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The short actin filaments in the erythrocyte's membrane skeleton are shown to be largely oriented tangent to the lipid bilayer. Actin "proto"-filaments have previously been described as junctional centers intertriangulated by spectrin; however, the protofilaments may simultaneously serve as pinning centers between the network and the overlying bilayer. The latter function now seems of particular importance because near-normal network assembly has been reported with transgenic mouse sphero-erythrocytes that lack the primary linkage protein Band 3. To assess possible physical constraints on actin protofilaments in intact membranes, fluorescence polarization microscopy (FPM) has been used to study rhodamine phalloidin-labeled red cell ghosts. A basis for interpreting FPM images of cells is provided by FPM applied to isolated actin filaments. These are labeled with the same rhodamine probes and imaged at various orientations with respect to the polarizers, including filament orientations perpendicular to the image plane. High aperture and fluorophore conjugation effects are found to be minimal, enabling development of a simple, semi-empirical model which indicates that protofilaments are generally within approximately 20 degrees of the membrane tangent plane.
Mounting data show that fatty acids (FA) and fatty acid synthase (FAS) function could be potential targets for multiple myeloma (MM) therapy. Our study aimed at comparing the FA composition of erythrocyte membranes of MM patients and healthy controls. MM patients had higher saturated FA and n-6 polyunsaturated FA (PUFA) and lower monounsaturated, n-3 PUFA and trans-FA indices than controls. The n-3/n-6 PUFA ratio was lower in MM patients and there was distinct clustering of variants of individual FA in MM patients. The FA content of erythrocyte membrane could serve as a diagnostic and/or predictive biomarker in MM.
Naproxen sodium is a nonsteroidal anti-inflammatory drug (NSAID) having antipyretic and analgesic properties, mainly used for the treatment of rheumatoid arthritis and osteoarthritis. Eryptosis is an alternative term used for suicidal erythrocyte death. In the current study, eryptotic effect of naproxen sodium characterized by membrane blebbing was investigated in erythrocytes after 48 hours of treatment with different concentrations (1-25 µM). The experimental work related to investigation of eryptosis was done by cell size measurement and confirmation of calcium role in the induction of membrane blebbing. As a possible mechanism of eryptosis, oxidative stress induced by naproxen sodium was determined by catalase, glutathione peroxidase, and superoxide dismutase activities. Similarly, hemolytic effect of naproxen sodium was also determined by hemolysis measurement. Results of our study illustrated that the therapeutic doses (10-25 µM) of naproxen sodium induce oxidative stress, confirmed by significant decrease in superoxide dismutase, catalase, and glutathione peroxidase activities that lead to the triggering of cell death by eryptosis and hemolysis.
This study aimed to determine whether oxidative damage to the erythrocyte occurs in preeclampsia, and relates to disease severity. The oxidative status of intact erythrocytes from preeclamptic patients and normal pregnant women was determined using spin echo 1H-NMR, which measures both the concentration and redox state of intracellular glutathione. Previous studies of preeclampsia have only measured total glutathione levels. Membrane fragility was determined from the degree of lysis caused by incubation in hypotonic saline. Erythrocytes from moderate-severe preeclamptic patients underwent more lysis than erythrocytes from control pregnant women (p < .05) or mild preeclamptic patients. It is suggested that increased lysis results from oxidative damage to the erythrocyte membrane, causing a decrease in membrane fluidity and reducing its ability to withstand osmotic changes. Intracellular glutathione was more oxidized in erythrocytes from pregnant women compared to nonpregnant controls (p < .05), and there was a less significant trend toward more oxidized glutathione with increasing severity of preeclampsia. The moderate-severe group showed a clear division in glutathione redox status: some patients had very oxidized glutathione while others had a normal redox balance. This novel finding suggests that some patients may be unusually susceptible to erythrocyte glutathione oxidation, possibly leading to general cellular damage, in particular HELLP Syndrome.
Neurodegenerative diseases have many similar pathological conditions, and very few studies exist which detail their molecular features. Proteins like Na+/K+-ATPase (NKA), α-spectrin (SPTA) and drebrin have been reported to be involved in the integrity of neuronal cell membrane and their functions. Furthermore, recent studies have highlighted their implication in neurodegeneration. In the current study, we wanted to identify the role of NKA, SPTA and drebrin in the erythrocyte membranes obtained from the blood of patients with neurodegenerative disorders (NDs) subjected to motor impairment such as Parkinson's disease, amyotrophic lateral sclerosis, ataxia and dementia. We have studied the activity of NKA and the expression of NKA, SPTA and drebrin in the erythrocyte membrane by quantitative real-time PCR and Western blot obtained from the blood samples of patients with NDs culminating in movement and memory dysfunction. We observed a significant reduction in the expressions of NKA, SPTA and drebrin when compared to control and significant variations among the recruited ND samples. On correlating, we found a significant relationship between the expressions and the clinical features such as bradykinesia. Thus, we suggest that the reduction in the expressions of NKA, SPTA and drebrin could function as tools of assessment and speculate the particular neurodegenerative condition.
We report the construction of erythrocyte membrane-cloaked Janus polymeric motors (EM-JPMs) which are propelled by near-infrared (NIR) laser irradiation and are successfully applied in thrombus ablation. Chitosan (a natural polysaccharide with positive charge, CHI) and heparin (glycosaminoglycan with negative charge, Hep) were selected as wall materials to construct biodegradable and biocompatible capsules through the layer-by-layer self-assembly technique. By partially coating the capsule with a gold (Au) layer through sputter coating, a NIR-responsive Janus structure was obtained. Due to the asymmetric distribution of Au, a local thermal gradient was generated upon NIR irradiation, resulting in the movement of the JPMs through the self-thermophoresis effect. The reversible "on/off" motion of the JPMs and their motile behavior were easily tuned by the incident NIR laser intensity. After biointerfacing the Janus capsules with an erythrocyte membrane, the EM-JPMs displayed red blood cell related properties, which enabled them to move efficiently in relevant biological environments (cell culture, serum, and blood). Furthermore, this therapeutic platform exhibited excellent performance in ablation of thrombus through photothermal therapy. As man-made micromotors, these biohybrid EM-JPMs hold great promise of navigating in vivo for active delivery while overcoming the drawbacks of existing synthetic therapeutic platforms. We expect that this biohybrid motor has considerable potential to be widely used in the biomedical field.
In this study, curcumin-loaded porous poly(lactic-co-glycolic acid) (PLGA) nanoparticles (NPs) were prepared and surface modified with red blood cell membranes (RBCM) to yield biomimetic RBCM-p-PLGA@Cur NPs. The NPs displayed a visible cell-membrane structure at their exterior and had a uniform size of 162 ± 3 nm. In vitro studies showed that drug release from non-porous PLGA NPs was slow and that much of the drug remained trapped in the NPs. In contrast, release was accelerated from the porous PLGA NPs, and after the RBCM coating, a sustained release over 48 h was obtained. Confocal microscopy and flow cytometry results revealed that the RBCM-p-PLGA NPs led to a greater cellular uptake by H22 hepatocarcinoma cells than the uncoated analogue NPs, but could avoid phagocytosis by macrophages. The drug-free formulations were highly biocompatible, while the drug-loaded systems were effective in killing cancer cells. RBCM-p-PLGA@Cur NPs possess potent anti-tumor activity in a murine H22 xenograft cancer model (in terms of reduced tumor volume and mass, as well as inducing apoptosis of tumor cells), and have no observable systemic toxicity. Overall, our study demonstrates that the use of the RBCM to cloak nanoscale drug delivery systems holds great promise for targeted cancer treatment, and can ameliorate the severe side effects currently associated with chemotherapy.
Red blood cells (RBCs) lose plasma membrane in the spleen as they age, but the cells and molecules involved are yet to be identified. Sickle cell disease and infection by Plasmodium falciparum cause oxidative stress that induces aggregates of cross-linked proteins with N-linked high-mannose glycans (HMGs). These glycans can be recognised by mannose-binding lectins, including the mannose receptor (CD206), expressed on macrophages and specialised phagocytic endothelial cells in the spleen to mediate the extravascular haemolysis characteristic of these diseases. We postulated this system might also mediate removal of molecules and membrane in healthy individuals. Surface expression of HMGs on RBCs from patients who had previously undergone splenectomy was therefore assessed: high levels were indeed observable as large membrane aggregates. Glycomic analysis by mass spectrometry identified a mixture of Man5-9 GlcNAc2 structures. HMG levels correlated well with manual pit counts (r = 0.75-0.85). To assess further whether HMGs might act as a splenic reticuloendothelial function test, we measured levels on RBCs from patients with potential functional hyposplenism, some of whom exhibited high levels that may indicate risk of complications.
The erythrocyte membrane plays a pivotal role in erythrocyte functioning. Many membrane protein aberrations are known that result in hemolytic anemia, however, the origin of numerous disorders is not known to date. To extend the current set of diagnostic tools, we used a novel proteome-wide approach to quantitatively analyze membrane proteins of healthy donor and patient erythrocytes. Blue-native PAGE has proven to be a powerful tool for separation of membrane proteins and their complexes, but has hitherto not been applied to erythrocyte membranes to find biomarkers. Using this technique, we detected almost 150 protein spots, from which more than 500 proteins could be identified by LC-MS/MS. Further, we successfully assessed the potential of using CyDye labeling to quantify the membrane proteins. Our final goal was to determine if this approach is suited to detect protein level changes in disordered erythrocyte membranes, and we could successfully confirm that erythrocyte spectrin levels were dramatically decreased for a hemolytic anemia patient. This approach provides a new tool to detect potential biomarkers and can contribute to an improved understanding of the causes of erythrocyte membrane defects in patients suffering from hemolytic anemia.
Cholesterol is the most abundant lipid in the erythrocyte. During its blood-stage development, the malaria parasite establishes an active cholesterol gradient across the various membrane systems within the infected erythrocyte. Interestingly, some antimalarial compounds have recently been shown to disrupt cholesterol homeostasis in the intraerythrocytic stages of Plasmodium falciparum. These studies point to the importance of cholesterol for parasite growth. Previously, reduction of cholesterol from the erythrocyte membrane by treatment with methyl-β-cyclodextrin (MβCD) was shown to inhibit parasite invasion and growth. In addition, MβCD treatment of trophozoite-stage P. falciparum was shown to result in parasite expulsion from the host cell. We have revisited these phenomena by using live video microscopy, ultrastructural analysis, and response to antimalarial compounds. By using time-lapse video microscopy of fluorescently tagged parasites, we show that MβCD treatment for just 30 min causes dramatic expulsion of the trophozoite-stage parasites. This forceful expulsion occurs within 10 s. Remarkably, the plasma membrane of the host cell from which the parasite has been expelled does not appear to be compromised. The parasitophorous vacuolar membrane (PVM) continued to surround the extruded parasite, but the PVM appeared damaged. Treatment with antimalarial compounds targeting PfATP4 or PfNCR1 prevented MβCD-mediated extrusion of the parasites, pointing to a potential role of cholesterol dynamics underlying the expulsion phenomena. We also confirmed the essential role of erythrocyte plasma membrane cholesterol for invasion and growth of P. falciparum. This defect can be partially complemented by cholesterol and desmosterol but not with epicholesterol, revealing stereospecificity underlying cholesterol function. Overall, our studies advance previous observations and reveal unusual cell biological features underlying cholesterol depletion of the infected erythrocyte plasma membrane. IMPORTANCE Malaria remains a major challenge in much of the world. Symptoms of malaria are caused by the growth of parasites belonging to Plasmodium spp. inside the red blood cells (RBCs), leading to their destruction. The parasite depends upon its host for much of its nutritional needs. Cholesterol is a major lipid in the RBC plasma membrane, which is the only source of this lipid for malaria parasites. We have previously shown that certain new antimalarial compounds disrupt cholesterol homeostasis in P. falciparum. Here, we use live time-lapse video microscopy to show dramatic expulsion of the parasite from the host RBC when the cholesterol content of the RBC is reduced. Remarkably, this expulsion is inhibited by the antimalarials that disrupt lipid homeostasis. We also show stereospecificity of cholesterol in supporting parasite growth inside RBC. Overall, these results point to a critical role of cholesterol in the physiology of malaria parasites.
Mature erythrocytes (red blood cells (RBCs)) undergo the programmed cell death (PCD) pathway of necroptosis in response to bacterial pore-forming toxins (PFTs) that target human CD59 (hCD59) but not hCD59-independent PFTs. Here, we investigate the biochemical mechanism of RBC necroptosis with a focus on the mechanism of induction and the minimal requirements for such RBC death. Binding or crosslinking of the hCD59 receptor led to Syk-dependent induction of vesiculated morphology (echinocytes) that was associated with phosphorylation of Band 3 and was required for Fas ligand (FasL) release. FasL-dependent phosphorylation of receptor-interacting protein kinase 1 (RIP1) in combination with plasma membrane pore formation was required for execution of RBC necroptosis. RIP1 phosphorylation led to the phosphorylation of RIP3, which was also critical for RBC necroptosis. Notably, RBC necroptosis was mediated by FasL and not by other candidate inducers, including tumor necrosis factor alpha (TNF-α) and TNF-related apoptosis-inducing ligand (TRAIL). Other types of RBC damage, such as eryptotic damage, failed to induce necroptosis when combined with hCD59 crosslinking. This work sheds light on the requirements for this recently discovered PCD in RBCs and provides a clear picture of the biochemical mechanism of induction of RBC necroptosis.
Plasma membrane redox system (PMRS) is an electron transport chain system ubiquitously present throughout all cell types. It transfers electron from intracellular substrates to extracellular acceptors for regulation of redox status. Curcumin, isolated from Curcuma longa, has modulatory effects on cellular physiology due to its membrane interaction ability and antioxidant potential. The present study investigates the effect of curcumin on PMRS activity of erythrocytes isolated from Wistar rats in vitro and in vivo and validated through an in silico docking simulation study using Molegro Virtual Docker (MVD). Effects of curcumin were also evaluated on level of glutathione (GSH) and the oxidant potential of plasma measured in terms of plasma ferric equivalent oxidative potentials (PFEOP). Results show that curcumin significantly (p < 0.01) downregulated the PMRS activity in a dose-dependent manner. Molecular docking results suggest that curcumin interacts with amino acids at the active site cavity of cytochrome b 5 reductase, a key constituent of PMRS. Curcumin also increased the GSH level in erythrocytes and plasma while simultaneously decreasing the oxidant potential (PFEOP) of plasma. Altered PMRS activity and redox status are associated with the pathophysiology of several health complications including aging and diabetes; hence, the above finding may explain part of the role of curcumin in health beneficial effects.
The tight coupling between cerebral blood flow and neural activity is a key feature of normal brain function and forms the basis of functional hyperemia. The mechanisms coupling neural activity to vascular responses, however, remain elusive despite decades of research. Recent studies have shown that cerebral functional hyperemia begins in capillaries, and red blood cells (RBCs) act as autonomous regulators of brain capillary perfusion. RBCs then respond to local changes of oxygen tension (PO2) and regulate their capillary velocity. Using ex vivo microfluidics and in vivo two-photon microscopy, we examined RBC capillary velocity as a function of PO2 and showed that deoxygenated hemoglobin and band 3 interactions on RBC membrane are the molecular switch that responds to local PO2 changes and controls RBC capillary velocity. Capillary hyperemia can be controlled by manipulating RBC properties independent of the neurovascular unit, providing an effective strategy to treat or prevent impaired functional hyperemia.
Basal-like breast cancer exhibits a triple-negative phenotype and has a poor prognosis, even with traditional chemical and anti-human epidermal growth factor receptor (HER) treatments. However, the high mutation rate of this obstinate cancer type renders it suitable for immunotherapy. Photothermal therapy (PTT) is a high-efficiency method for inducing tumor neoantigen release in situ, which has great potential for use in cancer immunotherapy. Here, we prepared a biomimetic black phosphorus quantum dot (BPQDs) formulation to induce breast cancer cell apoptosis in situ by near-infrared (NIR) laser irradiation to mobilize the immune system to eliminate the residual and metastatic cancer cells. Erythrocyte membranes (RMs) were used to coat the BPQDs, forming a BPQD-RM nanovesicle (BPQD-RMNV) biomimetic formulation that exhibited a long circulation time and tumor accumulation in vivo. The basal-like 4T1 breast tumor underwent apoptosis and necrosis with the irradiation and recruited dendritic cells (DCs) to capture the tumor antigens in vivo. Furthermore, programmed cell death protein 1 (PD-1) antibody (aPD-1) was employed to prevent the CD8+ T cells from exhaustion. Notably, BPQD-RMNV-mediated PTT combined with aPD-1 treatment significantly delayed residual and metastatic tumor growth in vivo. Hence, BPQD-RMNV-mediated PTT combined with immune checkpoint blockade antibody increased the infiltration and activity of CD8+ T cells in the tumor, which directly restrained basal-like breast tumor growth in vivo.
Erythrocytes are exceptionally suited for analysis of non-exocytotic release mechanisms of ATP, because these cells under physiological conditions lack vesicles. Previous studies have indicated, that Pannexin1 (Panx1) provides a key ATP permeation pathway in many cell types, including human and frog erythrocytes. Here we show that erythrocytes of Panx1(-/-) mice lend further support to this conclusion. However, ATP release, although attenuated, was still observed in Panx1(-/-) mouse erythrocytes. In contrast to Panx1(+/+) cells, this release was not correlated with uptake of extracellularly applied dyes, was insensitive to Panx1 channel blockers, and was inhibited by dipyridamole and stimulated by iloprost. Thus, in erythrocytes, two independent pathways mediate the release of ATP. We also show that glyburide is a strong inhibitor of Panx1 channels.
Acquired protection from Plasmodium falciparum malaria takes years to develop, probably reflecting the ability of the parasites to evade immunity. A recent example of this is the binding of the Fc region of IgM to VAR2CSA-type PfEMP1. This interferes with specific IgG recognition and phagocytosis of opsonized infected erythrocytes (IEs) without compromising the placental IE adhesion mediated by this PfEMP1 type. IgM also binds via Fc to several other PfEMP1 proteins, where it has been proposed to facilitate rosetting (binding of uninfected erythrocytes to a central IE). To further dissect the functional role of Fc -mediated IgM binding to PfEMP1, we studied the PfEMP1 protein HB3VAR06, which mediates rosetting and binds IgM. Binding of IgM to this PfEMP1 involved the Fc domains Cμ3-Cμ4 in IgM and the penultimate DBL domain (DBLζ2) at the C-terminus of HB3VAR06. However, IgM binding did not inhibit specific IgG labelling of HB3VAR06 or shield IgG-opsonized IEs from phagocytosis. Instead, IgM was required for rosetting, and each pentameric IgM molecule could bind two HB3VAR06 molecules. Together, our data indicate that the primary function of Fc -mediated IgM binding in rosetting is not to shield IE from specific IgG recognition and phagocytosis as in VAR2CSA-type PfEMP1. Rather, the function appears to be strengthening of IE-erythrocyte interactions. In conclusion, our study provides new evidence on the molecular details and functional significance of rosetting, a long-recognized marker of parasites that cause severe P. falciparum malaria.
The blood stage malaria parasite, the merozoite, has a small window of opportunity during which it must successfully target and invade a human erythrocyte. The process of invasion is nonetheless remarkably rapid. To date, mechanistic models of invasion have focused predominantly on the parasite actomyosin motor contribution to the energetics of entry. Here, we have conducted a numerical analysis using dimensions for an archetypal merozoite to predict the respective contributions of the host-parasite interactions to invasion, in particular the role of membrane wrapping. Our theoretical modeling demonstrates that erythrocyte membrane wrapping alone, as a function of merozoite adhesive and shape properties, is sufficient to entirely account for the first key step of the invasion process, that of merozoite reorientation to its apex and tight adhesive linkage between the two cells. Next, parasite-induced reorganization of the erythrocyte cytoskeleton and release of parasite-derived membrane can also account for a considerable energetic portion of actual invasion itself, through membrane wrapping. Thus, contrary to the prevailing dogma, wrapping by the erythrocyte combined with parasite-derived membrane release can markedly reduce the expected contributions of the merozoite actomyosin motor to invasion. We therefore propose that invasion is a balance between parasite and host cell contributions, evolved toward maximal efficient use of biophysical forces between the two cells.
The unique properties of erythrocytes are largely determined by its fibrillar network under the plasma membrane. Spectrin, one major component of the membrane skeleton, has been suggested to play a central role in this process. To understand the mechanism underlying this process, the effect of the sulfhydryl groups of erythrocyte membrane on spectrin structure and function was studied. By using non-denaturing gel analysis, dithiothreitol was found to protect spectrin in its tetramer state. In contrast, iodoacetamide and N-ethylmaleimide enhanced conversion of the spectrin tetramer to dimer and decreased its binding to the membrane. Moreover, when the membrane was treated with cadmium, the tetramer was converted to the dimer on the membrane, while zinc had no effect. Hemolysis experiments showed that cadmium could lyse erythrocytes in vitro. These results indicated that preservation of the spectrin tetramer or even higher oligomer states, by the sulfhydryl groups may be important to the membrane integrity and the intact cell functions.
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