Inhibitory Effect of Thymol on Suicidal Erythrocyte Death

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Eryptosis, the suicidal erythrocyte death, is characterized by cell membrane scrambling and cell shrinkage. Eryptosis may be triggered by excessive hyperosmotic or isosmotic cell shrinkage leading to increase of cytosolic Ca²⁺ concentration. Eryptosis is further stimulated by the K⁺ ionophore valinomycin, which leads to exit of KCl and osmotically obliged water, or by energy (glucose) depletion, which compromises the function of the Na⁺/K⁺ ATPase thus increasing cytosolic Na⁺ concentration. The present study explored whether the Na⁺ ionophore monensin affects erythrocyte cell volume and eryptosis. The cell membrane scrambling was estimated from binding of annexin V to phosphatidylserine at the erythrocyte surface, cell volume from forward scatter in FACS analysis, cytosolic Ca²⁺ concentration from Fluo3 fluorescence and the cytosolic ATP concentration from a luciferase-based assay. Within 24 hours, exposure to monensin (0.1-10 µg/ml) significantly increased forward scatter, cytosolic Ca²⁺ concentration and annexin V-binding. Glucose depletion was followed by decreased forward scatter and increased cytosolic Ca²⁺ concentration and annexin V-binding. The effect on forward scatter was partially reversed, the effect on cytosolic Ca²⁺ concentration and annexin V binding augmented by additional treatment with monensin. In conclusion, monensin dissociates the alterations of cell membrane and cell volume in suicidal erythrocyte death.

Section: Discussionmentioning

confidence: 99%

Monensin Induced Suicidal Erythrocyte Death

Bhavsar

Eberhard

Bobbala

et al. 2010

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“…Tanshinone IIA may further potentiate the erj^jtotic effect of other eryptosis triggering xenobiotics [48,72,[79][80][81][82][83][84][85][86][87][88][89][90][91][92]. Accelerated eryptosis may lead to anemia [37] and adherence of phosphatidylserine-exposing erythrocjrtes to the vascular wall with the respective impairment of microcirculation [93][94][95][96][97].…”

Section: Discussionmentioning

confidence: 99%

Tanshinone IIA Stimulates Erythrocyte Phosphatidylserine Exposure

Zelenak

Pasham

Jilani

et al. 2012

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Tanshinone IIA, an antimicrobial, antioxidant, antianaphylactic, antifibrotic, vasodilating, antiatherosclerotic, organo-protective and antineoplastic component from the rhizome of Salvia miltiorrhiza, is known to trigger apoptosis of tumor cells. Tanshinone IIA is effective in part through mitochondrial depolarization and altered gene expression. Erythrocytes lack mitochondria and nuclei but may undergo eryptosis, an apoptosis-like suicidal cell death characterized by cell shrinkage and cell membrane scrambling with phosphatidylserine exposure at the cell surface. Eryptosis is triggered by increase of cytosolic Ca²⁺ activity, ATP depletion and ceramide formation. The present study explored, whether tanshinone IIA elicits eryptosis. Cytosolic Ca²⁺-concentration was determined from Fluo3-fluorescence, cell volume from forward scatter, phosphatidylserine exposure from binding of fluorescent annexin V, hemolysis from hemoglobin concentration in the supernatant, ATP concentration utilizing luciferin–luciferase and ceramide formation utilizing fluorescent anticeramide antibodies. Clearance of circulating erythrocytes was estimated by CFSE-labeling. A 48 h exposure to tanshinone IIA (≥10 µM) significantly increased cytosolic Ca²⁺-concentration, decreased ATP concentration (25 µM), increased lactate concentration (25 µM), increased ceramide formation (25 µM), decreased forward scatter, increased annexin-V-binding and increased (albeit to a much smaller extent) hemolysis. The effect of 25 µM tanshinone IIA on annexin-V binding was partially reversed in the nominal absence of Ca²⁺. Labelled tanshinone IIA-treated erythrocytes were more rapidly cleared from the circulating blood in comparison to untreated erythrocytes. The present observations reveal a completely novel effect of tanshinone IIA, i.e. triggering of Ca²⁺ entry, ATP depletion and ceramide formation in erythrocytes, events eventually leading to eryptosis with cell shrinkage and cell membrane scrambling.

“…Moreover, eryptosis is triggered or modified by a wide variety of substances [3,32,[55][56][57][58][59][60]. Several of the eryptosis-inducing diseases and xenobiotics have already been shown to influence the course of malaria, i.e.…”

Section: Discussionmentioning

confidence: 99%

Effect of Amphotericin B on Parasitemia and Survival of <i>Plasmodium Berghei</i>-infected Mice

Siraskar

Ballal

Bobbala

et al. 2010

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Premature death of Plasmodium-infected erythrocytes is considered to favourably influence the clinical course of malaria. Amphotericin B has previously been shown to trigger suicidal erythrocyte death or eryptosis, which is characterized by cell membrane scrambling leading to phosphatidylserine exposure at the cell surface. Phosphatidylserine-exposing cells are rapidly cleared from circulating blood. The present study thus tested whether amphotericin B exerts a direct effect on Plasmodium falciparum and influences eryptosis of infected erythrocytes, parasitemia and host survival in murine malaria. To this end, human erythrocytes were infected in vitro with Plasmodium falciparum and mice were infected with Plasmodium berghei ANKA by in vivo intraperitoneal injection of parasitized murine erythrocytes (1x10⁶). Half of the infected mice received amphotericin B (1.5 mg/kg b.w. i.v.) from the 8^th day of infection. Amphotericin B (≧ 1 µM) compromised the intracellular development of the parasite in human erythrocytes as evident from in vitro growth and DNA amplification assays. Amphotericin B further augmented the eryptosis of infected human erythrocytes. The administration of amphotericin B to infected mice tended to delay the increase of parasitemia and significantly delayed host death. All nontreated mice died from malaria within 27 days. In contrast, some 50% of amphotericin B-treated mice survived for more than 27 days after infection. In conclusion, amphotericin B augmented the suicidal death of infected erythrocytes and delayed the lethal course of malaria in Plasmodium berghei infected mice.