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Expert Reviews in Molecular Medicine Aug 2022Thrombosis is a common disorder with a relevant burden of morbidity and mortality worldwide, particularly among elderly patients. Growing evidence demonstrated a direct... (Review)
Review
Thrombosis is a common disorder with a relevant burden of morbidity and mortality worldwide, particularly among elderly patients. Growing evidence demonstrated a direct role of oxidative stress in thrombosis, with various cell types contributing to this process. Among them, erythrocytes produce high quantities of intracellular reactive oxygen species (ROS) by NADPH oxidase activation and haemoglobin autoxidation. Concomitantly, extracellular ROS released by other cells in the blood flow can be uptaken and accumulate within erythrocytes. This oxidative milieu can alter erythrocyte membrane structure, leading to an impaired erythrocyte function, and promoting erythrocytes lysis, binding to endothelial cells, activation of platelet and of coagulation factors, phosphatidylserine exposure and release of microvesicles. Moreover, these abnormal erythrocytes are able to adhere to the vessel wall, contributing to thrombin generation within the thrombus. This process results in accelerated haemolysis and in a hypercoagulable state, in which structurally impaired erythrocytes contribute to increase thrombus size, to reduce its permeability and susceptibility to lysis. However, the wide plethora of mechanisms by which oxidised erythrocytes contribute to thrombosis is not completely elucidated. This review discusses the main biochemical aspects linking erythrocytes, oxidative stress and thrombosis, addressing their potential implication for clinical and therapeutic management.
Topics: Aged; Endothelial Cells; Erythrocytes; Hemoglobins; Humans; NADPH Oxidases; Oxidative Stress; Phosphatidylserines; Reactive Oxygen Species; Thrombin; Thrombosis
PubMed: 36017709
DOI: 10.1017/erm.2022.25 -
The Journal of Cell Biology Jun 2021TMEM41B and VMP1 are integral membrane proteins of the endoplasmic reticulum (ER) and regulate the formation of autophagosomes, lipid droplets (LDs), and lipoproteins....
TMEM41B and VMP1 are integral membrane proteins of the endoplasmic reticulum (ER) and regulate the formation of autophagosomes, lipid droplets (LDs), and lipoproteins. Recently, TMEM41B was identified as a crucial host factor for infection by all coronaviruses and flaviviruses. The molecular function of TMEM41B and VMP1, which belong to a large evolutionarily conserved family, remains elusive. Here, we show that TMEM41B and VMP1 are phospholipid scramblases whose deficiency impairs the normal cellular distribution of cholesterol and phosphatidylserine. Their mechanism of action on LD formation is likely to be different from that of seipin. Their role in maintaining cellular phosphatidylserine and cholesterol homeostasis may partially explain their requirement for viral infection. Our results suggest that the proper sorting and distribution of cellular lipids are essential for organelle biogenesis and viral infection.
Topics: Autophagosomes; Autophagy; Cholesterol; Endoplasmic Reticulum; HeLa Cells; Humans; Lipid Droplets; Membrane Proteins; Phosphatidylserines; Protein Transport
PubMed: 33929485
DOI: 10.1083/jcb.202103105 -
American Journal of Physiology. Cell... Oct 2022Platelets play a key role in maintaining hemostasis. However, dysregulated platelet activation can lead to pathological thrombosis or bleeding. Once a platelet gets... (Review)
Review
Platelets play a key role in maintaining hemostasis. However, dysregulated platelet activation can lead to pathological thrombosis or bleeding. Once a platelet gets activated, it will either become an aggregatory platelet or eventually a procoagulant platelet with both types playing distinct roles in thrombosis and hemostasis. Although aggregatory platelets have been extensively studied, procoagulant platelets have only recently come into the spotlight. Procoagulant platelets are a subpopulation of highly activated platelets that express phosphatidylserine and P-selectin on their surface, allowing for coagulation factors to bind and thrombin to be generated. In recent years, novel roles for procoagulant platelets have been identified and they have increasingly been implicated in thromboinflammatory diseases. Here, we provide an up-to-date review on the mechanisms resulting in the formation of procoagulant platelets and how they contribute to hemostasis, thrombosis, and thromboinflammation.
Topics: Blood Coagulation; Blood Platelets; Humans; Inflammation; P-Selectin; Phosphatidylserines; Platelet Activation; Thrombin; Thromboinflammation; Thrombosis
PubMed: 35993516
DOI: 10.1152/ajpcell.00252.2022 -
Molecular Pharmaceutics Jan 2023Phospholipids are lipids that constitute the basic structure of cell membranes. In-depth research has shown that in addition to supporting cell structures, phospholipids... (Review)
Review
Phospholipids are lipids that constitute the basic structure of cell membranes. In-depth research has shown that in addition to supporting cell structures, phospholipids participate in multiple cellular processes, including promoting cell signal transduction, guiding protein translocation, activating enzymatic activity, and eliminating dysfunctional/redundant organelles/cells. Diabetes is a chronic metabolic disease with a complicated etiology and pathology. Studies have shown that the level of certain phospholipids, for example, the ratio of phosphatidylcholine (PC) to phosphatidylethanolamine (PE) in liver tissue, is negatively associated with insulin sensitivity. In addition, PS is a phospholipid exhibiting extensive cellular functions in diabetes. For this review, we analyzed many PS studies focusing on diabetes and insulin sensitivity in recent years and found that PS participates in controlling insulin secretion, regulating insulin signaling transduction, and participating in the progression of diabetic complications by mediating coagulation disorders in the microvasculature or targeting mitochondria. Moreover, PS supplements in food and PS-containing liposomes have been shown to protect against type 1 and type 2 diabetes (T1D and T2D, respectively) in animal studies. Therefore, by summarizing the regulatory roles played by PS in diabetes and the potential of successfully using PS or PS-containing liposomes for diabetic therapy, we hope to provide new ideas for further research into the mechanisms of diabetes and for drug development for treating diabetes and its complications.
Topics: Animals; Liposomes; Phosphatidylserines; Diabetes Mellitus, Type 2; Insulin Resistance; Phospholipids; Phosphatidylethanolamines
PubMed: 36480277
DOI: 10.1021/acs.molpharmaceut.2c00707 -
Developmental Cell Jul 2023Cell extrusion is a universal mode of cell removal from tissues, and it plays an important role in regulating cell numbers and eliminating unwanted cells. However, the...
Cell extrusion is a universal mode of cell removal from tissues, and it plays an important role in regulating cell numbers and eliminating unwanted cells. However, the underlying mechanisms of cell delamination from the cell layer are unclear. Here, we report a conserved execution mechanism of apoptotic cell extrusion. We found extracellular vesicle (EV) formation in extruding mammalian and Drosophila cells at a site opposite to the extrusion direction. Lipid-scramblase-mediated local exposure of phosphatidylserine is responsible for EV formation and is crucial for executing cell extrusion. Inhibition of this process disrupts prompt cell delamination and tissue homeostasis. Although the EV has hallmarks of an apoptotic body, its formation is governed by the mechanism of microvesicle formation. Experimental and mathematical modeling analysis illustrated that EV formation promotes neighboring cells' invasion. This study showed that membrane dynamics play a crucial role in cell exit by connecting the actions of the extruding cell and neighboring cells.
Topics: Animals; Phosphatidylserines; Apoptosis; Drosophila; Endocytosis; Extracellular Vesicles; Mammals
PubMed: 37315563
DOI: 10.1016/j.devcel.2023.05.008 -
Current Opinion in Immunology Feb 2020In various biological processes, phosphatidylserine (PtdSer) that is normally sequestered to the inner leaflet of the plasma membrane (PM) is exposed to the cell... (Review)
Review
In various biological processes, phosphatidylserine (PtdSer) that is normally sequestered to the inner leaflet of the plasma membrane (PM) is exposed to the cell surface. When platelets are activated, they expose PtdSer to activate the blood-clotting factors. Cells undergoing apoptosis and senescent neutrophils expose PtdSer that is recognized as an 'eat me' signal by phagocytes for clearance. The PtdSer-exposure and its internalization are mediated by phospholipid scramblases and flippases, respectively. Both have recently been molecularly identified, and their functional mechanism and physiological roles are being elucidated.
Topics: Adenosine Triphosphatases; Animals; Cell Membrane; Humans; Models, Molecular; Phosphatidylserines
PubMed: 31837595
DOI: 10.1016/j.coi.2019.11.009 -
Biochemistry. Biokhimiia Mar 2022Apoptosis is the most thoroughly studied type of regulated cell death. Certain events, such as externalization of phosphatidylserine (PS) into the outer leaflet of... (Review)
Review
Apoptosis is the most thoroughly studied type of regulated cell death. Certain events, such as externalization of phosphatidylserine (PS) into the outer leaflet of plasma membrane, mitochondrial outer membrane permeabilization, caspase cascade activation, DNA fragmentation and blebbing, are widely considered to be hallmarks of apoptosis as well as being traditionally viewed as irreversible. This review shows that under particular circumstances these events can also participate in physiological processes not associated with initiation of apoptosis, such as cell differentiation, division, and motility, as well as non-apoptotic types of cell death. Moreover, these events may often be reversible. This review focuses on three processes: phosphatidylserine externalization, blebbing, and activation of apoptotic caspases. Mitochondrial outer membrane permeabilization and DNA fragmentation are not discussed.
Topics: Apoptosis; Caspases; Phosphatidylserines
PubMed: 35526851
DOI: 10.1134/S0006297922030014 -
Neuroscience Research Jun 2021Phospholipids are asymmetrically distributed at the plasma membrane. Phosphatidylserine (PtdSer) is exclusively located in the inner leaflet of the cell membrane while... (Review)
Review
Phospholipids are asymmetrically distributed at the plasma membrane. Phosphatidylserine (PtdSer) is exclusively located in the inner leaflet of the cell membrane while phosphatidylcholine (PtdCho) and glycolipids are mainly located in the outer leaflet of the membrane. However, this asymmetry is disrupted in various physiological situations, and PtdSer is exposed on the cell surface. In platelets, exposed PtdSer functions as a scaffold for the coagulation reaction, while in dead cells, exposed PtdSer serves as an "Eat-me" signal for efferocytosis. In the developing brain, synaptic connections are over-formed during the fetal period, but about half of the neurons are removed by apoptosis, and synaptic and dendritic compartments of living neurons are also removed by phagocytes. During these processes, glial cells such as microglia and astrocyte engulf unwanted dead cells and compartments in living cells using several phagocytic receptors, recognizing PtdSer by direct binding or an indirect way using secreted molecules. Based on recent findings, we will discuss how the compartments in living neurons are eliminated for the neuronal circuit plasticity.
Topics: Apoptosis; Brain; Cell Membrane; Phosphatidylserines; Phospholipids
PubMed: 33476682
DOI: 10.1016/j.neures.2021.01.003 -
The EMBO Journal Jul 2023The mature mammalian brain connectome emerges during development via the extension and pruning of neuronal connections. Glial cells have been identified as key players...
The mature mammalian brain connectome emerges during development via the extension and pruning of neuronal connections. Glial cells have been identified as key players in the phagocytic elimination of neuronal synapses and projections. Recently, phosphatidylserine has been identified as neuronal "eat-me" signal that guides elimination of unnecessary input sources, but the associated transduction systems involved in such pruning are yet to be described. Here, we identified Xk-related protein 8 (Xkr8), a phospholipid scramblase, as a key factor for the pruning of axons in the developing mammalian brain. We found that mouse Xkr8 is highly expressed immediately after birth and required for phosphatidylserine exposure in the hippocampus. Mice lacking Xkr8 showed excess excitatory nerve terminals, increased density of cortico-cortical and cortico-spinal projections, aberrant electrophysiological profiles of hippocampal neurons, and global brain hyperconnectivity. These data identify phospholipid scrambling by Xkr8 as a central process in the labeling and discrimination of developing neuronal projections for pruning in the mammalian brain.
Topics: Animals; Mice; Phospholipid Transfer Proteins; Apoptosis Regulatory Proteins; Apoptosis; Phosphatidylserines; Axons; Neuronal Plasticity; Mammals; Membrane Proteins
PubMed: 37211968
DOI: 10.15252/embj.2022111790 -
Journal of Cancer Research and Clinical... Dec 2021Cancer immunotherapy is a major breakthrough in tumor therapy and has been used in monotherapy or combination therapy. However, it has been associated with poor immune... (Review)
Review
Cancer immunotherapy is a major breakthrough in tumor therapy and has been used in monotherapy or combination therapy. However, it has been associated with poor immune tolerance in some patients or immune-related adverse events. Therefore, ideal and reliable tumor elimination strategies are urgently needed to overcome these shortcomings. Phosphatidylserine (PS) is a negatively charged phospholipid, usually present in the inner lobules of eukaryotic cell membranes. Under certain physiological or pathological conditions, PS may be exposed on the outer leaflets of apoptotic cells serving as recognition signals by phagocytes and modulating the immune response. On the contrary, increased exposure of PS in the tumor microenvironment can significantly antagonize the body's anti-tumor immunity, thereby promoting tumor growth and metastasis. During radiotherapy and chemotherapy, PS-mediated immunosuppression increases the PS levels in necrotic tissue in the tumor microenvironment, further suppressing tumor immunity. PS-targeted therapy is a promising strategy in cancer immunotherapy. It inhibits tumor growth and improves the anti-tumor activity of immune checkpoint inhibitors. A comprehensive understanding of the mechanism of PS-targeted therapy opens up a new perspective for future cancer immunotherapies.
Topics: Animals; Humans; Immune Checkpoint Inhibitors; Immunotherapy; Neoplasms; Phosphatidylserines; Tumor Microenvironment
PubMed: 34499223
DOI: 10.1007/s00432-021-03792-3