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Frontiers in Molecular Neuroscience 2022Erythrocytes undergo certain morphological changes resembling apoptosis during senescence or in an abnormal state/site, which is termed eryptosis. This process is... (Review)
Review
Erythrocytes undergo certain morphological changes resembling apoptosis during senescence or in an abnormal state/site, which is termed eryptosis. This process is characterized by phosphatidylserine (PS) exposure, membrane blebbing, and cell shrinkage. Eryptotic erythrocytes are subsequently removed macrophage-mediated efferocytosis. In hemorrhagic stroke (HS), blood within an artery rapidly bleeds into the brain tissue or the subarachnoid space, resulting in severe neurological deficits. A hypoxic, over-oxidative, and pro-inflammatory microenvironment in the hematoma leads to oxidative stress, hyperosmotic shock, energy depletion, and Cl removal in erythrocytes, which eventually triggers eryptosis. In addition, eryptosis following intracerebral hemorrhage favors hematoma clearance, which sheds light on a common mechanism of intrinsic phagocytosis. In this review, we summarized the canonical mechanisms of eryptosis and discussed its pathological conditions associated with HS. Understanding the role of eryptosis in HS may uncover additional potential interventions for further translational clinical research.
PubMed: 35966018
DOI: 10.3389/fnmol.2022.932931 -
Antioxidants (Basel, Switzerland) Oct 2021Preterm babies are highly susceptible to oxidative stress (OS) due to an imbalance between the oxidant and antioxidant systems. The generation of free radicals (FR)... (Review)
Review
Preterm babies are highly susceptible to oxidative stress (OS) due to an imbalance between the oxidant and antioxidant systems. The generation of free radicals (FR) induces oxidative damage to multiple body organs and systems. OS is the main factor responsible for the development of typical premature infant diseases, such as bronchopulmonary dysplasia, retinopathy of prematurity, necrotizing enterocolitis, intraventricular hemorrhage, periventricular leukomalacia, kidney damage, eryptosis, and also respiratory distress syndrome and patent ductus arteriosus. Many biomarkers have been detected to early identify newborns at risk of developing a free radical-mediated disease and to investigate new antioxidant strategies. This review reports the current knowledge on OS in the preterm newborns and the newest findings concerning the use of OS biomarkers as diagnostic tools, as well as in implementing antioxidant therapeutic strategies for the prevention and treatment of these diseases and their sequelae.
PubMed: 34829543
DOI: 10.3390/antiox10111672 -
Cellular Physiology and Biochemistry :... 2016Erythrocytes (RBCs) are extremely sensitive cells, and although they do not have nuclei and mitochondria, are important health indicators. This is particularly true... (Review)
Review
Erythrocytes (RBCs) are extremely sensitive cells, and although they do not have nuclei and mitochondria, are important health indicators. This is particularly true because, during inflammation, whether it is systemic or chronic, the haematological system is constantly exposed to circulating inflammatory mediators. RBCs have a highly specialized and organized membrane structure, which interacts and reacts to inflammatory molecule insults, and undergo programmed cell death, similar to apoptosis, known as eryptosis. Over the past years, eryptosis studies have focussed on determining if membrane changes have occurred, particularly whether a phosphatidylserine (PS) flip, Ca2+ leakage into the cell, changes to ceramide and cell shrinkage have occurred. Mostly, flow cytometry is used, but confocal microscopy and ultrastructural studies also confirm eryptosis. Here, we provide a comprehensive overview of eryptosis, where we revisit the biochemical process of the process, review all literature in PUBMED, that is shown under the search word, "eryptosis", and also discuss current methodologies to determine the presence of eryptosis; included in the discussion of the methodologies, we discuss a pitfalls section for each method. This paper is therefore a comprehensive synopsis of current knowledge of eryptosis and discusses how RBCs may provide an essential in vivo cell model system to study not only inflammation in disease, but also track disease progression and treatment regimes.
Topics: Biological Products; Calcium; Cell Size; Cells, Cultured; Ceramides; Eryptosis; Erythrocyte Membrane; Flow Cytometry; Humans; Oxidative Stress; Phosphatidylserines; Prescription Drugs; Reactive Oxygen Species; Small Molecule Libraries
PubMed: 27771701
DOI: 10.1159/000447895 -
Cells Feb 2022Human erythrocytes are organelle-free cells packaged with iron-containing hemoglobin, specializing in the transport of oxygen. With a total number of approximately 25... (Review)
Review
Human erythrocytes are organelle-free cells packaged with iron-containing hemoglobin, specializing in the transport of oxygen. With a total number of approximately 25 trillion cells per individual, the erythrocyte is the most abundant cell type not only in blood but in the whole organism. Despite their low complexity and their inability to transcriptionally upregulate antioxidant defense mechanisms, they display a relatively long life time, of 120 days. This ensures the maintenance of tissue homeostasis where the clearance of old or damaged erythrocytes is kept in balance with erythropoiesis. Whereas the regulatory mechanisms of erythropoiesis have been elucidated over decades of intensive research, the understanding of the mechanisms of erythrocyte clearance still requires some refinement. Here, we present the main pathways leading to eryptosis, the programmed death of erythrocytes, with special emphasis on Ca influx, the generation of ceramide, oxidative stress, kinase activation, and iron metabolism. We also compare stress-induced erythrocyte death with erythrocyte ageing and clearance, and discuss the similarities between eryptosis and ferroptosis, the iron-dependent regulated death of nucleated blood cells. Finally, we focus on the pathologic consequences of deranged eryptosis, and discuss eryptosis in the context of different infectious diseases, e.g., viral or parasitic infections, and hematologic disorders.
Topics: Calcium; Eryptosis; Erythrocytes; Erythropoiesis; Humans; Iron
PubMed: 35159312
DOI: 10.3390/cells11030503 -
International Journal of Molecular... Mar 2023Despite lacking the central apoptotic machinery, senescent or damaged RBCs can undergo an unusual apoptosis-like cell death, termed eryptosis. This premature death can... (Review)
Review
Despite lacking the central apoptotic machinery, senescent or damaged RBCs can undergo an unusual apoptosis-like cell death, termed eryptosis. This premature death can be caused by, or a symptom of, a wide range of diseases. However, various adverse conditions, xenobiotics, and endogenous mediators have also been recognized as triggers and inhibitors of eryptosis. Eukaryotic RBCs are unique among their cell membrane distribution of phospholipids. The change in the RBC membrane composition of the outer leaflet occurs in a variety of diseases, including sickle cell disease, renal diseases, leukemia, Parkinson's disease, and diabetes. Eryptotic erythrocytes exhibit various morphological alterations such as shrinkage, swelling, and increased granulation. Biochemical changes include cytosolic Ca increase, oxidative stress, stimulation of caspases, metabolic exhaustion, and ceramide accumulation. Eryptosis is an effective mechanism for the elimination of dysfunctional erythrocytes due to senescence, infection, or injury to prevent hemolysis. Nevertheless, excessive eryptosis is associated with multiple pathologies, most notably anemia, abnormal microcirculation, and prothrombotic risk; all of which contribute to the pathogenesis of several diseases. In this review, we provide an overview of the molecular mechanisms, physiological and pathophysiological relevance of eryptosis, as well as the potential role of natural and synthetic compounds in modulating RBC survival and death.
Topics: Humans; Eryptosis; Erythrocytes; Apoptosis; Cell Death; Anemia, Sickle Cell; Oxidative Stress; Calcium; Phosphatidylserines
PubMed: 36982153
DOI: 10.3390/ijms24065079 -
Frontiers in Cellular and Infection... 2021Erythrocytes possess an unusual programmed cell death mechanism termed eryptosis, and several compounds have been previously claimed to induce eryptosis . Malaria...
Erythrocytes possess an unusual programmed cell death mechanism termed eryptosis, and several compounds have been previously claimed to induce eryptosis . Malaria parasites (genus ) reside in erythrocytes during the pathogenic part of their life cycle, and the potential of several eryptosis inducers to act as antimalarials has been tested in recent years. However, the eryptosis-inducing capacity of these compounds varies significantly between eryptosis-focused studies and malaria investigations. Here, we investigated the reasons for these discrepancies, we developed a protocol to investigate eryptosis in malaria cultures and we re-evaluated the potential of eryptosis inducers as antimalarials. First, we showed that eryptosis read-out is dependent on culture conditions. Indeed, conditions that have consistently been used to study eryptosis do not support growth and prime erythrocytes for eryptosis. Next, we defined culture conditions that allow the detection of eryptosis while supporting survival. Finally, we selected six eryptosis-inducers based on their clinical use, molecular target and antimalarial activities, and re-evaluated their eryptosis inducing capacities and their potential as antimalarials. We demonstrate that none of these compounds affect the viability of naïve or -infected erythrocytes . Nevertheless, three of these compounds impair parasite development, although through a mechanism unrelated to eryptosis and yet to be elucidated. We conclude that careful consideration of experimental set up is key for the accurate assessment of the eryptosis-inducing potential of compounds and their evaluation as potential antimalarials.
Topics: Antimalarials; Eryptosis; Erythrocytes; Humans; Malaria; Malaria, Falciparum; Plasmodium; Plasmodium falciparum
PubMed: 33777843
DOI: 10.3389/fcimb.2021.630812 -
Frontiers in Immunology 2022Eryptosis is a programmed cell death-like process that occurs in red blood cells. Although the red blood cells are anucleated, there are similarities between eryptosis... (Review)
Review
Eryptosis is a programmed cell death-like process that occurs in red blood cells. Although the red blood cells are anucleated, there are similarities between eryptosis and apoptosis, such as increased calcium efflux, calpain activation, phosphatidylserine exposure, cell blebbing and cell shrinkage. Eryptosis occurs physiologically in red blood cells, as a consequence of the natural senescence process of these cells, but it can also be stimulated in pathological situations such as metabolic syndromes, uremic syndromes, polycythemia vera, anemias such as sickle cell anemia and thalassemia, and infectious processes including infection. Infection-induced eryptosis is believed to contribute to damage caused by , but it's still a topic of debate in the literature. In this review, we provided an overview of eryptosis mechanisms and its possible pathogenic role in malaria.
Topics: Anemia, Sickle Cell; Apoptosis; Eryptosis; Erythrocytes; Humans; Malaria
PubMed: 35634341
DOI: 10.3389/fimmu.2022.855795 -
Kidney & Blood Pressure Research 2022Renal anemia is an important complication of chronic kidney disease (CKD). In addition to insufficient secretion of erythropoietin (EPO) and erythropoiesis disorders,... (Review)
Review
BACKGROUND
Renal anemia is an important complication of chronic kidney disease (CKD). In addition to insufficient secretion of erythropoietin (EPO) and erythropoiesis disorders, the impact of eryptosis on renal anemia demands attention. However, a systemic analysis concerning the pathophysiology of eryptosis has not been expounded.
SUMMARY
The complicated conditions in CKD patients, including oxidative stress, osmotic stress, metabolic stress, accumulation of uremic toxins, and iron deficiency, affect the normal skeleton structure of red blood cells (RBCs) and disturbs ionic homeostasis, causing phosphatidylserine to translocate to the outer lobules of the RBC membrane that leads to early elimination and/or shortening of the RBC lifespan. Inadequate synthesis of RBCs cannot compensate for their accelerated destruction, thus exacerbating renal anemia. Meanwhile, EPO treatment alone will not reverse renal anemia. A variety of eryptosis inhibitors have so far been found, but evidence of their effectiveness in the treatment of CKD remains to be established.
KEY MESSAGES
In this review, the pathophysiological processes and factors influencing eryptosis in CKD were elucidated. The aim of this review was to underline the importance of eryptosis in renal anemia and determine some promising research directions or possible therapeutic targets to correct anemia in CKD.
Topics: Anemia; Eryptosis; Erythrocytes; Erythropoiesis; Humans; Renal Insufficiency, Chronic
PubMed: 35114677
DOI: 10.1159/000522133 -
Metabolites Dec 2021Many factors in the surrounding environment have been reported to influence erythrocyte deformability. It is likely that some influences represent reversible changes in... (Review)
Review
Many factors in the surrounding environment have been reported to influence erythrocyte deformability. It is likely that some influences represent reversible changes in erythrocyte rigidity that may be involved in physiological regulation, while others represent the early stages of eryptosis, i.e., the red cell self-programmed death. For example, erythrocyte rigidification during exercise is probably a reversible physiological mechanism, while the alterations of red blood cells (RBCs) observed in pathological conditions (inflammation, type 2 diabetes, and sickle-cell disease) are more likely to lead to eryptosis. The splenic clearance of rigid erythrocytes is the major regulator of RBC deformability. The physicochemical characteristics of the surrounding environment (thermal injury, pH, osmolality, oxidative stress, and plasma protein profile) also play a major role. However, there are many other factors that influence RBC deformability and eryptosis. In this comprehensive review, we discuss the various elements and circulating molecules that might influence RBCs and modify their deformability: purinergic signaling, gasotransmitters such as nitric oxide (NO), divalent cations (magnesium, zinc, and Fe), lactate, ketone bodies, blood lipids, and several circulating hormones. Meal composition (caloric and carbohydrate intake) also modifies RBC deformability. Therefore, RBC deformability appears to be under the influence of many factors. This suggests that several homeostatic regulatory loops adapt the red cell rigidity to the physiological conditions in order to cope with the need for oxygen or fuel delivery to tissues. Furthermore, many conditions appear to irreversibly damage red cells, resulting in their destruction and removal from the blood. These two categories of modifications to erythrocyte deformability should thus be differentiated.
PubMed: 35050126
DOI: 10.3390/metabo12010004 -
Cellular Physiology and Biochemistry :... Jul 2021Chronic kidney disease is frequently accompanied by anemia, hypoxemia, and hypoxia. It has become clear that the impaired erythropoietin production and altered iron... (Clinical Trial)
Clinical Trial
BACKGROUND/AIMS
Chronic kidney disease is frequently accompanied by anemia, hypoxemia, and hypoxia. It has become clear that the impaired erythropoietin production and altered iron homeostasis are not the sole causes of renal anemia. Eryptosis is a process of red blood cells (RBC) death, like apoptosis of nucleated cells, characterized by Ca influx and phosphatidylserine (PS) exposure to the outer RBC membrane leaflet. Eryptosis can be induced by uremic toxins and occurs before senescence, thus shortening RBC lifespan and aggravating renal anemia. We aimed to assess eryptosis and intracellular oxygen levels of RBC from hemodialysis patients (HD-RBC) and their response to hypoxia, uremia, and uremic toxins uptake inhibition.
METHODS
Using flow cytometry, RBC from healthy individuals (CON-RBC) and HD-RBC were subjected to PS (Annexin-V), intracellular Ca (Fluo-3/AM) and intracellular oxygen (Hypoxia Green) measurements, at baseline and after incubation with uremic serum and/or hypoxia (5% O), with or without ketoprofen. Baseline levels of uremic toxins were quantified in serum and cytosol by high performance liquid chromatography.
RESULTS
Here, we show that HD-RBC have less intracellular oxygen and that it is further decreased post-HD. Also, incubation in 5% O and uremia triggered eryptosis in vitro by exposing PS. Hypoxia itself increased the PS exposure in HD-RBC and CON-RBC, and the addition of uremic serum aggravated it. Furthermore, inhibition of the organic anion transporter 2 with ketoprofen reverted eryptosis and restored the levels of intracellular oxygen. Cytosolic levels of the uremic toxins pCS and IAA were decreased after dialysis.
CONCLUSION
These findings suggest the participation of uremic toxins and hypoxia in the process of eryptosis and intracellular oxygenation.
Topics: Adolescent; Adult; Aged; Annexin A5; Calcium; Cell Hypoxia; Eryptosis; Erythrocytes; Female; Humans; Male; Middle Aged; Oxygen; Renal Insufficiency, Chronic; Uremia
PubMed: 34259420
DOI: 10.33594/000000396