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Biochemical Pharmacology Dec 2022In mammalian cells, phospholipids and cholesterol are assembled into bilayer membranes forming the plasma membrane, nuclear envelope, mitochondria, endoplasmic... (Review)
Review
In mammalian cells, phospholipids and cholesterol are assembled into bilayer membranes forming the plasma membrane, nuclear envelope, mitochondria, endoplasmic reticulum, Golgi apparatus, lysosomes, and endosomes. Phospholipids are divided into classes based on the molecular structures, including phosphatidylcholine, phosphatidylethanolamine, phosphatidylserine, phosphatidic acid, phosphatidylinositol, phosphatidylglycerol, cardiolipin, and sphingomyelin. In addition to their structural roles, phospholipids play important roles in many cellular processes, such as membrane protein regulation, membrane trafficking, cell growth, apoptosis, and intracellular signaling. Thus, abnormal phospholipid metabolism is associated with various diseases. In mammalian cells, phospholipid classes are generated through several enzymatic steps, predominantly in the endoplasmic reticulum, mitochondria, and Golgi apparatus. In recent years, various enzymes involved in the biosynthesis of phospholipid classes have been identified. However, little is known about the regulatory mechanisms underlying the biosynthesis of phospholipid classes. Using our recently developed enzymatic fluorometric assays for all major phospholipid classes, we have demonstrated changes in phospholipid composition in intracellular organelles during cell growth. In this review, we summarize the current understanding of the properties and functions of phospholipid biosynthesis enzymes, and discuss their regulatory mechanisms.
Topics: Animals; Phospholipids; Endoplasmic Reticulum; Mitochondria; Cell Membrane; Phosphatidylserines; Mammals
PubMed: 36241095
DOI: 10.1016/j.bcp.2022.115296 -
Molecular Biology Reports May 2023Myricetin, a type of flavonol commonly found in fruits and herbs, has demonstrated anticancer properties by triggering the process of apoptosis or programmed cell death...
BACKGROUND
Myricetin, a type of flavonol commonly found in fruits and herbs, has demonstrated anticancer properties by triggering the process of apoptosis or programmed cell death in tumor cells. Despite the absence of mitochondria and nuclei, erythrocytes can undergo programmed cell death, also known as eryptosis.This process is characterized by cell shrinkage, externalization of phosphatidylserine (PS) on the cell membrane, and the formation of membrane blebs. The signaling of eryptosis involves Ca influx, the formation of reactive oxygen species (ROS), and the accumulation of cell surface ceramide. The present study explored the effects of myricetin on eryptosis.
METHODS AND RESULTS
Human erythrocytes were exposed to various concentrations of myricetin (2-8 µM) for 24 h. Flow cytometry was used to assess the markers of eryptosis, including PS exposure, cellular volume, cytosolic Ca concentration, and ceramide accumulation. In addition, the levels of intracellular ROS were measured using the 2',7'-dichlorofluorescin diacetate (DCFDA) assay. The myricetin-treated (8 µM) erythrocytes significantly increased Annexin-positive cells, Fluo-3 fluorescence intensity, DCF fluorescence intensity, and the accumulation of ceramide. The impact of myricetin on the binding of annexin-V was significantly reduced, but not completely eliminated, by the nominal removal of extracellular Ca.
CONCLUSION
Myricetin triggers eryptosis, which is accompanied and, at least in part, caused by Ca influx, oxidative stress and increase of ceramide abundance.
Topics: Humans; Reactive Oxygen Species; Eryptosis; Oxidative Stress; Erythrocytes; Ceramides; Annexins; Calcium; Phosphatidylserines; Cell Size; Hemolysis
PubMed: 36905403
DOI: 10.1007/s11033-023-08350-3 -
Biochemical Pharmacology Jul 2023Mammalian cells contain more than a thousand different glycerophospholipid species that are essential membrane components and signalling molecules, with... (Review)
Review
Mammalian cells contain more than a thousand different glycerophospholipid species that are essential membrane components and signalling molecules, with phosphatidylserine (PS) giving membranes their negative surface charge. Depending on the tissue, PS is important in apoptosis, blood clotting, cancer pathogenesis, as well as muscle and brain function, processes that are dependent on the asymmetrical distribution of PS on the plasma membrane and/or the capacity of PS to act as anchorage for various signalling proteins. Recent studies have implicated hepatic PS in the progression of non-alcoholic fatty liver disease (NAFLD), either as beneficial in the context of suppressing hepatic steatosis and fibrosis, or on the other hand as a potential contributor to the progression of liver cancer. This review provides an extensive overview of hepatic phospholipid metabolism, including its biosynthetic pathways, intracellular trafficking and roles in health and disease, further taking a deeper dive into PS metabolism, including associate and causative evidence of the role of PS in advanced liver disease.
Topics: Animals; Humans; Non-alcoholic Fatty Liver Disease; Phosphatidylserines; Liver; Liver Neoplasms; Phospholipids; Lipid Metabolism; Mammals
PubMed: 37217141
DOI: 10.1016/j.bcp.2023.115621 -
Biochemical and Biophysical Research... Jan 2017Programmed cell clearance is a highly regulated physiological process of elimination of dying cells that occurs rapidly and efficiently in healthy organisms. It thus... (Review)
Review
Programmed cell clearance is a highly regulated physiological process of elimination of dying cells that occurs rapidly and efficiently in healthy organisms. It thus ensures proper development as well as homeostasis. Recent studies have disclosed a considerable degree of conservation of cell clearance pathways between nematodes and higher organisms. The externalization of the anionic phospholipid phosphatidylserine (PS) has emerged as an important "eat-me" signal for phagocytes and its exposition on apoptotic cells is controlled by phospholipid translocases and scramblases. However, there is mounting evidence that PS exposure occurs not only in apoptosis, but may also be actively expressed on the surface of cells undergoing other forms of cell death including necrosis; PS is also expressed on the surface of engulfing cells. Additionally, PS may act as a "save-me" signal during axonal regeneration. Here we discuss mechanisms of PS exposure and its recognition by phagocytes as well as the consequences of PS signaling in nematodes and in mammals.
Topics: Animals; Apoptosis; Caenorhabditis elegans; Cell Death; Humans; Models, Biological; Phagocytes; Phagocytosis; Phosphatidylserines; Signal Transduction
PubMed: 27919685
DOI: 10.1016/j.bbrc.2016.12.005 -
Cancer Letters Oct 2022Identifying a universal biomarker for cancer treatment remains a major challenge in cancer therapy. Extracellular exposure of phosphatidylserine (PS) is tightly... (Review)
Review
Identifying a universal biomarker for cancer treatment remains a major challenge in cancer therapy. Extracellular exposure of phosphatidylserine (PS) is tightly regulated and is an "eat me" signal for phagocytosis in healthy cells. Although cancer cells and vasculature express high levels of externalized PS, they do not undergo apoptosis, making them a promising biomarker for cancer treatment. Annexin A5 (ANXA5) is the native binding partner of PS and can actively target and deliver chemotherapies to the tumor microenvironment (TME) via PS expression. ANXA5 acts as a bridge between the innate and adaptive immune systems and contributes to an immunostimulatory profile in the TME. ANXA5-enzyme prodrug therapies allow for systemic delivery of prodrugs and targeted killing at the tumor site. ANXA5-carbon nanotube conjugates have been used to physically ablate tumors via photothermal therapy. This review aims to explore the expression of PS in cancer cells and how ANXA5 has been used as a chemotherapeutic and targeting agent for cancer.
Topics: Annexin A5; Apoptosis; Humans; Neoplasms; Phagocytosis; Phosphatidylserines; Prodrugs; Tumor Microenvironment
PubMed: 35940392
DOI: 10.1016/j.canlet.2022.215857 -
Trends in Biochemical Sciences Sep 2017Nature repeatedly repurposes, in that molecules that serve as metabolites, energy depots, or polymer subunits are at the same time used to deliver signals within and... (Review)
Review
Nature repeatedly repurposes, in that molecules that serve as metabolites, energy depots, or polymer subunits are at the same time used to deliver signals within and between cells. The preeminent example of this repurposing is ATP, which functions as a building block for nucleic acids, an energy source for enzymatic reactions, a phosphate donor to regulate intracellular signaling, and a neurotransmitter to control the activity of neurons. A series of recent studies now consolidates the view that phosphatidylserine (PtdSer), a common phospholipid constituent of membrane bilayers, is similarly repurposed for use as a signal between cells and that the ligands and receptors of the Tyro3/Axl/Mer (TAM) family of receptor tyrosine kinases (RTKs) are prominent transducers of this signal.
Topics: Animals; Humans; Ligands; Phosphatidylserines; Receptor Protein-Tyrosine Kinases; Signal Transduction
PubMed: 28734578
DOI: 10.1016/j.tibs.2017.06.004 -
Progress in Lipid Research Jul 2021Various human tissues and cells express phospholipase A1 member A (PLA1A), including the liver, lung, prostate gland, and immune cells. The enzyme belongs to the... (Review)
Review
Various human tissues and cells express phospholipase A1 member A (PLA1A), including the liver, lung, prostate gland, and immune cells. The enzyme belongs to the pancreatic lipase family. PLA1A specifically hydrolyzes sn-1 fatty acid of phosphatidylserine (PS) or 1-acyl-lysophosphatidylserine (1-acyl-lysoPS). PS externalized by activated cells or apoptotic cells or extracellular vesicles is a potential source of substrate for the production of unsaturated lysoPS species by PLA1A. Maturation and functions of many immune cells, such as T cells, dendritic cells, macrophages, and mast cells, can be regulated by PLA1A and lysoPS. Several lysoPS receptors, including GPR34, GPR174 and P2Y10, have been identified. High serum levels and high PLA1A expression are associated with autoimmune disorders such as Graves' disease and systemic lupus erythematosus. Increased expression of PLA1A is associated with metastatic melanomas. PLA1A may contribute to cardiometabolic disorders through mediating cholesterol transportation and producing lysoPS. Furthermore, PLA1A is necessary for hepatitis C virus assembly and can play a role in the antivirus innate immune response. This review summarizes recent findings on PLA1A expression, lysoPS and lysoPS receptors in autoimmune disorders, cancers, cardiometabolic disorders, antivirus immune responses, as well as regulations of immune cells.
Topics: Fatty Acids; Humans; Lysophospholipids; Male; Melanoma; Phosphatidylserines; Phospholipases A1; Skin Neoplasms
PubMed: 34166709
DOI: 10.1016/j.plipres.2021.101112 -
Proceedings of the National Academy of... Jun 2023Phagocytic clearance of degenerating neurons is triggered by "eat-me" signals exposed on the neuronal surface. The conserved neuronal eat-me signal phosphatidylserine...
Phagocytic clearance of degenerating neurons is triggered by "eat-me" signals exposed on the neuronal surface. The conserved neuronal eat-me signal phosphatidylserine (PS) and the engulfment receptor Draper (Drpr) mediate phagocytosis of degenerating neurons in . However, how PS is recognized by Drpr-expressing phagocytes in vivo remains poorly understood. Using multiple models of dendrite degeneration, we show that the chemokine-like protein Orion can bind to PS and is responsible for detecting PS exposure on neurons; it is supplied cell-non-autonomously to coat PS-exposing dendrites and to mediate interactions between PS and Drpr, thus enabling phagocytosis. As a result, the accumulation of Orion on neurons and on phagocytes produces opposite outcomes by potentiating and suppressing phagocytosis, respectively. Moreover, the Orion dosage is a key determinant of the sensitivity of phagocytes to PS exposed on neurons. Lastly, mutagenesis analyses show that the sequence motifs shared between Orion and human immunomodulatory proteins are important for Orion function. Thus, our results uncover a missing link in PS-mediated phagocytosis in and imply conserved mechanisms of phagocytosis of neurons.
Topics: Animals; Humans; Apoptosis; Chemokines; Drosophila; Drosophila Proteins; Neurons; Phagocytosis; Phosphatidylserines
PubMed: 37276397
DOI: 10.1073/pnas.2303392120 -
FEBS Letters Jan 2015Phospholipid scramblase activity is involved in the collapse of phospholipid (PL) asymmetry at the plasma membrane leading to externalization of phosphatidylserine. This... (Review)
Review
Phospholipid scramblase activity is involved in the collapse of phospholipid (PL) asymmetry at the plasma membrane leading to externalization of phosphatidylserine. This activity is crucial for initiation of the blood coagulation cascade and for recognition/elimination of apoptotic cells by macrophages. Efforts to identify gene products associated with this activity led to the characterization of PL scramblase (PLSCR) and XKR family members which contribute to phosphatidylserine exposure in response to apoptotic stimuli. Meanwhile, TMEM16 family members were identified to externalize phosphatidylserine in response to elevated calcium in Scott syndrome platelets, which is critical for activation of the coagulation cascade. Herein, we report their mechanisms of gene regulation, molecular functions independent of their scrambling activity, and their potential roles in pathogenic conditions.
Topics: Animals; Apoptosis; Blood Coagulation Disorders; Blood Platelets; Cell Membrane; Humans; Phosphatidylserines; Phospholipid Transfer Proteins
PubMed: 25479087
DOI: 10.1016/j.febslet.2014.11.036 -
International Journal of Molecular... Mar 2022Human red blood cells (RBCs), senescent or damaged due to particular stress, can be removed by programmed suicidal death, a process called eryptosis. There are various... (Review)
Review
Human red blood cells (RBCs), senescent or damaged due to particular stress, can be removed by programmed suicidal death, a process called eryptosis. There are various molecular mechanisms underlying eryptosis. The most frequent is the increase in the cytoplasmic concentration of Ca ions, later exposure of erythrocytes to oxidative stress, hyperosmotic shock, ceramide formation, stimulation of caspases, and energy depletion. Phosphatidylserine (PS) exposed by eryptotic RBCs due to interaction with endothelial CXC-Motiv-Chemokin-16/Scavenger-receptor, causes the RBCs to adhere to vascular wall with consequent damage to the microcirculation. Eryptosis can be triggered by various xenobiotics and endogenous molecules, such as high cholesterol levels. The possible diseases associated with eryptosis are various, including anemia, chronic kidney disease, liver failure, diabetes, hypertension, heart failure, thrombosis, obesity, metabolic syndrome, arthritis, and lupus. This review addresses and collates the existing ex vivo and animal studies on the inhibition of eryptosis by food-derived phytochemicals and natural compounds including phenolic compounds (PC), alkaloids, and other substances that could be a therapeutic and/or co-adjuvant option in eryptotic-driven disorders, especially if they are introduced through the diet.
Topics: Anemia; Animals; Calcium; Eryptosis; Erythrocytes; Humans; Oxidative Stress; Phosphatidylserines; Phytochemicals
PubMed: 35328440
DOI: 10.3390/ijms23063019