Eryptosis is a regulated cell death (RCD) of mature erythrocytes initially described as a counterpart of apoptosis for enucleated cells. However, over the recent years, a growing number of studies have emphasized certain differences between both cell death modalities. In this review paper, we underline the hallmarks of eryptosis and apoptosis and highlight resemblances and dissimilarities between both RCDs. We summarize and critically discuss differences in the impact of caspase-3, Ca2+ signaling, ROS signaling pathways, opposing roles of casein kinase 1α, protein kinase C, Janus kinase 3, cyclin-dependent kinase 4, and AMP-activated protein kinase to highlight a certain degree of divergence between apoptosis and eryptosis. This review emphasizes the crucial importance of further studies that focus on deepening our knowledge of cell death machinery and identifying novel differences between cell death of nucleated and enucleated cells. This might provide evidence that erythrocytes can be defined as viable entities capable of programmed cell destruction. Additionally, the revealed cell type-specific patterns in cell death can facilitate the development of cell death-modulating therapeutic agents.
Aim: We determined the long-term role of increased RDW (red blood cell distribution width) detected during cardiac decompensation.Methods: We followed 3697 patients [mean age 71.4 years (±SD 10.1), 59.1% males] hospitalized for acute heart failure (HF) and assessed the five-year all-cause mortality risk associated with tertiles of RDW.Results: Patients with RDW in the top tertile showed roughly twofold higher 5-year mortality risk than those in the bottom tertile. The association remained significant not only after adjustments for potential covariates but even if we excluded patients who deceased during the first year of follow-up [HRR 1.76 (95% CIs:1.42-2.18), p < 0.0001].Conclusion: The high degree of anisocytosis represents an independent predictor of poor prognosis in HF patients, even long-term after an acute manifestation.
- MeSH
- erytrocytární znaky * MeSH
- erytrocyty cytologie patologie metabolismus MeSH
- hospitalizace * MeSH
- lidé středního věku MeSH
- lidé MeSH
- následné studie MeSH
- prognóza MeSH
- senioři nad 80 let MeSH
- senioři MeSH
- srdeční selhání * krev mortalita MeSH
- Check Tag
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- senioři nad 80 let MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
Globin adducts of various chemicals, persisting in organism over the whole lifetime of erythrocytes, have been used as biomarkers of cumulative exposures to parent compounds. After removal of aged erythrocytes from the bloodstream, cleavage products of these adducts are excreted with urine as alternative, non-invasively accessible biomarkers. In our biomonitoring studies on workers exposed to ethylene oxide, its adduct with globin, N-(2-hydroxyethyl)valine, and the related urinary cleavage product N-(2-hydroxyethyl)-L-valyl-L-leucine have been determined. To describe a toxicokinetic relationship between the above types of biomarkers, a general compartmental model for simulation of formation and removal of globin adducts has been constructed in the form of code in R statistical computing environment. The essential input variables include lifetime of erythrocytes, extent of adduct formation following a single defined exposure, and parameters of exposure scenario, while other possible variables are optional. It was shown that both biomarkers reflect the past exposures differently as the adduct level in globin is a mean value of adduct levels across all compartments (subpopulations of erythrocytes of the same age) while excretion of cleavage products reflects the adduct level in the oldest compartment. Application of the model to various scenarios of continuous exposure demonstrated its usefulness for human biomonitoring data interpretation.
- MeSH
- biologické markery * moč krev MeSH
- biologické modely MeSH
- biologický monitoring * MeSH
- erytrocyty * metabolismus účinky léků MeSH
- ethylenoxid toxicita farmakokinetika moč MeSH
- globiny metabolismus MeSH
- lidé MeSH
- počítačová simulace MeSH
- pracovní expozice * MeSH
- toxikokinetika MeSH
- valin analogy a deriváty farmakokinetika moč krev MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
INTRODUCTION: Red blood cells (RBCs), also known as erythrocytes, are underestimated in their role in the immune system. In mammals, erythrocytes undergo maturation that involves the loss of nuclei, resulting in limited transcription and protein synthesis capabilities. However, the nucleated nature of non-mammalian RBCs is challenging this conventional understanding of RBCs. Notably, in bony fishes, research indicates that RBCs are not only susceptible to pathogen attacks but express immune receptors and effector molecules. However, given the abundance of RBCs and their interaction with every physiological system, we postulate that they act in surveillance as sentinels, rapid responders, and messengers. METHODS: We performed a series of in vitro experiments with Cyprinus carpio RBCs exposed to Aeromonas hydrophila, as well as in vivo laboratory infections using different concentrations of bacteria. RESULTS: qPCR revealed that RBCs express genes of several inflammatory cytokines. Using cyprinid-specific antibodies, we confirmed that RBCs secreted tumor necrosis factor alpha (TNFα) and interferon gamma (IFNγ). In contrast to these indirect immune mechanisms, we observed that RBCs produce reactive oxygen species and, through transmission electron and confocal microscopy, that RBCs can engulf particles. Finally, RBCs expressed and upregulated several putative toll-like receptors, including tlr4 and tlr9, in response to A. hydrophila infection in vivo. DISCUSSION: Overall, the RBC repertoire of pattern recognition receptors, their secretion of effector molecules, and their swift response make them immune sentinels capable of rapidly detecting and signaling the presence of foreign pathogens. By studying the interaction between a bacterium and erythrocytes, we provide novel insights into how the latter may contribute to overall innate and adaptive immune responses of teleost fishes.
- MeSH
- Aeromonas hydrophila * imunologie MeSH
- cytokiny * metabolismus imunologie MeSH
- erytrocyty * imunologie metabolismus MeSH
- fagocytóza imunologie MeSH
- gramnegativní bakteriální infekce * imunologie MeSH
- kapři * imunologie mikrobiologie MeSH
- nemoci ryb * imunologie mikrobiologie MeSH
- PAMP struktury imunologie MeSH
- přirozená imunita MeSH
- zvířata MeSH
- Check Tag
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
Intravenous thrombolysis with a recombinant tissue plasminogen activator (rt-PA) is the first-line treatment of acute ischemic stroke. However, successful recanalization is relatively low and the underlying processes are not completely understood. The goal was to provide insights into clinically important factors potentially limiting rt-PA efficacy such as clot size, rt-PA concentration, clot age and also rt-PA in combination with heparin anticoagulant. We established a static in vitro thrombolytic model based on red blood cell (RBC) dominant clots prepared using spontaneous clotting from the blood of healthy donors. Thrombolysis was determined by clot mass loss and by RBC release. The rt-PA became increasingly less efficient for clots larger than 50 μl at a clinically relevant concentration of 1.3 mg/l. A tenfold decrease or increase in concentration induced only a 2-fold decrease or increase in clot degradation. Clot age did not affect rt-PA-induced thrombolysis but 2-hours-old clots were degraded more readily due to higher activity of spontaneous thrombolysis, as compared to 5-hours-old clots. Finally, heparin (50 and 100 IU/ml) did not influence the rt-PA-induced thrombolysis. Our study provided in vitro evidence for a clot size threshold: clots larger than 50 μl are hard to degrade by rt-PA. Increasing rt-PA concentration provided limited thrombolytic efficacy improvement, whereas heparin addition had no effect. However, the higher susceptibility of younger clots to thrombolysis may prompt a shortened time from the onset of stroke to rt-PA treatment.
- MeSH
- cévní mozková příhoda farmakoterapie MeSH
- erytrocyty účinky léků metabolismus MeSH
- fibrinolytika terapeutické užití MeSH
- hemokoagulace účinky léků MeSH
- heparin * terapeutické užití MeSH
- ischemická cévní mozková příhoda * farmakoterapie MeSH
- lidé MeSH
- rekombinantní proteiny * terapeutické užití MeSH
- tkáňový aktivátor plazminogenu * terapeutické užití MeSH
- trombolytická terapie * metody MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
In humans and many animals, a trade-off between a sufficiently high concentration of erythrocytes (hematocrit) to bind oxygen and sufficiently low blood viscosity to allow rapid blood flow has been achieved during evolution. The optimal value lies between the extreme cases of pure blood plasma, which cannot practically transport any oxygen, and 100% hematocrit, which would imply very slow blood flow or none at all. As oxygen delivery to tissues is the main task of the cardiovascular system, it is reasonable to expect that maximum oxygen delivery has been achieved during evolution. Optimal hematocrit theory, based on this optimality principle, has been successful in predicting hematocrit values of about 0.3-0.5, which are indeed observed in the systemic circulation of humans and many animal species. Similarly, the theory can explain why a hematocrit higher than normal, ranging from 0.5 to 0.7, can promote better exertional performance. Here, we present a review of theoretical approaches to the calculation of the optimal hematocrit value under different conditions and discuss them in a broad physiological context. Several physiological and medical implications are outlined, for example, in view of blood doping, temperature adaptation, dehydration, and life at high altitudes.
- MeSH
- erytrocyty fyziologie metabolismus MeSH
- hematokrit metody MeSH
- kyslík * krev metabolismus MeSH
- lidé MeSH
- modely kardiovaskulární MeSH
- viskozita krve fyziologie MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- přehledy MeSH
Necroptosis is considered a programmed necrosis that requires receptor-interacting protein kinase 1 (RIPK1), receptor-interacting protein kinase 3 (RIPK3), and pore-forming mixed lineage kinase domain-like protein (MLKL) to trigger a regulated cell membrane lysis. Membrane rupture in necroptosis has been shown to fuel innate immune response due to release of damage-associated molecular patterns (DAMPs). Recently published studies indicate that mature erythrocytes can undergo necroptosis as well. In this review, we provide an outline of multiple cell death modes occurring in erythrocytes, discuss possible immunological aspects of diverse erythrocyte cell deaths, summarize available evidence related to the ability of erythrocytes to undergo necroptosis, outline key involved molecular mechanisms, and discuss the potential implication of erythrocyte necroptosis in the physiology and pathophysiology. Furthermore, we aim to highlight the interplay between necroptosis and eryptosis signaling in erythrocytes, emphasizing specific characteristics of these pathways distinct from their counterparts in nucleated cells. Thus, our review provides a comprehensive summary of the current knowledge of necroptosis in erythrocytes. To reflect critical differences between necroptosis of nucleated cells and necroptosis of erythrocytes, we suggest a term erythronecroptosis for necroptosis of enucleated cells.
- MeSH
- eryptóza MeSH
- erytrocyty * metabolismus patologie MeSH
- lidé MeSH
- nekroptóza * MeSH
- nekróza MeSH
- protein-serin-threoninkinasy interagující s receptory metabolismus MeSH
- proteinkinasy metabolismus MeSH
- signální transdukce MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- přehledy MeSH
Docosahexaenoic acid (DHA) is an omega-3 polyunsaturated fatty acid with promising anticancer potential. Anaemia is a frequent adverse effect of anticancer treatment caused in part by eryptosis and haemolysis. Thus, it is important to investigate the role of DHA in red blood cell (RBC) death. RBCs were treated with anticancer concentrations (10-100 μM) of DHA under different physiological conditions, and fluorescence-assisted cell sorting was employed to measure eryptotic markers. Cell membrane scrambling was detected by annexin-V-FITC labelling, cytoplasmic Ca2+ by Fluo4/AM, cell size by forward scatter (FSC), and oxidative stress by H2DCFDA. Haemolytic markers were also assayed by photometric methods. DHA caused significant phospholipid scrambling with Ca2+ accumulation, loss of cellular volume, and oxidative stress. These changes were associated with dacrocyte formation, as revealed by electron microscopy. Moreover, DHA exhibited a dual effect on membrane integrity: it was haemolytic under isotonic conditions and anti-haemolytic in hypotonic environments. Importantly, inhibition of Rac1 GTPase activity with NSC23766 significantly reduced DHA-mediated haemolysis, as did co-administration of either sucrose or polyethylene glycol 8,000. Conversely, the presence of 125 mM KCl and urea without extracellular Ca2+ significantly exacerbated DHA toxicity. In conclusion, this is the first report that identifies key biochemical mechanisms underlying the cytotoxic effects of DHA in RBCs, promoting further development and validation of DHA in anticancer therapy.
- MeSH
- eryptóza * účinky léků MeSH
- erytrocyty účinky léků metabolismus MeSH
- hemolýza * účinky léků MeSH
- kyseliny dokosahexaenové * farmakologie MeSH
- lidé MeSH
- oxidační stres * účinky léků MeSH
- signální transdukce účinky léků MeSH
- vápník * metabolismus MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- MeSH
- enzymy metabolismus MeSH
- erytrocyty metabolismus MeSH
- genetické nemoci vrozené MeSH
- glykolýza fyziologie MeSH
- hemolytická nesférocytická kongenitální anemie genetika MeSH
- hemolytické anemie * diagnóza terapie MeSH
- hemolýza genetika MeSH
- lidé MeSH
- pyruvátkinasa genetika nedostatek MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- přehledy MeSH
Overall, reactive oxygen species (ROS) signalling significantly contributes to initiation and mo-dulation of multiple regulated cell death (RCD) pathways. Lately, more information has become available about RCD modalities of erythrocytes, including the role of ROS. ROS accumulation has therefore been increasingly recognized as a critical factor involved in eryptosis (apoptosis of erythrocytes) and erythro-necroptosis (necroptosis of erythrocytes). Eryptosis is a Ca2+-dependent apoptosis-like RCD of erythrocytes that occurs in response to oxidative stress, hyperosmolarity, ATP depletion, and a wide range of xenobiotics. Moreover, eryptosis seems to be involved in the pathogenesis of multiple human diseases and pathological processes. Several studies have reported that erythrocytes can also undergo necroptosis, a lytic RIPK1/RIPK3/MLKL-mediated RCD. As an example, erythronecroptosis can occur in response to CD59-specific pore-forming toxins. We have systematically summarized available studies regarding the involvement of ROS and oxidative stress in these two distinct RCDs of erythrocytes. We have focused specifically on cellular signalling pathways involved in ROS-mediated cell death decisions in erythrocytes. Furthermore, we have summarized dysregulation of related erythrocytic antioxidant defence systems. The general concept of the ROS role in eryptotic and necroptotic cell death pathways in erythrocytes seems to be established. However, further studies are required to uncover the complex role of ROS in the crosstalk and interplay between the survival and RCDs of erythrocytes.
- MeSH
- eryptóza * fyziologie MeSH
- erytrocyty metabolismus MeSH
- lidé MeSH
- oxidace-redukce MeSH
- reaktivní formy kyslíku metabolismus MeSH
- vápník metabolismus MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
