ABSTRACT
Merozoites utilize sialic acids on the red blood cell (RBC) cell surface to rapidly adhere to and invade the RBCs. Newcastle disease virus (NDV) displays a strong affinity toward membrane-bound sialic acids. Incubation of NDV with the malaria parasites dose-dependently reduces its cellular viability. The antiplasmodial activity of NDV is specific, as incubation with Japanese encephalitis virus, duck enteritis virus, infectious bronchitis virus, and influenza virus did not affect the parasite propagation. Interestingly, NDV is reducing more than 80% invasion when RBCs are pretreated with the virus. Removal of the RBC surface proteins or the NDV coat proteins results in disruption of the virus binding to RBC. It suggests the involvement of specific protein: ligand interaction in virus binding. We established that the virus engages with the parasitized RBCs (PRBCs) through its hemagglutinin neuraminidase (HN) protein by recognizing sialic acid-containing glycoproteins on the cell surface. Blocking of the HN protein with free sialic acid or anti-HN antibodies abolished the virus binding as well as its ability to reduce parasite growth. Interestingly, the purified HN from the virus alone could inhibit the parasite's growth in a dose-dependent manner. NDV binds strongly to knobless murine parasite strain Plasmodium yoelii and restricted the parasite growth in mice. Furthermore, the virus was found to preferentially target the PRBCs compared to normal erythrocytes. Immunolocalization studies reveal that NDV is localized on the plasma membrane as well as weakly inside the PRBC. NDV causes neither any infection nor aggregation of the human RBCs. Our findings suggest that NDV is a potential candidate for developing targeted drug delivery platforms for the Plasmodium-infected RBCs.
Subject(s)
Erythrocytes , N-Acetylneuraminic Acid , Newcastle disease virus , Newcastle disease virus/physiology , Newcastle disease virus/metabolism , Erythrocytes/parasitology , Erythrocytes/metabolism , Animals , N-Acetylneuraminic Acid/metabolism , Humans , Plasmodium yoelii/metabolism , Mice , HN Protein/metabolism , Malaria/parasitology , Malaria/metabolismABSTRACT
Enucleated erythrocytes are characteristic of adult mammals. In contrast, fish, amphibians, reptiles, birds, and fetal mammals possess nucleated erythrocytes in their circulation. Erythroid maturation is regulated by erythropoietin (EPO) and its receptor (EPOR), which are conserved among vertebrates. In mammals, EPOR on the erythroid progenitor membrane disappears after terminal differentiation. However, in western clawed frog, Xenopus tropicalis, mature erythrocytes maintain EPOR expression, suggesting that they have non-canonical functions of the EPO-EPOR axis rather than proliferation and differentiation. In this study, we investigated the non-canonical functions of EPOR in Xenopus mature erythrocytes. EPO stimulation of peripheral erythrocytes did not induce proliferation but induced phosphorylation of intracellular proteins, including signal transducer and activator of transcription 5 (STAT5). RNA-Seq analysis of EPO-stimulated peripheral erythrocytes identified 45 differentially expressed genes (DEGs), including cytokine inducible SH2 containing protein gene (cish) and suppressor of cytokine signaling 3 gene (socs3), negative regulators of the EPOR-Janus kinase (JAK)-STAT pathway. These phosphorylation studies and pathway analysis demonstrated the activation of the JAK-STAT pathway through EPO-EPOR signaling in erythrocytes. Through comparison with EPO-responsive genes in mouse erythroid progenitors obtained from a public database, we identified 31 novel EPO-responsive genes indicating non-canonical functions. Among these, we focused on ornithine decarboxylase 1 gene (odc1), which is the rate-limiting enzyme in polyamine synthesis and affects hematopoietic progenitor differentiation and the endothelial cell response to hypoxic stress. An EPO-supplemented culture of erythrocytes showed increased odc1 expression followed by a decrease in polyamine-rich erythrocytes, suggesting EPO-responsive polyamine excretion. These findings will advance our knowledge of the unknown regulatory systems under the EPO-EPOR axis and functional differences between vertebrates' nucleated and enucleated erythrocytes.
Subject(s)
Erythrocytes , Erythropoietin , Receptors, Erythropoietin , Xenopus , Animals , Erythropoietin/metabolism , Erythropoietin/genetics , Receptors, Erythropoietin/metabolism , Receptors, Erythropoietin/genetics , Erythrocytes/metabolism , Signal Transduction , Gene Expression Regulation , Erythroblasts/metabolismABSTRACT
Garlic (Allium sativum) is recognized as functional food, rich in bioactive compounds that can combat diseases associated with oxidative stress. This study aims to investigate the protective potential of aqueous garlic extract against hemolysis and oxidation. Despite being caused by membrane fragility, hemolysis can lead to inflammation through the oxidation of its products, and in some cases, even exacerbate it in certain pathological contexts. Supplementation with antioxidant molecules can improves oxidative status, in this study, we selected garlic, an excellent functional food, and targeted its effects using aqueous extract and pure molecules. The aqueous garlic extract was prepared under safe conditions and subjected to toxicity on human neutrophils and red blood cells before experimentation. The results indicate that aqueous garlic extract significantly reduces hemolysis with a maximum protection of 98. 74 ± 1. 08 % at a concentration of 5µg/ml. Additionally, experiments were conducted with pure compounds found in garlic such as quercetin, gallic acid, and caffeic acid. The outcomes show that quercetin reduces hemolysis of RBC with a maximum protection of 88. 8 ± 2. 89 % at 20 µM followed by caffeic acid and gallic acid. The action mechanism of the extract was tested on human neutrophil cells, the extract significantly reduced luminol-amplified chemiluminescence of PMA-stimulated neutrophils up to 50 % at 10 µg/ml in addition to its ability to directly scavenge hydrogen peroxide. Our results suggest that aqueous garlic extract exerts promising anti-inflammatory activity in vitro. Through its dual protection against hemolysis and Ros production, garlic may indirectly prevent inflammation reducing the oxidation of hemolysis products. These abilities make garlic aqueous extract promising candidate for improving cardiovascular health, reducing oxidative stress and modulating immunity.
Subject(s)
Antioxidants , Erythrocytes , Garlic , Hemolysis , Inflammation , Neutrophils , Oxidation-Reduction , Plant Extracts , Garlic/chemistry , Humans , Plant Extracts/pharmacology , Plant Extracts/chemistry , Hemolysis/drug effects , Neutrophils/drug effects , Neutrophils/metabolism , Inflammation/prevention & control , Inflammation/drug therapy , Oxidation-Reduction/drug effects , Antioxidants/pharmacology , Antioxidants/chemistry , Erythrocytes/drug effects , Erythrocytes/metabolism , Oxidative Stress/drug effects , Water/chemistryABSTRACT
The retromer is a cellular structure that recruits and recycles proteins inside the cell. In mammalian and yeast, the retromer components have been widely studied, but very little in parasites. In yeast, it is formed by a SNX-BAR membrane remodeling heterodimer and the cargo selecting complex (CSC), composed by three proteins. One of them, the Vps26 protein, possesses a flexible and intrinsically disordered region (IDR), that facilitates interactions with other proteins and contributes to the retromer binding to the endosomal membrane. In Entamoeba histolytica, the protozoan parasite responsible for human amoebiasis, the retromer actively participates during the high mobility and phagocytosis of trophozoites, but the molecular details in these events, are almost unknown. Here, we studied the EhVps26 role in phagocytosis. Bioinformatic analyses of EhVps26 revealed a typical arrestin folding structure of the protein, and a long and charged IDR, as described in other systems. EhVps26 molecular dynamics simulations (MDS) allowed us to predict binding pockets for EhVps35, EhSNX3, and a PX domain-containing protein; these pockets were disorganized in a EhVps26 truncated version lacking the IDR. The AlphaFold2 software predicted the interaction of EhVps26 with EhVps35, EhVps29 and EhSNX3, in a model similar to the reported mammalian crystals. By confocal and transmission electron microscopy, EhVps26 was found in the trophozoites plasma membrane, cytosol, endosomes, and Golgi-like apparatus. During phagocytosis, it followed the erythrocytes pathway, probably participating in cargoes selection and recycling. Ehvps26 gene knocking down evidenced that the EhVps26 protein is necessary for efficient phagocytosis.
Subject(s)
Computational Biology , Entamoeba histolytica , Phagocytosis , Protozoan Proteins , Entamoeba histolytica/metabolism , Protozoan Proteins/metabolism , Protozoan Proteins/genetics , Protozoan Proteins/chemistry , Computational Biology/methods , Humans , Molecular Dynamics Simulation , Vesicular Transport Proteins/metabolism , Vesicular Transport Proteins/genetics , Vesicular Transport Proteins/chemistry , Protein Binding , Amino Acid Sequence , Erythrocytes/parasitology , Erythrocytes/metabolismABSTRACT
Background: Erythrocyte dysfunction is a characteristic of diabetes mellitus (DM). However, erythrocyte-associated biomarkers do not adequately explain the high prevalence of DM. Here, we describe red blood cell distribution width to albumin ratio (RAR) as a novel inflammatory biomarker for evaluating an association with DM prevalence and prognosis of all-cause mortality. Methods: Data analyzed in this study were extracted from the National Health and Nutrition Examination Survey (NHANES) 1999-2020. A total of 40,558 participants (non-DM and DM) were enrolled in the study; RAR quartiles were calibrated at Q1 [2.02,2.82] mL/g, Q2 (2.82,3.05] mL/g, Q3 (3.05,3.38] mL/g, and Q4 (3.38,12.08] mL/g. A total of 8,482 DM patients were followed (for a median of 84 months), of whom 2,411 died and 6,071 survived. The prevalence and prognosis associated with RAR and DM were analyzed; age and sex were stratified to analyze the prevalence of RAR in DM and the sensitivity of long-term prognosis. Results: Among non-DM (n=30,404) and DM (n=10,154) volunteers, DM prevalence in RAR quartiles was 8.23%, 15.20%, 23.92%, and 36.39%. The multivariable odds ratio (OR) was significant for RAR regarding DM, at 1.68 (95% CI 1.42, 1.98). Considering Q1 as a foundation, the Q4 OR was 2.57 (95% CI 2.11, 3.13). The percentages of DM morbidity varied across RAR quartiles for dead (n=2,411) and surviving (n=6,071) DM patients. Specifically, RAR quartile mortality ratios were 20.31%, 24.24%, 22.65%, and 29.99% (P<0.0001). The multivariable hazard ratio (HR) for RAR was 1.80 (95% CI 1.57, 2.05). Considering Q1 as a foundation, the Q4 HR was 2.59 (95% CI 2.18, 3.09) after adjusting for confounding factors. Sensitivity analysis revealed the HR of male DM patients to be 2.27 (95% CI 1.95, 2.64), higher than females 1.56 (95% CI 1.31, 1.85). DM patients who were 60 years of age or younger had a higher HR of 2.08 (95% CI1.61, 2.70) as compared to those older than 60 years, who had an HR of 1.69 (95% CI 1.47, 1.94). The HR of RAR in DM patients was optimized by a restricted cubic spline (RCS) model; 3.22 was determined to be the inflection point of an inverse L-curve. DM patients with a RAR >3.22 mL/g suffered shorter survival and higher mortality as compared to those with RAR ≤3.22 mL/g. OR and HR RAR values were much higher than those of regular red blood cell distribution width. Conclusions: The predictive value of RAR is more accurate than that of RDW for projecting DM prevalence, while RAR, a DM risk factor, has long-term prognostic power for the condition. Survival time was found to be reduced as RAR increased for those aged ≤60 years among female DM patients.
Subject(s)
Diabetes Mellitus , Erythrocyte Indices , Nutrition Surveys , Humans , Male , Female , Prognosis , Middle Aged , Prevalence , Diabetes Mellitus/epidemiology , Diabetes Mellitus/blood , Adult , Aged , Biomarkers/blood , Erythrocytes/metabolism , Serum Albumin/analysis , Serum Albumin/metabolismABSTRACT
BACKGROUND: Megaloblastic anemia is a subtype of anemia with increased red blood cell volume. These megaloblastic cells can be easily destroyed in the bone marrow and spleen, leading to ineffective hematopoiesis. Insulin-degrading enzymes (IDE) in erythrocytes can break down the insulin into amino acid fragments; thus, when hemolysis occurs, IDE can be released into the blood, resulting in low insulin measurement values. METHODS: This article reports a case of false insulin test results due to the hemolysis resulting from megaloblastic anemia. RESULTS: The patient's first fasting glucose results indicated that the glucose and C-peptide levels were within the normal range while her insulin level was abnormally low. After hemolysis was corrected, the relevant indicators were re-evaluated and all the results were normal. CONCLUSIONS: This article reports a patient diagnosed with megaloblastic anemia, whose dysmorphic erythrocytes cause severe extravascular hemolysis. It was the occurrence of hemolysis that the IDE released into the blood, leading to the abnormal insulin test result.
Subject(s)
Anemia, Megaloblastic , Hemolysis , Insulin , Humans , Anemia, Megaloblastic/diagnosis , Anemia, Megaloblastic/blood , Female , Insulin/blood , Blood Glucose/metabolism , Blood Glucose/analysis , Erythrocytes/metabolism , False Positive ReactionsABSTRACT
Introduction: The acute respiratory distress syndrome (ARDS) is a common complication of severe COVID-19 and contributes to patient morbidity and mortality. ARDS is a heterogeneous syndrome caused by various insults, and results in acute hypoxemic respiratory failure. Patients with ARDS from COVID-19 may represent a subgroup of ARDS patients with distinct molecular profiles that drive disease outcomes. Here, we hypothesized that longitudinal transcriptomic analysis may identify distinct dynamic pathobiological pathways during COVID-19 ARDS. Methods: We identified a patient cohort from an existing ICU biorepository and established three groups for comparison: 1) patients with COVID-19 ARDS that survived hospitalization (COVID survivors, n = 4), 2) patients with COVID-19 ARDS that did not survive hospitalization (COVID non-survivors, n = 5), and 3) patients with ARDS from other causes as a control group (ARDS controls, n = 4). RNA was isolated from peripheral blood mononuclear cells (PBMCs) at 4 time points (Days 1, 3, 7, and 10 following ICU admission) and analyzed by bulk RNA sequencing. Results: We first compared transcriptomes between groups at individual timepoints and observed significant heterogeneity in differentially expressed genes (DEGs). Next, we utilized the likelihood ratio test to identify genes that exhibit different patterns of change over time between the 3 groups and identified 341 DEGs across time, including hemoglobin subunit alpha 2 (HBA1, HBA2), hemoglobin subunit beta (HBB), von Willebrand factor C and EGF domains (VWCE), and carbonic anhydrase 1 (CA1), which all demonstrated persistent upregulation in the COVID non-survivors compared to COVID survivors. Of the 341 DEGs, 314 demonstrated a similar pattern of persistent increased gene expression in COVID non-survivors compared to survivors, associated with canonical pathways of iron homeostasis signaling, erythrocyte interaction with oxygen and carbon dioxide, erythropoietin signaling, heme biosynthesis, metabolism of porphyrins, and iron uptake and transport. Discussion: These findings describe significant differences in gene regulation during patient ICU course between survivors and non-survivors of COVID-19 ARDS. We identified multiple pathways that suggest heme and red blood cell metabolism contribute to disease outcomes. This approach is generalizable to larger cohorts and supports an approach of longitudinal sampling in ARDS molecular profiling studies, which may identify novel targetable pathways of injury and resolution.
Subject(s)
COVID-19 , Erythrocytes , Gene Expression Profiling , Homeostasis , Iron , Respiratory Distress Syndrome , SARS-CoV-2 , Transcriptome , Humans , COVID-19/genetics , COVID-19/blood , Male , Respiratory Distress Syndrome/genetics , Respiratory Distress Syndrome/blood , Middle Aged , SARS-CoV-2/physiology , Female , Iron/metabolism , Erythrocytes/metabolism , Aged , Longitudinal StudiesABSTRACT
Density reversal of senescent red blood cells has been known for a long time, yet the identity of the candidate ion transporter(s) causing the senescent cells to swell is still elusive. While performing fractionation of RBCs from healthy individuals in Percoll density gradient and characterization of the separated fractions, we identified a subpopulation of cells in low-density fraction (1.02% ± 0.47) showing signs of senescence such as loss of membrane surface area associated with a reduction in band 3 protein abundance, and Phosphatidylserine (PS) exposure to the outer membrane. In addition, we found that these cells are overloaded with Na+ and Ca2+. Using a combination of blockers and activators of ion pumps and channels, we revealed reduced activity of Plasma membrane Ca2+ ATPase and an increase in Ca2+ and Na+ leaks through ion channels in senescent-like cells. Our data revealed that Ca2+ overload in these cells is a result of reduced PMCA activity and facilitated Ca2+ uptake via a hyperactive Piezo1 channel. However, we could not exclude the contribution of other Ca2+-permeable ion channels in this scenario. In addition, we found, as a universal mechanism, that an increase in intracellular Ca2+ reduced the initially high selectivity of Piezo1 channel for Ca2+ and allowed higher Na+ uptake, Na+ accumulation, and swelling.
Subject(s)
Calcium , Erythrocytes , Ion Channels , Humans , Erythrocytes/metabolism , Ion Channels/metabolism , Calcium/metabolism , Cellular Senescence , Sodium/metabolism , Plasma Membrane Calcium-Transporting ATPases/metabolismABSTRACT
Measurement of cellular resting membrane potential (RMP) is important in understanding ion channels and their role in regulation of cell function across a wide range of cell types. However, methods available for the measurement of RMP (including patch clamp, microelectrodes, and potential-sensitive fluorophores) are expensive, slow, open to operator bias, and often result in cell destruction. We present non-contact, label-free membrane potential estimation which uses dielectrophoresis to determine the cytoplasm conductivity slope as a function of medium conductivity. By comparing this to patch clamp data available in the literature, we have demonstratet the accuracy of this approach using seven different cell types, including primary suspension cells (red blood cells, platelets), cultured suspension cells (THP-1), primary adherent cells (chondrocytes, human umbilical mesenchymal stem cells), and adherent (HeLa) and suspension (Jurkat) cancer cell lines. Analysis of the effect of ion channel inhibitors suggests the effects of pharmaceutical agents (TEA on HeLa; DMSO and neuraminidase on red blood cells) can also be measured. Comparison with published values of membrane potential suggest that the differences between our estimates and values recorded by patch clamp are accurate to within published margins of error. The method is low-cost, non-destructive, operator-independent and label-free, and has previously been shown to allow cells to be recovered after measurement.
Subject(s)
Electrophoresis , Membrane Potentials , Humans , Membrane Potentials/physiology , Electrophoresis/methods , HeLa Cells , Jurkat Cells , Patch-Clamp Techniques/methods , Erythrocytes/cytology , Erythrocytes/metabolismABSTRACT
The development of thrombolytic drug carriers capable of thrombus-targeting, prolonged circulation time, intelligent responsive release, and the ability to inhibit thrombotic recurrences remains a promising but significant challenge. To tackle this, an artificial polysaccharide microvesicle drug delivery system (uPA-CS/HS@RGD-ODE) was constructed. It is composed of cationic chitosan and anionic heparin assembled in a layer by layer structure, followed by surface modification using RGD peptide and 2-(N-oxide-N,N-diethylamino) ethylmethacrylate (ODE) before encapsulation of urokinase-type plasminogen activator (uPA). The effect of chitosan on the basic performances of uPA-CS/HS@RGD-ODE was estimated. The in vitro results suggest the uPA carrier, CS/HS@RGD-ODE, displayed outstanding targeting specific to activated platelets (61 %) and microenvironment-responsiveness at pH 6.5, facilitating thrombus-targeting and a controlled drug release, respectively. Most importantly, in vivo experiment suggests ODE from uPA-CS/HS@RGD-ODE substantially extends the half-life of uPA (120 min), as uPA-CS/HS@RGD-ODE can adhere onto erythrocytes and deliver uPA under cover of erythrocytes enabling a prolonged circulation time in the bloodstream. Further tail vein and abdominal aorta thrombosis models confirmed uPA-CS/HS@RGD-ODE exhibited superior targeting and thrombolysis capabilities compared to systemic administration of free uPA. To the knowledge of authors, this may be the first study to develop new drug carriers for delivery of thrombolytic drugs under the cover of erythrocytes for extended drug half-lives.
Subject(s)
Chitosan , Drug Carriers , Erythrocytes , Fibrinolytic Agents , Thrombosis , Urokinase-Type Plasminogen Activator , Urokinase-Type Plasminogen Activator/metabolism , Animals , Chitosan/chemistry , Chitosan/pharmacology , Erythrocytes/drug effects , Erythrocytes/metabolism , Drug Carriers/chemistry , Fibrinolytic Agents/chemistry , Fibrinolytic Agents/pharmacology , Thrombosis/drug therapy , Drug Liberation , Thrombolytic Therapy/methods , Heparin/chemistry , Heparin/pharmacology , Oligopeptides/chemistry , Oligopeptides/pharmacology , Humans , Half-Life , Mice , Drug Delivery Systems/methods , Male , Polysaccharides/chemistry , Polysaccharides/pharmacologyABSTRACT
Malaria remains a major global threat, representing a severe public health problem worldwide. Annually, it is responsible for a high rate of morbidity and mortality in many tropical developing countries where the disease is endemic. The causative agent of malaria, Plasmodium spp., exhibits a complex life cycle, alternating between an invertebrate vector, which transmits the disease, and the vertebrate host. The disease pathology observed in the vertebrate host is attributed to the asexual development of Plasmodium spp. inside the erythrocyte. Once inside the red blood cell, malaria parasites cause extensive changes in the host cell, increasing membrane rigidity and altering its normal discoid shape. Additionally, during their intraerythrocytic development, malaria parasites incorporate and degrade up to 70 % of host cell hemoglobin. This mechanism is essential for parasite development and represents an important drug target. Blocking the steps related to hemoglobin endocytosis or degradation impairs parasite development and can lead to its death. The ultrastructural analysis of hemoglobin endocytosis on Plasmodium spp. has been broadly explored along the years. However, it is only recently that the proteins involved in this process have started to emerge. Here, we will review the most important features related to hemoglobin endocytosis and catabolism on malaria parasites. A special focus will be given to the recent analysis obtained through 3D visualization approaches and to the molecules involved in these mechanisms.
Subject(s)
Endocytosis , Malaria , Plasmodium , Animals , Humans , Malaria/parasitology , Malaria/metabolism , Plasmodium/metabolism , Plasmodium/physiology , Erythrocytes/parasitology , Erythrocytes/metabolism , Cell Membrane/metabolism , Hemoglobins/metabolismABSTRACT
During infection, the host employs nutritional immunity to restrict access to iron. Staphylococcus lugdunensis has been recognized for its ability to utilize host-derived heme to overcome iron restriction. However, the mechanism behind this process involves the release of hemoglobin from erythrocytes, and the hemolytic factors of S. lugdunensis remain poorly understood. S. lugdunensis encodes four phenol-soluble modulins (PSMs), short peptides with hemolytic activity. The peptides SLUSH A, SLUSH B, and SLUSH C are ß-type PSMs, and OrfX is an α-type PSM. Our study shows the SLUSH locus to be essential for the hemolytic phenotype of S. lugdunensis. All four peptides individually exhibited hemolytic activity against human and sheep erythrocytes, but synergism with sphingomyelinase was observed exclusively against sheep erythrocytes. Furthermore, our findings demonstrate that SLUSH is crucial for allowing the utilization of erythrocytes as the sole source of nutritional iron and confirm the transcriptional regulation of SLUSH by Agr. Additionally, our study reveals that SLUSH peptides stimulate the human immune system. Our analysis identifies SLUSH as a pivotal hemolytic factor of S. lugdunensis and demonstrates its concerted action with heme acquisition systems to overcome iron limitation in the presence of host erythrocytes.
Subject(s)
Erythrocytes , Hemolysis , Iron , Staphylococcus lugdunensis , Erythrocytes/metabolism , Staphylococcus lugdunensis/metabolism , Humans , Iron/metabolism , Animals , Sheep , Bacterial Proteins/metabolism , Bacterial Proteins/genetics , Peptides/metabolism , Peptides/chemistry , Staphylococcal Infections/microbiology , Staphylococcal Infections/metabolism , Bacterial ToxinsABSTRACT
BACKGROUND: Alectinib is a second-generation anaplastic lymphoma kinase (ALK) inhibitor indicated for ALK-mutated non-small-cell lung cancer. Recently, the association between alectinib and red cell morphological abnormalities has been reported in a few case series. This retrospective observational study aims to determine the frequency of occurrence of acanthocytosis in patients taking alectinib and to evaluate the red cell indices, biochemical markers of haemolysis and eosin-5-maleimide (EMA) binding assay results in patients receiving alectinib. METHODS: Patients who were on alectinib and had a complete blood count test performed in Queen Elizabeth Hospital Haematology Laboratory between 1 May 2021 and 31 August 2021 were included in the study. Haematological investigations that had been performed before and after the commencement of alectinib were reviewed. RESULTS: Fifty patients receiving alectinib were evaluated in this analysis. One hundred per cent of patients showed 3+ acanthocytes on the peripheral blood smears. Compared with the test results before starting alectinib, the post-alectinib blood tests showed a significantly lower haemoglobin concentration, red blood cell count and haematocrit; and a significantly higher mean corpuscular haemoglobin, mean corpuscular haemoglobin concentration and red cell distribution width. All the tested patients showed a marked reduction in EMA mean channel fluorescence compared with normal control. CONCLUSION: Our cohort revealed that alectinib caused significant acanthocytosis in all patients. Alectinib was also associated with changes in red cell indices and biochemical markers of haemolysis, compatible with a spherocytic and anisopoikilocytic morphology with haemolysis. Patients on alectinib had reduced EMA binding.
Subject(s)
Carbazoles , Erythrocytes , Piperidines , Humans , Piperidines/therapeutic use , Piperidines/pharmacology , Carbazoles/pharmacology , Male , Female , Middle Aged , Retrospective Studies , Aged , Erythrocytes/drug effects , Erythrocytes/metabolism , Erythrocyte Indices/drug effects , Adult , Protein Kinase Inhibitors/pharmacology , Protein Kinase Inhibitors/therapeutic use , Carcinoma, Non-Small-Cell Lung/drug therapy , Carcinoma, Non-Small-Cell Lung/blood , Carcinoma, Non-Small-Cell Lung/pathology , Lung Neoplasms/drug therapy , Lung Neoplasms/blood , Lung Neoplasms/pathology , Aged, 80 and over , Hematologic TestsABSTRACT
Porphyromonas gingivalis has been demonstrated to have the strongest association with periodontitis. Within the host, P. gingivalis relies on acquiring iron and heme through the aggregation and lysis of erythrocytes, which are important factors in the growth and virulence of P. gingivalis. Additionally, the excess obtained heme is deposited on the surface of P. gingivalis, protecting the cells from oxidative damage. Based on these biological properties of the interaction between P. gingivalis and erythrocytes, this study developed an erythrocyte membrane nanovesicle loaded with gallium porphyrins to mimic erythrocytes. The nanovesicle can target and adhere with P. gingivalis precisely, being lysed and utilized by P. gingivalis as erythrocytes. Ingested gallium porphyrin replaces iron porphyrin in P. gingivalis, causing intracellular metabolic disruption. Deposited porphyrin generates a large amount of reactive oxygen species (ROS) under blue light, causing oxidative damage, and its lethality is enhanced by bacterial metabolic disruption, synergistically killing P. gingivalis. Our results demonstrate that this strategy can target and inhibit P. gingivalis, reduce its invasion of epithelial cells, and alleviate the progression of periodontitis.
Subject(s)
Erythrocytes , Periodontitis , Porphyrins , Porphyromonas gingivalis , Porphyromonas gingivalis/drug effects , Porphyromonas gingivalis/metabolism , Porphyromonas gingivalis/chemistry , Periodontitis/microbiology , Periodontitis/drug therapy , Periodontitis/pathology , Erythrocytes/drug effects , Erythrocytes/metabolism , Humans , Porphyrins/chemistry , Porphyrins/pharmacology , Animals , Reactive Oxygen Species/metabolism , Gallium/chemistry , Gallium/pharmacology , Mice , Anti-Bacterial Agents/pharmacology , Anti-Bacterial Agents/chemistry , Biomimetic Materials/chemistry , Biomimetic Materials/pharmacologyABSTRACT
The growing world population and increasing life expectancy are driving the need to improve the quality of blood transfusion, organ transplantation, and preservation. Here, to improve the ability of red blood cells (RBCs) for normothermic machine perfusion, a biocompatible blood silicification approach termed "shielding-augmenting RBC-in-nanoscale amorphous silica (SARNAS)" has been developed. The key to RBC surface engineering and structure augmentation is the precise control of the hydrolysis form of silicic acid to realize stabilization of RBC within conformal nanoscale silica-based exoskeletons. The formed silicified RBCs (Si-RBCs) maintain membrane/structural integrity, normal cellular functions (e.g., metabolism, oxygen-carrying capability), and enhance resistance to external stressors as well as tunable mechanical properties, resulting in nearly 100% RBC cryoprotection. In vivo experiments confirm their excellent biocompatibility. By shielding RBC surface antigens, the Si-RBCs provide universal blood compatibility, the ability for allogeneic mechanical perfusion, and more importantly, the possibility for cross-species transfusion. Being simple, reliable, and easily scalable, the SARNAS strategy holds great promise to revolutionize the use of engineered blood for future clinical applications.
Subject(s)
Biocompatible Materials , Erythrocytes , Silicon Dioxide , Erythrocytes/metabolism , Silicon Dioxide/chemistry , Biocompatible Materials/chemistry , Animals , Humans , Perfusion/methods , Blood Preservation/methods , Blood Transfusion/methods , MiceABSTRACT
The translation of silver-based nanotechnology 'from bench to bedside' requires a deep understanding of the molecular aspects of its biological action, which remains controversial at low concentrations and non-spherical morphologies. Here, we present a hemocompatibility approach based on the effect of the distinctive electronic charge distribution in silver nanoparticles (nanosilver) on blood components. According to spectroscopic, volumetric, microscopic, dynamic light scattering measurements, pro-coagulant activity tests, and cellular inspection, we determine that at extremely low nanosilver concentrations (0.125-2.5µg ml-1), there is a relevant interaction effect on the serum albumin and red blood cells (RBCs). This explanation has its origin in the surface charge distribution of nanosilver particles and their electron-mediated energy transfer mechanism. Prism-shaped nanoparticles, with anisotropic charge distributions, act at the surface level, generating a compaction of the native protein molecule. In contrast, the spherical nanosilver particle, by exhibiting isotropic surface charge, generates a polar environment comparable to the solvent. Both morphologies induce aggregation at NPs/bovine serum albumin ≈ 0.044 molar ratio values without altering the coagulation cascade tests; however, the spherical-shaped nanosilver exerts a negative impact on RBCs. Overall, our results suggest that the electron distributions of nanosilver particles, even at extremely low concentrations, are a critical factor influencing the molecular structure of blood proteins' and RBCs' membranes. Isotropic forms of nanosilver should be considered with caution, as they are not always the least harmful.
Subject(s)
Erythrocytes , Metal Nanoparticles , Serum Albumin, Bovine , Silver , Silver/chemistry , Metal Nanoparticles/chemistry , Erythrocytes/metabolism , Erythrocytes/chemistry , Humans , Serum Albumin, Bovine/chemistry , Serum Albumin, Bovine/metabolism , Surface Properties , Animals , Cattle , Blood Coagulation/drug effects , Blood Proteins/metabolism , Blood Proteins/chemistry , Materials TestingABSTRACT
OBJECTIVE: To clarify the effect of iodoacetic acid(IAA) on the blood system and electrolyte balance, hence further study the intrinsic relation of blood routine parameters and electrolyte levels, major hematological toxicity effects and their pattern after IAA treatment. METHODS: Forty-eight 21-day-old male SPF grade Sprague-Dawley(SD) rats were gavaged with 0, 6.25, 12.5 and 25 mg/kg IAA for 31 days. After detections of blood routine and plasma inorganic ion levels, Spearman correlation coefficients were performed to evaluate their relationship. Changes in ferritin, transferrin, hepcidin, C-reactive protein and glyceraldehyde-3-phosphate dehydrogenase(GAPDH) were assessed by enzyme-linked immunosorbent assays. The EDock bioinformatics tool was applied to docking model of IAA and GAPDH. RESULTS: Compared to the control, high-dose IAA exposure had obvious inhibition effect on rat leukocytes with the total number declined by 51.12%, and neutrophils were particularly sensitive to IAA with the number reduced by 73.66%(P<0.01), and rat erythrocytes exhibited a small cell low pigment effect with hemoglobin and hematocrit decreased by 8.60% and 8.70%, respectively(P<0.05). But IAA had little effects on the platelet. Plasma iron, phosphorus, zinc and potassium levels were repressed significantly, while chlorine, sodium and magnesium levels were elevated obviously through IAA exposure. However, plasma calcium levels were hardly affected by IAA. In comparison with the control, iron levels declined by 67.09%, whereas magnesium levels increased by 131.82% in the high-dose group(P<0.01). Overall, correlation analyses uncovered that plasma iron metabolism was most strongly and positively correlated with levels of leukocyte, erythrocyte and platelet system parameters after IAA exposure, and the correlation coefficients of leukocyte number, mean hemoglobin content and mean erythrocyte volume were 0.637, 0.410 and 0.365, respectively(P<0.05). Compared to the control, in the high-dose IAA group, the plasma content of C-reactive protein was significantly upregulated by 13.30%(P<0.05), and plasma levels of transferrin and ferromodulin were also respectively elevated by 12.73% and 11.02%(P<0.05). But plasma levels of ferritin and GAPDH did not differ between groups. The docking model exhibited that IAA could bind to the 150 Cys active site of rat GAPDH did. CONCLUSION: IAA not only had toxic effects on rat leukocytes and the plasma electrolyte balance, but also generated inflammation and iron deficiency, leading to smaller erythrocytes and lower pigment.
Subject(s)
Iodoacetic Acid , Rats, Sprague-Dawley , Animals , Rats , Male , Iodoacetic Acid/toxicity , Disinfectants/toxicity , Erythrocytes/drug effects , Erythrocytes/metabolism , C-Reactive Protein/metabolism , Leukocytes/drug effects , Ferritins/blood , Disinfection/methods , Transferrin , Hepcidins/bloodABSTRACT
OBJECTIVES: Experimental and acute exposure studies imply that manganese affects red blood cell production. Nevertheless, the association between environmental exposure and red blood cell distribution width (RDW) has yet to be explored. This research sought to assess the correlation between blood manganese levels and RDW within the general population of the United States. MATERIALS AND METHODS: Employing weighted multiple linear regression models, data from the 2011-2018 National Health and Nutrition Examination Survey (NHANES) were utilized to assess the correlation between manganese levels in the blood and RDW. Restricted cubic spline plots and two-piecewise linear regression models were also employed. RESULT: The analysis included a total of 15882 participants in which we determined an independent positive relationship between blood manganese levels and RDW among participants(ß = 0.079, P<0.001). Moreover, we identified a J-shaped association between blood manganese levels and RDW in total participants (inflection point for blood manganese: 7.32 ug/L) and distinct subgroups following adjusted covariates. Women exhibited a more pronounced association, even after controlling for adjusted covariates. CONCLUSIONS: We determined a J-shaped relationship between blood manganese levels and RDW with an inflection point at 7.32 ug/L for blood manganese. Nevertheless, fundamental research and large sample prospective studies are needed to determine the extent to which blood manganese levels correlate with RDW.