol 3-Kinases; Proto-Oncogene Proteins c-akt; Semen
PubMed: 37681929
DOI: 10.3390/cells12172196 -
The FEBS Journal May 2024Phosphatidic acid (PA), the simplest phospholipid, acts as a key metabolic intermediate and second messenger that impacts diverse cellular and physiological processes... (Review)
Review
Phosphatidic acid (PA), the simplest phospholipid, acts as a key metabolic intermediate and second messenger that impacts diverse cellular and physiological processes across species ranging from microbes to plants and mammals. The cellular levels of PA dynamically change in response to stimuli, and multiple enzymatic reactions can mediate its production and degradation. PA acts as a signalling molecule and regulates various cellular processes via its effects on membrane tethering, enzymatic activities of target proteins, and vesicular trafficking. Because of its unique physicochemical properties compared to other phospholipids, PA has emerged as a class of new lipid mediators influencing membrane structure, dynamics, and protein interactions. This review summarizes the biosynthesis, dynamics, and cellular functions and properties of PA.
Topics: Phosphatidic Acids; Humans; Animals; Signal Transduction; Cell Membrane
PubMed: 37103336
DOI: 10.1111/febs.16809