Enhanced Eryptosis Following Exposure to Lopinavir

Bissinger, Rosi; Waibel, Sabrina; Bouguerra, Ghada; Bhuyan, Abdulla Al Mamun; Abbès, Salem; Läng, Florian

doi:10.1159/000438601

Cited by 41 publications

(12 citation statements)

References 68 publications

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“…Example: Lopinavir treatment [22] induces oxidative stress and reduction of antioxidant glutathione as shown in Fig. 5.…”

Section: Methodsmentioning

confidence: 99%

“…Examples are provided by treatment of erythrocytes with the CDC25B phosphatase inhibitor NSC-95397 [35], the PLK1 kinase inhibitor BI-2536 [89], the protease inhibitor Lopinavir [22], the marine sponge-derived Fascaplycin [44], the selective histamine H1 receptor antagonist Terfenadine [58] and Fucoxanthin (a carotenoid from the chloroplasts of brown seaweeds) [25]. In parallel examples of substances interfering with eryptosis signalling, such as caspase inhibitor Z-VAD-FMK, p38 inhibitor SB203580, protein kinase C inhibitor staurosporine and casein kinase 1 CK1α inhibitor D4476 [9] are provided.…”

Section: Introductionmentioning

confidence: 99%

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Methods Employed in Cytofluorometric Assessment of Eryptosis, the Suicidal Erythrocyte Death

Jèmaà¹,

Fezai²,

Bissinger³

et al. 2017

Cell Physiol Biochem

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Suicidal erythrocyte death or eryptosis contributes to or even accounts for anemia in a wide variety of clinical conditions, such as iron deficiency, dehydration, hyperphosphatemia, vitamin D excess, chronic kidney disease (CKD), hemolytic-uremic syndrome, diabetes, hepatic failure, malignancy, arteriitis, sepsis, fever, malaria, sickle-cell disease, beta-thalassemia, Hb-C and G6PD-deficiency, Wilsons disease, as well as advanced age. Moreover, eryptosis is triggered by a myriad of xenobiotics and endogenous substances including cytotoxic drugs and uremic toxins. Eryptosis is characterized by cell membrane scrambling with phosphatidylserine exposure to the erythrocyte surface. Triggers of eryptosis include oxidative stress, hyperosmotic shock, and energy depletion. Signalling involved in the regulation of eryptosis includes Ca²⁺ entry, ceramide, caspases, calpain, p38 kinase, protein kinase C, Janus-activated kinase 3, casein kinase 1α, cyclin-dependent kinase 4, AMP-activated kinase, p21-activated kinase 2, cGMP-dependent protein kinase, mitogen- and stress-activated kinase MSK1/2, and ill-defined tyrosine kinases. Inhibitors of eryptosis may prevent anaemia in clinical conditions associated with enhanced eryptosis and stimulators of eryptosis may favourably influence the clinical course of malaria. Additional experimentation is required to uncover further clinical conditions with enhanced eryptosis, as well as further signalling pathways, further stimulators, and further inhibitors of eryptosis. Thus, a detailed description of the methods employed in the analysis of eryptosis may help those, who enter this exciting research area. The present synopsis describes the experimental procedures required for the analysis of phosphatidylserine exposure at the cell surface with annexin-V, cell volume with forward scatter, cytosolic Ca²⁺ activity ([Ca²⁺]_i) with Fluo3, oxidative stress with 2′,7′-dichlorodihydrofuorescein diacetate (DCFDA), glutathione (GSH) with mercury orange 1(4-chloromercuryphenyl-azo-2-naphthol), lipid peroxidation with BODIPY 581/591 C11 fluorescence, and ceramide abundance with specific antibodies. The contribution of kinases and caspases is defined with the use of the respective inhibitors. It is hoped that the present detailed description of materials and methods required for the analysis of eryptosis encourages further scientists to enter this highly relevant research area.

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“…Example: Lopinavir treatment [22] induces oxidative stress and reduction of antioxidant glutathione as shown in Fig. 5.…”

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Methods Employed in Cytofluorometric Assessment of Eryptosis, the Suicidal Erythrocyte Death

Jèmaà¹,

Fezai²,

Bissinger³

et al. 2017

Cell Physiol Biochem

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“…Another research group identified Lopinavir as a potent oxidative stress inducer, which causes ER stress, a common ART-induced side effect, in hepatocytes and in intestinal epithelial cells [12]. Instead, in erythrocytes from healthy volunteers Lopinavir treatment enhanced eryptosis, correlated again with oxidative stress [21]. Therefore, ART-treatment seems to increase oxidative stress in many different types of cellular models; unfortunately, the molecular mechanism underlying this effect is not yet fully elucidated and little is known about the relationship between oxidative stress and ART-treatment in CNS.…”

Section: Discussionmentioning

confidence: 99%

HIV Protease Inhibitors Apoptotic Effect in SH-SY5Y Neuronal Cell Line

Tricarico

França

Pacor

et al. 2016

Cell Physiol Biochem

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Background: Prophylactic treatment regimens to prevent mother-to-child HIV transmission include protease inhibitors Lopinavir and Ritonavir. Lopinavir and Ritonavir have been reported to be able to induce intracellular oxidative stress in diverse cellular models, however scarce informations are available about protease inhibitor effects of in the central nervous system (CNS). In our study we evaluated the impact of protease inhibitors on a cell neuronal model. Methods: We treated a neuroblastoma cell line (SH-SY5Y) with increasing doses of Lopinavir and Ritonavir (0.1-1-10-25-50 µM), used alone or in combination, evaluating the impact of these drugs in terms of mitochondrial activity, with MTT cell proliferation assay; mRNA expression of heme oxygenase (HemeOH) and reactive oxygen species (ROS) levels with 2',7'-dichlorofluorescin diacetate (H2DCFDA) in order to assess oxidative stress; apoptotic cell death with flow cytometry. Results: We observed that Lopinavir and Ritonavir treatment, at 25 and/or 50 µM concentrations, induced mitochondrial damage, increase of heme oxygenase RNA expression levels and ROS generation, followed by apoptosis in SH-SY5Y. Conclusions: Our in vitro model demonstrates a damaging effect of HIV protease inhibitors on the neuroblastoma cell line, thus partially mimicking the impact of these drugs on the CNS of children born to HIV positive mothers undergone to antiretroviral treatment.

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“…Eryptosis is triggered by complement, hyperosmotic shock, energy depletion, oxidative stress, cellular K + loss, increase of temperature and a wide variety of xenobiotics [32, 43, 54, 64, 72-111]. …”

Section: Introductionmentioning

confidence: 99%

Eryptosis - the Neglected Cause of Anemia in End Stage Renal Disease

Läng

Bissinger

Abed

et al. 2017

Kidney Blood Press Res

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End stage renal disease (ESRD) invariably leads to anemia which has been mainly attributed to compromised release of erythropoietin from the defective kidneys with subsequent impairment of erythropoiesis. However, erythropoietin replacement only partially reverses anemia pointing to the involvement of additional mechanisms. As shown more recently, anemia of ESRD is indeed in large part a result of accelerated erythrocyte loss due to suicidal erythrocyte death or eryptosis, characterized by cell shrinkage and cell membrane scrambling with phosphatidylserine translocation to the cell surface. Phosphatidylserine exposing erythrocytes are bound to and engulfed by macrophages and are thus rapidly cleared from circulating blood. If the loss of erythrocytes cannot be fully compensated by enhanced erythropoiesis, stimulation of eryptosis leads to anemia. Eryptotic erythrocytes may further adhere to the vascular wall and thus impair microcirculation. Stimulators of eryptosis include complement, hyperosmotic shock, energy depletion, oxidative stress, and a wide variety of xenobiotics. Signaling involved in the stimulation of eryptosis includes increase of cytosolic Ca²⁺ activity, ceramide, caspases, calpain, p38 kinase, protein kinase C, Janus-activated kinase 3, casein kinase 1α, and cyclin-dependent kinase 4. Eryptosis is inhibited by AMP-activated kinase, p21-activated kinase 2, cGMP-dependent protein kinase, mitogen- and stress-activated kinase MSK1/2, and some illdefined tyrosine kinases. In ESRD eryptosis is stimulated at least in part by a plasma component, as it is triggered by exposure of erythrocytes from healthy individuals to plasma from ESRD patients. Several eryptosis-stimulating uremic toxins have been identified, such as vanadate, acrolein, methylglyoxal, indoxyl sulfate, indole-3-acetic acid and phosphate. Attempts to fully reverse anemia in ESRD with excessive stimulation of erythropoiesis enhances the number of circulating suicidal erythrocytes and bears the risk of interference with micocirculation, At least in theory, anemia in ESRD could preferably be treated with replacement of erythropoietin and additional inhibition of eryptosis thus avoiding eryptosis-induced impairment of microcirculation. A variety of eryptosis inhibitors have been identified, their efficacy in ESRD remains, however, to be shown.

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Enhanced Eryptosis Following Exposure to Lopinavir

Cited by 41 publications

References 68 publications

Methods Employed in Cytofluorometric Assessment of Eryptosis, the Suicidal Erythrocyte Death

Methods Employed in Cytofluorometric Assessment of Eryptosis, the Suicidal Erythrocyte Death

HIV Protease Inhibitors Apoptotic Effect in SH-SY5Y Neuronal Cell Line

Eryptosis - the Neglected Cause of Anemia in End Stage Renal Disease

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