DMT1-Mutant Erythrocytes have Shortened Life Span, Accelerated Glycolysis and Increased Oxidative Stress

Zidova, Zuzana; Kapralova, Katarina; Kořalková, Pavla; Mojzíková, Renata; Dolezal, Dalibor; Divoký, Vladimír; Horváthová, Monika

doi:10.1159/000369665

Cited by 21 publications

(14 citation statements)

References 38 publications

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“…In various papers, others and we have shown the effect of an upregulated inflammatory profile due to conditions like Alzheimer’s disease, Parkinson’s disease, T2D and rheumathoid arthritis in blood of these patients. Various research papers that support the effects of these upregulated cytokines resulting in a dysregulated immune system, specifically resulting in eryptosis, is therefore important to note646566676869707172.…”

Section: Discussionmentioning

confidence: 99%

Effects of IL-1β, IL-6 and IL-8 on erythrocytes, platelets and clot viscoelasticity

Bester

Pretorius

2016

Sci Rep

255

206

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Complex interactions exist between cytokines, and the interleukin family plays a fundamental role in inflammation. Particularly circulating IL-1β, IL-6 and IL-8 are unregulated in systemic and chronic inflammatory conditions. Hypercoagulability is an important hallmark of inflammation, and these cytokines are critically involved in abnormal clot formation, erythrocyte pathology and platelet hyper-activation, and these three cytokines have known receptors on platelets. Although these cytokines are always unregulated in inflammation, we do not know how the individual cytokines act upon the structure of erythrocytes and platelets, and which of the viscoelastic clot parameters are changed. Here we study the effects of IL-1β, IL-6 and IL-8 at low physiological levels, representative of chronic inflammation, by using scanning electron microscopy and thromboelastography. All three interleukins caused the viscoelastic properties to display an increased hypercoagulability of whole blood and pathology of both erythrocytes and platelets. The most pronounced changes were noted where all three cytokines caused platelet hyper-activation and spreading. Erythrocyte structure was notably affected in the presence of IL-8, where the morphological changes resembled that typically seen in eryptosis (programmed cell death). We suggest that erythrocytes and platelets are particularly sensitive to cytokine presence, and that they are excellent health indicators.

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Section: Discussionmentioning

confidence: 99%

Effects of IL-1β, IL-6 and IL-8 on erythrocytes, platelets and clot viscoelasticity

Bester

Pretorius

2016

Sci Rep

255

206

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“…Induction of eryptosis has thus proven a sensitive measure of cytotoxicity [56]. Cellular mechanisms leading to eryptosis include increase of cytosolic Ca 2+ activity ([Ca 2+ ] i ) [56], ceramide [72], oxidative stress [56,73,74], energy depletion [56], caspases [56,75,76], casein kinase 1α, Janus-activated kinase JAK3, protein kinase C, and p38 kinase [56]. Cellular mechanisms counteracting eryptosis include AMP activated kinase AMPK, cGMP-dependent protein kinase, PAK2 kinase [56], cyclin-dependent kinase CDK4 [77], mitogen-and stress-activated kinase MSK1/2 [78], and sorafenib/ sunitinib sensitive kinases [56].…”

Section: Introductionmentioning

confidence: 99%

Enhanced Eryptosis Following Exposure to Dolutegravir

Bhuyan

Signoretto

Bissinger³

et al. 2016

Cell Physiol Biochem

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Background/Aims: The viral integrase enzyme inhibitor dolutegravir is utilized for the treatment of immunodeficiency virus (HIV) infection. Knowledge on cytotoxicity of dolutegravir is limited. The present study thus explored, whether dolutegravir is able to trigger suicidal erythrocyte death or eryptosis, which is characterized by cell shrinkage and cell membrane scrambling with phosphatidylserine translocation to the erythrocyte surface. Cellular mechanisms involved in the triggering of eryptosis include increase of cytosolic Ca²⁺ activity ([Ca²⁺]_i), oxidative stress, ceramide, and activation of protein kinase C, p38 kinase, casein kinase, and caspases. The present study explored, whether Dolutegravir induces eryptosis and, if so, to gain insight into cellular mechanisms involved. Methods: Utilizing flow cytometry, phosphatidylserine exposure at the cell surface was estimated from annexin-V-binding, cell volume from forward scatter, [Ca²⁺]_i from Fluo3-fluorescence, ROS formation from DCFDA dependent fluorescence, and ceramide abundance utilizing specific antibodies. Hemolysis was quantified from haemoglobin concentration in the supernatant. Results: A 48 hours exposure of human erythrocytes to dolutegravir significantly increased the percentage of annexin-V-binding cells (≥ 4.8 µM), significantly increased hemolysis (19.1 µM), but did not significantly modify forward scatter. Dolutegravir significantly increased Fluo3-fluorescence (≥ 4.8 µM), DCFDA fluorescence (19.1 µM) and ceramide abundance (19.1 µM). The effect of dolutegravir on annexin-V-binding was significantly blunted by removal of extracellular Ca²⁺, but was not significantly modified by protein kinase C inhibitor staurosporine (1 µM), p38 kinase inhibitor SB203580 (2 µM), casein kinase inhibitor D4476 (10 µM) or pancaspase inhibitor zVAD (10 µM). Conclusions: Dolutegravir triggers cell shrinkage and phospholipid scrambling of the erythrocyte cell membrane, an effect at least in part due to Ca²⁺ entry, ceramide formation and oxidative stress.

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“…Eryptosis is further stimulated by casein kinase 1α, Janus-activated kinase JAK3, protein kinase C, p38 kinase and PAK2 kinase [5]. Eryptosis is inhibited by AMP activated kinase AMPK [5], cGMP-dependent protein kinase [5], mitogen-and stress-activated kinase MSK1/2 [11], sorafenib/sunitinib sensitive kinases [5] and the divalent metal transporter 1 [12]. Eryptosis is stimulated by a wide variety of xenobiotics [5,.…”

Section: Introductionmentioning

confidence: 99%

Triggering of Suicidal Erythrocyte Death by Fascaplysin

Mischitelli

Jèmaà

Almasry

et al. 2016

Cell Physiol Biochem

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Background/Aims: The bis-indole alkaloid Fascaplysin is effective against malignancy, an effect at least partially due to stimulation of tumor cell apoptosis. Similar to apoptosis of nucleated cells, erythrocytes could enter suicidal erythrocyte death or eryptosis, characterized by cell shrinkage and cell membrane scrambling with phosphatidylserine translocation to the erythrocyte surface. Triggers of eryptosis include increase of cytosolic Ca²⁺ activity ([Ca²⁺]_i), oxidative stress and ceramide. The present study explored, whether Fascaplysin induces eryptosis and, if so, to shed light on the cellular mechanisms involved. Methods: Flow cytometry was employed to estimate phosphatidylserine exposure at the cell surface from annexin-V-binding, cell volume from forward scatter, [Ca²⁺]_i from Fluo3-fluorescence, ROS formation from DCFDA dependent fluorescence, and ceramide abundance utilizing specific antibodies. Hemolysis was quantified from the hemoglobin concentration in the supernatant. Results: A 48 hours exposure of human erythrocytes to Fascaplysin (≥ 5 µM) significantly increased the percentage of annexin-V-binding cells, significantly decreased forward scatter, and significantly increased Fluo3-fluorescence, DCFDA fluorescence as well as ceramide abundance. The effect of Fascaplysin on annexin-V-binding and forward scatter was significantly blunted but not abolished by removal of extracellular Ca²⁺. Conclusions: Fascaplysin triggers cell shrinkage and phospholipid scrambling of the erythrocyte cell membrane, an effect at least in part due to Ca²⁺ entry, oxidative stress and ceramide.

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DMT1-Mutant Erythrocytes have Shortened Life Span, Accelerated Glycolysis and Increased Oxidative Stress

Cited by 21 publications

References 38 publications

Effects of IL-1β, IL-6 and IL-8 on erythrocytes, platelets and clot viscoelasticity

Effects of IL-1β, IL-6 and IL-8 on erythrocytes, platelets and clot viscoelasticity

Enhanced Eryptosis Following Exposure to Dolutegravir

Triggering of Suicidal Erythrocyte Death by Fascaplysin

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