Biophysical analysis of novel transport pathways induced in red blood cell membranes

Ginsburg, Hagaï; Stein, Wilfred D.

doi:10.1007/bf01869329

Cited by 90 publications

(59 citation statements)

References 38 publications

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“…There was an inverse relation between permeability and molecular size which, when analysed according to the Renkin equation, indicated a pore radius of 1.0-1.3 nm [30,31]. Since the hydrodynamic radius of poly(ethylene glycol) 1500 is about 1.2 nm [32], the two sets of measurement are in close agreement. Thus the open pore is large enough to admit most metabolites as well as hydrated inorganic ions, including Ca# + .…”

Section: Mitochondrialmentioning

confidence: 83%

The mitochondrial permeability transition pore and its role in cell death

Crompton

1999

Biochemical Journal

1,811

1,267

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This article reviews the involvement of the mitochondrial permeability transition pore in necrotic and apoptotic cell death. The pore is formed from a complex of the voltage-dependent anion channel (VDAC), the adenine nucleotide translocase and cyclophilin-D (CyP-D) at contact sites between the mitochondrial outer and inner membranes. In vitro, under pseudopathological conditions of oxidative stress, relatively high Ca2+ and low ATP, the complex flickers into an open-pore state allowing free diffusion of low-Mr solutes across the inner membrane. These conditions correspond to those that unfold during tissue ischaemia and reperfusion, suggesting that pore opening may be an important factor in the pathogenesis of necrotic cell death following ischaemia/reperfusion. Evidence that the pore does open during ischaemia/reperfusion is discussed. There are also strong indications that the VDAC-adenine nucleotide translocase-CyP-D complex can recruit a number of other proteins, including Bax, and that the complex is utilized in some capacity during apoptosis. The apoptotic pathway is amplified by the release of apoptogenic proteins from the mitochondrial intermembrane space, including cytochrome c, apoptosis-inducing factor and some procaspases. Current evidence that the pore complex is involved in outer-membrane rupture and release of these proteins during programmed cell death is reviewed, along with indications that transient pore opening may provoke ‘accidental’ apoptosis.

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Section: Mitochondrialmentioning

confidence: 83%

The mitochondrial permeability transition pore and its role in cell death

Crompton

1999

Biochemical Journal

1,811

1,267

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“…It is a well-known fact that, mature erythrocytes do not display endocytosis and no pathways are evident for up taking macromolecules by these cells [73,74]. But contrary to this, uptake of ferritin claiming that Plasmodium-infected red cells are capable of endocytosis have been reported [75]. Many changes occur in the host cell membrane during intracellular malarial parasite development with extensive degradation of spectrin, allowing endocytosis in pRBCs [76,77].…”

Section: Discussionmentioning

confidence: 99%

“…An alternative concept of a 'metabolic window' that forms during the ring stage of asexual parasite maturation, provides 'contact sites' between the HEM and the PVM [87]. The altered membrane permeability coupled with capability for endocytosis could be key factors responsible for the entry of the nanoparticles selectively into the pRBCs [2,5,75,80].…”

Section: Discussionmentioning

confidence: 99%

Bio-inspired artemether-loaded human serum albumin nanoparticles for effective control of malaria-infected erythrocytes

Sidhaye¹,

Bhuran²,

Zambare³

et al. 2016

Nanomedicine

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Aim: The intra-erythrocytic development of the malarial parasite is dependent on active uptake of nutrients, including human serum albumin (HSA), into parasitized red blood cells (pRBCs). We have designed HSA-based nanoparticles as a potential drug-delivery option for antimalarials. Methods: Artemether-loaded nanoparticles (AAN) were designed and antimalarial activity evaluated in-vitro/in-vivo using Plasmodium falciparum/Plasmodium berghei species, respectively. Results: Selective internalisation of AAN into Plasmodiuminfected RBCs in preference to healthy erythrocytes was observed using confocal-imaging.In-vitro studies showed 50% dose reduction for AAN as compared to drug-only controls to achieve IC50 levels of inhibition. The nanoparticles exhibited 2-fold higher peak drug concentrations in RBCs with antimalarial activity at 50% of therapeutic doses in P.bergeiinfected mice. Conclusion: HSA-based nanoparticles offer safe and effective approach for selective targeting of antimalarial drugs.

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“…The rate of GSSG efflux markedly exceeds the capacity of the constitutive erythrocyte pump, which can be activated only tenfold (Srivastava and Beutler, 1969). The growing intraerythrocytic parasite induces permeability pathways in the host-cell membrane through which various solutes can translocate along their concentration gradient (Ginsburg and Stein, 1987 ;. The ability to inhibit the efflux of GSSG with 5-nitro-2-(3-phenylpropylamino)benzoic acid (which inhibits these pathways) with the same efficacy as the transport of other solutes (Kirk et d., 1994) suggests that the same pathways may regulate the efflux of GSSG.…”

Section: Discussionmentioning

confidence: 99%

The Malaria Parasite Supplies Glutathione to its Host Cell — Investigation of Glutathione Transport and Metabolism in Human Erythrocytes Infected with Plasmodium Falciparum

Atamna

Ginsburg

1997

European Journal of Biochemistry

136

102

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Malaria-infected red blood cells are under a substantial oxidative stress. Glutathione metabolism may play an important role in antioxidant defense in these cells, as it does in other eukaryotes. In this work, we have determined the levels of reduced and oxidized glutathione (GSH and GSSG, respectively) and their distributions in the parasite, and in the host-cell compartments of human erythrocytes infected with the malaria parasite Plasmodium falciparum. In intact trophozoite-infected erythrocytes, [GSH] is low and [GSSG] is high, compared with the levels in normal erythrocytes. Normal erythrocytes and the parasite compartment display high GSH/GSSG ratios of 321.6 and 284.5, respectively, indicating adequate antioxidant defense. This ratio drops to 26.7 in the host-cell compartment, indicating a forceful oxidant challenge, the low ratios resulting from an increase in GSSG and a decline in GSH concentrations. On the other hand, the concentrations of GSH and GSSG in the parasite compartment remain physiological and comparable to their concentrations in normal red blood cells. This results from de novo glutathione synthesis and its recycling, assisted by the intensive activity of the hexose monophosphate shunt in the parasite. A large efflux of GSSG from infected cells has been observed, its rate being similar from free parasites and from intact infected cells. This result suggests that de novo synthesis by the parasite is the dominating process in infected cells. GSSG efflux from the intact infected cell is more than 60-fold higher than the rate observed in normal erythrocytes, and is mediated by permeability pathways that the parasite induces in the erythrocyte's membrane. The main route for GSSG efflux through the cytoplasmic membrane of the parasite seems to be due to a specific transport system and occurs against a concentration gradient. 1)-Glutamylcysteine [Glu(-Cys)] and GSH can penetrate through the pathways from the extracellular space into the host cytosol, but not into that of the parasite. This implies that the parasite membrane is impermeable to these peptides, and that the host cannot supply GSH to the parasite as suggested previously. Exogenous Glu(-Cys) is not converted into GSH in the host cell, arguing that GSH synthetase may not be functional. Compartment analysis of Mg" in infected erythrocytes revealed that the host compartment exhibits a low concentration of Mg2+ (0.5 mM) in comparison with the parasite compartment (4 mM) and the normal erythrocytes (1.5-3 mM). The drop in [Mg"] results in cessation of Glu(-Cys) synthesis, and hence of GSH synthesis in the host-cell compartment. The decrease in [Mg"] can affect other Mg2+-ATP-dependent functions, such as Na' and Ca2+ active efflux. The present investigation confirms that the host-cell compartment is oxidatively distressed, whereas the parasite is efficiently equipped with anti-oxidant means that protect the parasite from the oxidative injury. The parasite has a huge capacity for de nova synthesis of GSH and for the reduction of GSSG. Part o...

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Biophysical analysis of novel transport pathways induced in red blood cell membranes

Cited by 90 publications

References 38 publications

The mitochondrial permeability transition pore and its role in cell death

The mitochondrial permeability transition pore and its role in cell death

Bio-inspired artemether-loaded human serum albumin nanoparticles for effective control of malaria-infected erythrocytes

The Malaria Parasite Supplies Glutathione to its Host Cell — Investigation of Glutathione Transport and Metabolism in Human Erythrocytes Infected with Plasmodium Falciparum

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