International Journal of Molecular Sciences

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10 pages, 2133 KiB

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Sphingosine-1-phosphate Decreases Erythrocyte Dysfunction Induced by β-Amyloid

by Francesco Misiti, Pierluigi Diotaiuti, Giovanni Enrico Lombardo and Ester Tellone

Int. J. Mol. Sci. 2024, 25(10), 5184; https://doi.org/10.3390/ijms25105184 - 10 May 2024

Viewed by 1115

Abstract

Amyloid beta peptides (Aβ) have been identified as the main pathogenic agents in Alzheimer’s disease (AD). Soluble Aβ oligomers, rather than monomer or insoluble amyloid fibrils, show red blood cell (RBC) membrane-binding capacity and trigger several morphological and functional alterations in RBCs that [...] Read more.

Amyloid beta peptides (Aβ) have been identified as the main pathogenic agents in Alzheimer’s disease (AD). Soluble Aβ oligomers, rather than monomer or insoluble amyloid fibrils, show red blood cell (RBC) membrane-binding capacity and trigger several morphological and functional alterations in RBCs that can result in impaired oxygen transport and delivery. Since bioactive lipids have been recently proposed as potent protective agents against Aβ toxicity, we investigated the role of sphingosine-1-phosphate (S1P) in signaling pathways involved in the mechanism underlying ATP release in Ab-treated RBCs. In RBCs following different treatments, the ATP, 2,3 DPG and cAMP levels and caspase 3 activity were determined by spectrophotometric and immunoassay. S1P rescued the inhibition of ATP release from RBCs triggered by Ab, through a mechanism involving caspase-3 and restoring 2,3 DPG and cAMP levels within the cell. These findings reveal the molecular basis of S1P protection against Aβ in RBCs and suggest new therapeutic avenues in AD. Full article

(This article belongs to the Special Issue Roles of Erythrocytes in Human Health and Disease)

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11 pages, 1373 KiB

Open AccessArticle

Untargeted Lipidomics of Erythrocytes under Simulated Microgravity Conditions

by Cristina Manis, Antonio Murgia, Alessia Manca, Antonella Pantaleo, Giacomo Cao and Pierluigi Caboni

Int. J. Mol. Sci. 2023, 24(5), 4379; https://doi.org/10.3390/ijms24054379 - 22 Feb 2023

Cited by 2 | Viewed by 1785

Abstract

Lipidomics and metabolomics are nowadays widely used to provide promising insights into the pathophysiology of cellular stress disorders. Our study expands, with the use of a hyphenated ion mobility mass spectrometric platform, the understanding of the cellular processes and stress due to microgravity. [...] Read more.

Lipidomics and metabolomics are nowadays widely used to provide promising insights into the pathophysiology of cellular stress disorders. Our study expands, with the use of a hyphenated ion mobility mass spectrometric platform, the understanding of the cellular processes and stress due to microgravity. By lipid profiling of human erythrocytes, we annotated complex lipids such as oxidized phosphocholines, phosphocholines bearing arachidonic in their moiety, as well as sphingomyelins and hexosyl ceramides associated with microgravity conditions. Overall, our findings give an insight into the molecular alterations and identify erythrocyte lipidomics signatures associated with microgravity conditions. If the present results are confirmed in future studies, they may help to develop suitable treatments for astronauts after return to Earth. Full article

(This article belongs to the Special Issue Roles of Erythrocytes in Human Health and Disease)

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12 pages, 1967 KiB

Open AccessArticle

Sublingual Microcirculation Specificity of Sickle Cell Patients: Morphology of the Microvascular Bed, Blood Rheology, and Local Hemodynamics

by Sachi Sant, Etienne Gouraud, Camille Boisson, Elie Nader, Mounika Goparaju, Giovanna Cannas, Alexandra Gauthier, Philippe Joly, Céline Renoux, Salima Merazga, Christophe Hautier, Philippe Connes and Marianne Fenech

Int. J. Mol. Sci. 2023, 24(4), 3621; https://doi.org/10.3390/ijms24043621 - 11 Feb 2023

Cited by 2 | Viewed by 2505

Abstract

Patients with sickle cell disease (SCD) have poorly deformable red blood cells (RBC) that may impede blood flow into microcirculation. Very few studies have been able to directly visualize microcirculation in humans with SCD. Sublingual video microscopy was performed in eight healthy (HbAA [...] Read more.

Patients with sickle cell disease (SCD) have poorly deformable red blood cells (RBC) that may impede blood flow into microcirculation. Very few studies have been able to directly visualize microcirculation in humans with SCD. Sublingual video microscopy was performed in eight healthy (HbAA genotype) and four sickle cell individuals (HbSS genotype). Their hematocrit, blood viscosity, red blood cell deformability, and aggregation were individually determined through blood sample collections. Their microcirculation morphology (vessel density and diameter) and microcirculation hemodynamics (local velocity, local viscosity, and local red blood cell deformability) were investigated. The De Backer score was higher (15.9 mm⁻¹) in HbSS individuals compared to HbAA individuals (11.1 mm⁻¹). RBC deformability, derived from their local hemodynamic condition, was lower in HbSS individuals compared to HbAA individuals for vessels < 20 μm. Despite the presence of more rigid RBCs in HbSS individuals, their lower hematocrit caused their viscosity to be lower in microcirculation compared to that of HbAA individuals. The shear stress for all the vessel diameters was not different between HbSS and HbAA individuals. The local velocity and shear rates tended to be higher in HbSS individuals than in HbAA individuals, notably so in the smallest vessels, which could limit RBC entrapment into microcirculation. Our study offered a novel approach to studying the pathophysiological mechanisms of SCD with new biological/physiological markers that could be useful for characterizing the disease activity. Full article

(This article belongs to the Special Issue Roles of Erythrocytes in Human Health and Disease)

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17 pages, 2761 KiB

Open AccessArticle

Exploring Transcriptomic Landscapes in Red Blood Cells, in Their Extracellular Vesicles and on a Single-Cell Level

by Erja Kerkelä, Jenni Lahtela, Antti Larjo, Ulla Impola, Laura Mäenpää and Pirkko Mattila

Int. J. Mol. Sci. 2022, 23(21), 12897; https://doi.org/10.3390/ijms232112897 - 25 Oct 2022

Cited by 7 | Viewed by 5535

Abstract

Being enucleated, RBCs lack typical transcriptomes, but are known to contain small amounts of diverse long transcripts and microRNAs. However, the exact role and importance of these RNAs are lacking. Shedding of extracellular vesicles (EVs) from the plasma membrane constitutes an integral mechanism [...] Read more.

Being enucleated, RBCs lack typical transcriptomes, but are known to contain small amounts of diverse long transcripts and microRNAs. However, the exact role and importance of these RNAs are lacking. Shedding of extracellular vesicles (EVs) from the plasma membrane constitutes an integral mechanism of RBC homeostasis, by which RBCs remove unnecessary cytoplasmic content and cell membrane. To study this further, we explored the transcriptomes of RBCs and extracellular vesicles (EVs) of RBCs using next-generation sequencing. Furthermore, we performed single-cell RNA sequencing on RBCs, which revealed that approximately 10% of the cells contained detectable levels of mRNA and cells formed three subpopulations based on their transcriptomes. A decrease in the mRNA quantity was observed across the populations. Qualitative changes included the differences in the globin transcripts and changes in the expression of ribosomal genes. A specific splice form of a long non-coding RNA, Metastasis Associated Lung Adenocarcinoma Transcript 1 (MALAT1), was the most enriched marker in one subpopulation of RBCs, co-expressing with ribosomal structural transcripts. MALAT1 expression was confirmed by qPCR in CD71-enriched reticulocytes, which were also characterized with imaging flow cytometry at the single cell level. Analysis of the RBC transcriptome shows enrichment of pathways and functional categories required for the maturation of reticulocytes and erythrocyte functions. The RBC transcriptome was detected in their EVs, making these transcripts available for intercellular communication in blood. Full article

(This article belongs to the Special Issue Roles of Erythrocytes in Human Health and Disease)

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20 pages, 42635 KiB

Open AccessArticle

Mechano-Transduction Boosts the Aging Effects in Human Erythrocytes Submitted to Mechanical Stimulation

by Simone Dinarelli, Giovanni Longo, Antonio Francioso, Luciana Mosca and Marco Girasole

Int. J. Mol. Sci. 2022, 23(17), 10180; https://doi.org/10.3390/ijms231710180 - 5 Sep 2022

Cited by 4 | Viewed by 1660

Abstract

Erythrocytes’ aging and mechano-transduction are fundamental cellular pathways that determine the red blood cells’ (RBCs) behavior and function. The aging pattern can be influenced, in morphological, biochemical, and metabolic terms by the environmental conditions. In this paper, we studied the effect of a [...] Read more.

Erythrocytes’ aging and mechano-transduction are fundamental cellular pathways that determine the red blood cells’ (RBCs) behavior and function. The aging pattern can be influenced, in morphological, biochemical, and metabolic terms by the environmental conditions. In this paper, we studied the effect of a moderate mechanical stimulation applied through external shaking during the RBCs aging and revealed a strong acceleration of the aging pattern induced by such stimulation. Moreover, we evaluated the behavior of the main cellular effectors and resources in the presence of drugs (diamide) or of specific inhibitors of the mechano-transduction (probenecid, carbenoxolone, and glibenclamide). This approach provided the first evidence of a direct cross-correlation between aging and mechano-transduction and permitted an evaluation of the overall metabolic regulation and of the insurgence of specific morphological features, such as micro-vesicles and roughness alterations. Overall, for the first time the present data provided a schematic to understand the integration of distinct complex patterns in a comprehensive view of the cell and of its interactions with the environment. Mechano-transduction produces structural effects that are correlated with the stimulation and the strength of the environmental stimulation is paramount to effectively activate and trigger the biological cascades initiated by the mechano-sensing. Full article

(This article belongs to the Special Issue Roles of Erythrocytes in Human Health and Disease)

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15 pages, 3284 KiB

Open AccessArticle

Olive Oil Phenols Prevent Mercury-Induced Phosphatidylserine Exposure and Morphological Changes in Human Erythrocytes Regardless of Their Different Scavenging Activity

by Rosaria Notariale, Pasquale Perrone, Luigi Mele, Gennaro Lettieri, Marina Piscopo and Caterina Manna

Int. J. Mol. Sci. 2022, 23(10), 5693; https://doi.org/10.3390/ijms23105693 - 19 May 2022

Cited by 8 | Viewed by 2130

Abstract

Phosphatidylserine (PS) translocation to the external membrane leaflet represents a key mechanism in the pathophysiology of human erythrocytes (RBC) acting as an “eat me” signal for the removal of aged/stressed cells. Loss of physiological membrane asymmetry, however, can lead to adverse effects on [...] Read more.

Phosphatidylserine (PS) translocation to the external membrane leaflet represents a key mechanism in the pathophysiology of human erythrocytes (RBC) acting as an “eat me” signal for the removal of aged/stressed cells. Loss of physiological membrane asymmetry, however, can lead to adverse effects on the cardiovascular system, activating a prothrombotic activity. The data presented indicate that structurally related olive oil phenols prevent cell alterations induced in intact human RBC exposed to HgCl₂ (5–40 µM) or Ca²⁺ ionophore (5 µM), as measured by hallmarks including PS exposure, reactive oxygen species generation, glutathione depletion and microvesicles formation. The protective effect is observed in a concentration range of 1–30 µM, hydroxytyrosol being the most effective; its in vivo metabolite homovanillic alcohol still retains the biological activity of its dietary precursor. Significant protection is also exerted by tyrosol, in spite of its weak scavenging activity, indicating that additional mechanisms are involved in the protective effect. When RBC alterations are mediated by an increase in intracellular calcium, the protective effect is observed at higher concentrations, indicating that the selected phenols mainly act on Ca²⁺-independent mechanisms, identified as protection of glutathione depletion. Our findings strengthen the nutritional relevance of olive oil bioactive compounds in the claimed health-promoting effects of the Mediterranean Diet. Full article

(This article belongs to the Special Issue Roles of Erythrocytes in Human Health and Disease)

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16 pages, 3897 KiB

Open AccessArticle

Topological Relationships Cytoskeleton-Membrane Nanosurface-Morphology as a Basic Mechanism of Total Disorders of RBC Structures

by Elena Kozlova, Viktoria Sergunova, Ekaterina Sherstyukova, Olga Gudkova, Aleksandr Kozlov, Vladimir Inozemtsev, Snezhanna Lyapunova and Aleksandr Chernysh

Int. J. Mol. Sci. 2022, 23(4), 2045; https://doi.org/10.3390/ijms23042045 - 12 Feb 2022

Cited by 6 | Viewed by 2274

Abstract

The state of red blood cells (RBCs) and their functional possibilities depend on the structural organization of the membranes. Cell morphology and membrane nanostructure are compositionally and functionally related to the cytoskeleton network. In this work, the influence of agents (hemin, endogenous oxidation [...] Read more.

The state of red blood cells (RBCs) and their functional possibilities depend on the structural organization of the membranes. Cell morphology and membrane nanostructure are compositionally and functionally related to the cytoskeleton network. In this work, the influence of agents (hemin, endogenous oxidation during storage of packed RBCs, ultraviolet (UV) radiation, temperature, and potential of hydrogen (pH) changes) on the relationships between cytoskeleton destruction, membrane nanostructure, and RBC morphology was observed by atomic force microscope. It was shown that the influence of factors of a physical and biochemical nature causes structural rearrangements in RBCs at all levels of organization, forming a unified mechanism of disturbances in relationships “cytoskeleton-membrane nanosurface-cell morphology”. Filament ruptures and, consequently, large cytoskeleton pores appeared. The pores caused membrane topological defects in the form of separate grain domains. Increasing loading doses led to an increase in the number of large cytoskeleton pores and defects and their fusion at the membrane nanosurfaces. This caused the changes in RBC morphology. Our results can be used in molecular cell biology, membrane biophysics, and in fundamental and practical medicine. Full article

(This article belongs to the Special Issue Roles of Erythrocytes in Human Health and Disease)

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19 pages, 24801 KiB

Open AccessArticle

The Post-Storage Performance of RBCs from Beta-Thalassemia Trait Donors Is Related to Their Storability Profile

by Alkmini T. Anastasiadi, Efthymios C. Paronis, Vasiliki-Zoi Arvaniti, Athanasios D. Velentzas, Anastasia C. Apostolidou, Evangelos G. Balafas, Monika Dzieciatkowska, Nikolaos G. Kostomitsopoulos, Konstantinos Stamoulis, Issidora S. Papassideri, Angelo D’Alessandro, Anastasios G. Kriebardis, Marianna H. Antonelou and Vassilis L. Tzounakas

Int. J. Mol. Sci. 2021, 22(22), 12281; https://doi.org/10.3390/ijms222212281 - 13 Nov 2021

Cited by 10 | Viewed by 2315

Abstract

Blood donors with beta-thalassemia traits (βThal⁺) have proven to be good “storers”, since their stored RBCs are resistant to lysis and resilient against oxidative/proteotoxic stress. To examine the performance of these RBCs post-storage, stored βThal⁺ and control RBCs were reconstituted [...] Read more.

Blood donors with beta-thalassemia traits (βThal⁺) have proven to be good “storers”, since their stored RBCs are resistant to lysis and resilient against oxidative/proteotoxic stress. To examine the performance of these RBCs post-storage, stored βThal⁺ and control RBCs were reconstituted in plasma donated from transfusion-dependent beta-thalassemic patients and healthy controls, and incubated for 24 h at body temperature. Several physiological parameters, including hemolysis, were evaluated. Moreover, labeled fresh/stored RBCs from the two groups were transfused in mice to assess 24 h recovery. All hemolysis metrics were better in the group of heterozygotes and distinguished them against controls in the plasma environment. The reconstituted βThal⁺ samples also presented higher proteasome activity and fewer procoagulant extracellular vesicles. Transfusion to mice demonstrated that βThal⁺ RBCs present a marginal trend for higher recovery, regardless of the recipient’s immune background and the RBC storage age. According to correlation analysis, several of these advantageous post-storage characteristics are related to storage phenotypes, like the cytoskeleton composition, low cellular fragility, and enhanced membrane proteostasis that characterize stored βThal⁺ RBCs. Overall, it seems that the intrinsic physiology of βThal⁺ RBCs benefits them in conditions mimicking a recipient environment, and in the circulation of animal models; findings that warrant validation in clinical trials. Full article

(This article belongs to the Special Issue Roles of Erythrocytes in Human Health and Disease)

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Review

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14 pages, 766 KiB

Open AccessReview

The Role of Red Cell Distribution Width as a Prognostic Marker in Chronic Liver Disease: A Literature Review

by Hunain Aslam, Fouzia Oza, Khalid Ahmed, Jonathan Kopel, Mark M. Aloysius, Aman Ali, Dushyant Singh Dahiya, Muhammad Aziz, Abhilash Perisetti and Hemant Goyal

Int. J. Mol. Sci. 2023, 24(4), 3487; https://doi.org/10.3390/ijms24043487 - 9 Feb 2023

Cited by 15 | Viewed by 4511

Abstract

Liver disease is one of the leading public health problems faced by healthcare practitioners regularly. As such, there has been a search for an inexpensive, readily available, non-invasive marker to aid in monitoring and prognosticating hepatic disorders. Recently, red blood cell distribution width [...] Read more.

Liver disease is one of the leading public health problems faced by healthcare practitioners regularly. As such, there has been a search for an inexpensive, readily available, non-invasive marker to aid in monitoring and prognosticating hepatic disorders. Recently, red blood cell distribution width (RDW) has been found to be associated with various inflammatory conditions with implications for its use as a potential marker for assessing disease progression and prognosis in multiple conditions. Multiple factors effect red blood cell production whereby a dysfunction in any process can lead to anisocytosis. Furthermore, a chronic inflammatory state leads to increased oxidative stress and produces inflammatory cytokines causing dysregulation and increased intracellular uptake and use of both iron and vitamin B12, which leads to a reduction in erythropoiesis causing an increase in RDW. This literature review reviews in-depth pathophysiology that may lead to an increase in RDW and its potential correlation with chronic liver diseases, including hepatitis B, hepatitis C, hepatitis E, non-alcoholic fatty liver disease, autoimmune hepatitis, primary biliary cirrhosis, and hepatocellular carcinoma. In our review, we examine the use of RDW as a prognostic and predictive marker for hepatic injury and chronic liver disease. Full article

(This article belongs to the Special Issue Roles of Erythrocytes in Human Health and Disease)

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19 pages, 4208 KiB

Open AccessReview

Metabolic Reprogramming in Sickle Cell Diseases: Pathophysiology and Drug Discovery Opportunities

by Dina Alramadhani, Anfal S. Aljahdali, Osheiza Abdulmalik, B. Daniel Pierce and Martin K. Safo

Int. J. Mol. Sci. 2022, 23(13), 7448; https://doi.org/10.3390/ijms23137448 - 4 Jul 2022

Cited by 4 | Viewed by 4589

Abstract

Sickle cell disease (SCD) is a genetic disorder that affects millions of individuals worldwide. Chronic anemia, hemolysis, and vasculopathy are associated with SCD, and their role has been well characterized. These symptoms stem from hemoglobin (Hb) polymerization, which is the primary event in [...] Read more.

Sickle cell disease (SCD) is a genetic disorder that affects millions of individuals worldwide. Chronic anemia, hemolysis, and vasculopathy are associated with SCD, and their role has been well characterized. These symptoms stem from hemoglobin (Hb) polymerization, which is the primary event in the molecular pathogenesis of SCD and contributes to erythrocyte or red blood cell (RBC) sickling, stiffness, and vaso-occlusion. The disease is caused by a mutation at the sixth position of the β-globin gene, coding for sickle Hb (HbS) instead of normal adult Hb (HbA), which under hypoxic conditions polymerizes into rigid fibers to distort the shapes of the RBCs. Only a few therapies are available, with the universal effectiveness of recently approved therapies still being monitored. In this review, we first focus on how sickle RBCs have altered metabolism and then highlight how this understanding reveals potential targets involved in the pathogenesis of the disease, which can be leveraged to create novel therapeutics for SCD. Full article

(This article belongs to the Special Issue Roles of Erythrocytes in Human Health and Disease)

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13 pages, 325 KiB

Open AccessReview

Implication of COVID-19 on Erythrocytes Functionality: Red Blood Cell Biochemical Implications and Morpho-Functional Aspects

by Annamaria Russo, Ester Tellone, Davide Barreca, Silvana Ficarra and Giuseppina Laganà

Int. J. Mol. Sci. 2022, 23(4), 2171; https://doi.org/10.3390/ijms23042171 - 16 Feb 2022

Cited by 47 | Viewed by 10617

Abstract

Several diseases (such as diabetes, cancer, and neurodegenerative disorders) affect the morpho-functional aspects of red blood cells, sometimes altering their normal metabolism. In this review, the hematological changes are evaluated, with particular focus on the morphology and metabolic aspects of erythrocytes. Changes in [...] Read more.

Several diseases (such as diabetes, cancer, and neurodegenerative disorders) affect the morpho-functional aspects of red blood cells, sometimes altering their normal metabolism. In this review, the hematological changes are evaluated, with particular focus on the morphology and metabolic aspects of erythrocytes. Changes in the functionality of such cells may, in fact, help provide important information about disease severity and progression. The viral infection causes significant damage to the blood cells that are altered in size, rigidity, and distribution width. Lower levels of hemoglobin and anemia have been reported in several studies, and an alteration in the concentration of antioxidant enzymes has been shown to promote a dangerous state of oxidative stress in red blood cells. Patients with severe COVID-19 showed an increase in hematological changes, indicating a progressive worsening as COVID-19 severity progressed. Therefore, monitored hematological alterations in patients with COVID-19 may play an important role in the management of the disease and prevent the risk of a severe course of the disease. Finally, monitored changes in erythrocytes and blood, in general, may be one of the causes of the condition known as Long COVID. Full article

(This article belongs to the Special Issue Roles of Erythrocytes in Human Health and Disease)

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