-
1.
The Mystery of Red Blood Cells Extracellular Vesicles in Sleep Apnea with Metabolic Dysfunction.
Khalyfa, A, Sanz-Rubio, D
International journal of molecular sciences. 2021;(9)
Abstract
Sleep is very important for overall health and quality of life, while sleep disorder has been associated with several human diseases, namely cardiovascular, metabolic, cognitive, and cancer-related alterations. Obstructive sleep apnea (OSA) is the most common respiratory sleep-disordered breathing, which is caused by the recurrent collapse of the upper airway during sleep. OSA has emerged as a major public health problem and increasing evidence suggests that untreated OSA can lead to the development of various diseases including neurodegenerative diseases. In addition, OSA may lead to decreased blood oxygenation and fragmentation of the sleep cycle. The formation of free radicals or reactive oxygen species (ROS) can emerge and react with nitric oxide (NO) to produce peroxynitrite, thereby diminishing the bioavailability of NO. Hypoxia, the hallmark of OSA, refers to a decline of tissue oxygen saturation and affects several types of cells, playing cell-to-cell communication a vital role in the outcome of this interplay. Red blood cells (RBCs) are considered transporters of oxygen and nutrients to the tissues, and these RBCs are important interorgan communication systems with additional functions, including participation in the control of systemic NO metabolism, redox regulation, blood rheology, and viscosity. RBCs have been shown to induce endothelial dysfunction and increase cardiac injury. The mechanistic links between changes of RBC functional properties and cardiovascular are largely unknown. Extracellular vesicles (EVs) are secreted by most cell types and released in biological fluids both under physiological and pathological conditions. EVs are involved in intercellular communication by transferring complex cargoes including proteins, lipids, and nucleic acids from donor cells to recipient cells. Advancing our knowledge about mechanisms of RBC-EVs formation and their pathophysiological relevance may help to shed light on circulating EVs and to translate their application to clinical practice. We will focus on the potential use of RBC-EVs as valuable diagnostic and prognostic biomarkers and state-specific cargoes, and possibilities as therapeutic vehicles for drug and gene delivery. The use of RBC-EVs as a precision medicine for the diagnosis and treatment of the patient with sleep disorder will improve the prognosis and the quality of life in patients with cardiovascular disease (CVD).
-
2.
Pharmacogenomics with red cells: a model to study protein variants of drug transporter genes.
Flegel, WA, Srivastava, K, Sissung, TM, Goldspiel, BR, Figg, WD
Vox sanguinis. 2021;(2):141-154
-
-
Free full text
-
Abstract
The PharmacoScan pharmacogenomics platform screens for variation in genes that affect drug absorption, distribution, metabolism, elimination, immune adverse reactions and targets. Among the 1,191 genes tested on the platform, 12 genes are expressed in the red cell membrane: ABCC1, ABCC4, ABCC5, ABCG2, CFTR, SLC16A1, SLC19A1, SLC29A1, ATP7A, CYP4F3, EPHX1 and FLOT1. These genes represent 5 ATP-binding cassette proteins, 3 solute carrier proteins, 1 ATP transport protein and 3 genes associated with drug metabolism and adverse drug reactions. Only ABCG2 and SLC29A1 encode blood group systems, JR and AUG, respectively. We propose red cells as an ex vivo model system to study the effect of heritable variants in genes encoding the transport proteins on the pharmacokinetics of drugs. Altered pharmacodynamics in red cells could also cause adverse reactions, such as haemolysis, hitherto unexplained by other mechanisms.
-
3.
Enhanced Eryptosis in Glucose-6-Phosphate Dehydrogenase Deficiency.
Bouguerra, G, Talbi, K, Trabelsi, N, Chaouachi, D, Boudriga, I, Abbès, S, Menif, S
Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology. 2021;(6):761-772
Abstract
BACKGROUND/AIMS: Defects in the Glucose-6-Phosphate Dehydrogenase (G6PD) enzyme enhance cellular oxidative damage, thus impairing erythrocytes and radically shortening their lifespan. We aimed to study programmed erythrocyte cell death in G6PD-deficient patients, describe the molecular genetics basis of G6PD and investigate phenotype-genotype correlations. METHODS We explored eryptosis using the annexin V-binding assay, taken as an indicator of PS exposure at the erythrocyte surface. We assessed reactive oxygen species (ROS) production, intracellular calcium concentrations and ceramide formation at the cell surface. Prior to and following treatments, cells were analyzed by flow cytometry. Finally, we explored G6PD gene mutations through PCR-Sanger sequencing. RESULTS Before stimulation, PS-exposing erythrocytes were significantly higher in G6PD-deficient patients than in healthy volunteers. This was paralleled by a significant increase in reactive oxygen species production, suggesting that oxidative stress is the main trigger of PS exposure in G6PD-deficient erythrocytes. Five previously described mutations were detected in our patients. Two genotypes correlated with a significantly higher percentage of PS-exposing cells. CONCLUSION Our study uncovers a novel effect detected in G6PD-deficient erythrocytes which is cell membrane scrambling with PS translocation to the erythrocyte surface. Our findings shed a light on the mechanisms of premature erythrocyte clearance in G6PD deficiency.
-
4.
Hypochromic red cells as predictors of anemia in patients undergoing hemodialysis: an observational retrospective study.
Kee, YK, Jeon, HJ, Oh, J, Shin, DH
Scientific reports. 2021;(1):24215
Abstract
The percentage of hypochromic red blood cells (%HRC) estimates the availability of iron by evaluating the degree of hemoglobinization. We investigated whether %HRC was a predictor of anemia in patients undergoing hemodialysis. We recruited 142 patients undergoing routine hemodialysis between 2017 and 2019. Delta hemoglobin level (ΔHb)1mo-baseline was calculated as the difference between the hemoglobin level at 1 month after study enrollment and that at the time of study enrollment. Development of anemia was defined as hemoglobin level ≤ 15% of baseline. The median %HRC was 3.1%. There was a significant negative correlation between (ΔHb)1mo- baseline and %HRC (r = - 0.63, P < 0.001). The incidence of anemia was significantly higher in patients with %HRC > 3.1% than in those with %HRC ≤ 3.1%. In the multivariate logistic regression analysis, %HRC was significantly related to the development of anemia (odds ratio 2.57, 95% confidence interval [CI] 1.72-3.85, P < 0.001). The best cutoff value for %HRC to predict the development of anemia was 4.3%, with a sensitivity and specificity of 67.74 (95% CI, 54.7-79.1) and 97.50 (95% CI, 91.3- 99.7), respectively. %HRC is an independent predictor of anemia in patients undergoing hemodialysis. %HRC ≤ 4.3% is an early marker to consider changing the anemia treatment.
-
5.
Effects of menopausal hormone therapy on erythrocyte n-3 and n-6 PUFA concentrations in the Women's Health Initiative randomized trial.
Harris, WS, Tintle, NL, Manson, JE, Metherel, AH, Robinson, JG
The American journal of clinical nutrition. 2021;(6):1700-1706
-
-
Free full text
-
Abstract
BACKGROUND The factors other than dietary intake that determine tissue concentrations of EPA and DHA remain obscure. Prior studies suggested that, in women, endogenous estrogen may accelerate synthesis of DHA from ɑ-linolenic acid (ALA), but the effects of exogenous estrogen on RBC n-3 (ɷ-3) PUFA concentrations are unknown. OBJECTIVE We tested the hypothesis that menopausal hormone therapy (HT) would increase RBC n-3 PUFA concentrations. METHODS Postmenopausal women (ages 50-79 y) were assigned to HT or placebo in the Women's Health Initiative (WHI) randomized trial. The present analyses included a subset of 1170 women (ages 65-79 y) who had RBC PUFA concentrations measured at baseline and at 1 y as participants in the WHI Memory Study. HT included conjugated equine estrogens (E) alone for women without a uterus (n = 560) and E plus medroxyprogesterone acetate (P) for those with an intact uterus (n = 610). RBC n-3 and n-6 (ɷ-6) PUFAs were quantified. RESULTS Effects of E alone and E+P on PUFA profiles were similar and were thus combined in the analyses. Relative to the changes in the placebo group after 1 y of HT, docosapentaenoic acid (DPA; n-3) concentrations decreased by 10% (95% CI: 7.3%, 12.5%), whereas DHA increased by 11% (95% CI: 7.4%, 13.9%) in the HT group. Like DHA, DPA n-6 increased by 13% from baseline (95% CI: 10.0%, 20.3%), whereas linoleic acid decreased by 2.0% (95% CI: 1.0%, 4.1%; P values at least <0.01 for all). EPA and arachidonic acid concentrations were unchanged. CONCLUSIONS HT increased RBC concentrations of the terminal n-3 and n-6 PUFAs (DHA and DPA n-6). These findings are consistent with an estrogen-induced increase in DHA and DPA n-6 synthesis, which is consistent with an upregulation of fatty acid elongases and/or desaturases in the PUFA synthetic pathway. The clinical implications of these changes require further study. The Women's Health Initiative Memory Study is registered at clinicaltrials.gov as NCT00685009. Note that the data presented here were not planned as part of the original trial, and therefore are to be considered exploratory.
-
6.
Fetal oxygen supply can be improved by an effective cross-talk between fetal erythrocytes and vascular endothelium.
Chakraborty, P, Khamit, A, Hermesz, E
Biochimica et biophysica acta. Molecular basis of disease. 2021;(11):166243
Abstract
In twin/multiple pregnancy, siblings experience an adverse intrauterine environment which forms the major etiological factor leading to pathological conditions. The status of the developing fetus is highly determined by the nitric oxide (NO) level, that facilitates vasodilation which in turn modulates the oxygen and nutrition supply. As the umbilical cord (UC) lacks innervation, activation of the endothelial nitric oxide synthase (NOS3) is fundamental to maintain adequate NO production. Recent ground breaking fact showed that under stress conditions, circulating red blood cells (RBCs) can actively produces NO as a "rescue mechanism". Therefore, this study majorly focused on the molecular mechanisms that affected the redox environment by altering NOS3 activation - both in the UC arteries and vein endothelium and RBCs - that have impacts on developmental parameters, like birth weight. In connection to that, we pursued the communication efficiency between the vessels' endothelium and the circulating RBCs in demand of bioavailable NO. Our results indicated that twinning itself at stage 33-35 weeks, does not reduce the NOS3 level and its phosphorylation status in the cord vessels. However, RBC-NOS3 activation is highly upregulated during this period - providing additional evidence for the active regulatory role of fetal RBCs in the rate of blood flow - and this functional activity highly correlates with the birth weight of the fetuses. Detailed analysis on NOS3 signalling at different time points of gestation could establish a benchmark in understanding of the pathophysiological mechanisms involved in the process of developing neonatal vascular diseases.
-
7.
PIEZO1 and the mechanism of the long circulatory longevity of human red blood cells.
Rogers, S, Lew, VL
PLoS computational biology. 2021;(3):e1008496
Abstract
Human red blood cells (RBCs) have a circulatory lifespan of about four months. Under constant oxidative and mechanical stress, but devoid of organelles and deprived of biosynthetic capacity for protein renewal, RBCs undergo substantial homeostatic changes, progressive densification followed by late density reversal among others, changes assumed to have been harnessed by evolution to sustain the rheological competence of the RBCs for as long as possible. The unknown mechanisms by which this is achieved are the subject of this investigation. Each RBC traverses capillaries between 1000 and 2000 times per day, roughly one transit per minute. A dedicated Lifespan model of RBC homeostasis was developed as an extension of the RCM introduced in the previous paper to explore the cumulative patterns predicted for repetitive capillary transits over a standardized lifespan period of 120 days, using experimental data to constrain the range of acceptable model outcomes. Capillary transits were simulated by periods of elevated cell/medium volume ratios and by transient deformation-induced permeability changes attributed to PIEZO1 channel mediation as outlined in the previous paper. The first unexpected finding was that quantal density changes generated during single capillary transits cease accumulating after a few days and cannot account for the observed progressive densification of RBCs on their own, thus ruling out the quantal hypothesis. The second unexpected finding was that the documented patterns of RBC densification and late reversal could only be emulated by the implementation of a strict time-course of decay in the activities of the calcium and Na/K pumps, suggestive of a selective mechanism enabling the extended longevity of RBCs. The densification pattern over most of the circulatory lifespan was determined by calcium pump decay whereas late density reversal was shaped by the pattern of Na/K pump decay. A third finding was that both quantal changes and pump-decay regimes were necessary to account for the documented lifespan pattern, neither sufficient on their own. A fourth new finding revealed that RBCs exposed to levels of PIEZO1-medited calcium permeation above certain thresholds in the circulation could develop a pattern of early or late hyperdense collapse followed by delayed density reversal. When tested over much reduced lifespan periods the results reproduced the known circulatory fate of irreversible sickle cells, the cell subpopulation responsible for vaso-occlusion and for most of the clinical manifestations of sickle cell disease. Analysis of the results provided an insightful new understanding of the mechanisms driving the changes in RBC homeostasis during circulatory aging in health and disease.
-
8.
Poor Birth Outcomes in Malaria in Pregnancy: Recent Insights Into Mechanisms and Prevention Approaches.
Chua, CLL, Hasang, W, Rogerson, SJ, Teo, A
Frontiers in immunology. 2021;:621382
Abstract
Pregnant women in malaria-endemic regions are susceptible to malaria in pregnancy, which has adverse consequences on birth outcomes, including having small for gestational age and preterm babies. These babies are likely to have low birthweights, which predisposes to infant mortality and lifelong morbidities. During malaria in pregnancy, Plasmodium falciparum-infected erythrocytes express a unique variant surface antigen, VAR2CSA, that mediates sequestration in the placenta. This process may initiate a range of host responses that contribute to placental inflammation and dysregulated placental development, which affects placental vasculogenesis, angiogenesis and nutrient transport. Collectively, these result in the impairment of placental functions, affecting fetal development. In this review, we provide an overview of malaria in pregnancy and the different pathological pathways leading to malaria in pregnancy-associated low birthweight. We also discuss current prevention and management strategies for malaria in pregnancy, and some potential therapeutic interventions that may improve birth outcomes. Lastly, we outline some priorities for future research that could bring us one step closer to reducing this health burden.
-
9.
An Insight into the Stages of Ion Leakage during Red Blood Cell Storage.
Zimna, A, Kaczmarska, M, Szczesny-Malysiak, E, Wajda, A, Bulat, K, Alcicek, FC, Zygmunt, M, Sacha, T, Marzec, KM
International journal of molecular sciences. 2021;(6)
Abstract
Packed red blood cells (pRBCs), the most commonly transfused blood product, are exposed to environmental disruptions during storage in blood banks. In this study, temporal sequence of changes in the ion exchange in pRBCs was analyzed. Standard techniques commonly used in electrolyte measurements were implemented. The relationship between ion exchange and red blood cells (RBCs) morphology was assessed with use of atomic force microscopy with reference to morphological parameters. Variations observed in the Na+, K+, Cl-, H+, HCO3-, and lactate ions concentration show a complete picture of singly-charged ion changes in pRBCs during storage. Correlation between the rate of ion changes and blood group type, regarding the limitations of our research, suggested, that group 0 is the most sensitive to the time-dependent ionic changes. Additionally, the impact of irreversible changes in ion exchange on the RBCs membrane was observed in nanoscale. Results demonstrate that the level of ion leakage that leads to destructive alterations in biochemical and morphological properties of pRBCs depend on the storage timepoint.
-
10.
Temporal sequence of the human RBCs' vesiculation observed in nano-scale with application of AFM and complementary techniques.
Kaczmarska, M, Grosicki, M, Bulat, K, Mardyla, M, Szczesny-Malysiak, E, Blat, A, Dybas, J, Sacha, T, Marzec, KM
Nanomedicine : nanotechnology, biology, and medicine. 2020;:102221
Abstract
Based on the multimodal characterization of human red blood cells (RBCs), the link between the storage-related sequence of the nanoscale changes in RBC membranes in the relation to their biochemical profile as well as mechanical and functional properties was presented. On the background of the accumulation of RBCs waste products, programmed cell death and impaired rheological properties, progressive alterations in the RBC membranes including changes in their height and diameter as well as the in situ characterization of RBC-derived microparticles (RMPs) on the RBCs surface were presented. The advantage of atomic force microscopy (AFM) in RMPs visualization, even at the very early stage of vesiculation, was shown based on the results revealed by other reference techniques. The nanoscale characterization of RMPs was correlated with a decrease in cholesterol and triglycerides levels in the RBC membranes, proving the link between the lipids leakage from RBCs and the process of vesiculation.