Hemolysis Of Red Blood Cells Research Articles

Zilucoplan, a macrocyclic peptide inhibitor of human complement component 5, uses a dual mode of action to prevent terminal complement pathway activation.

The complement system is a key component of the innate immune system, and its aberrant activation underlies the pathophysiology of various diseases. Zilucoplan is a macrocyclic peptide that binds and inhibits the cleavage/activation of human complement component 5 (C5). We present in vitro and ex vivo data on the mechanism of action of zilucoplan for the inhibition of C5 activation, including two clinically relevant C5 polymorphisms at R885. The interaction of zilucoplan with C5, including for clinical C5 R885 variants, was investigated using surface plasmon resonance (SPR), hemolysis assays, and ELISA. The interference of C5b6 formation by zilucoplan was investigated by native gel analysis and hemolysis assay. The permeability of zilucoplan in a reconstituted basement membrane was assessed by the partition of zilucoplan on Matrigel-coated transwell chambers. Zilucoplan specifically bound human complement C5 with high affinity, competitively inhibited the binding of C5 to C3b, and blocked C5 cleavage by C5 convertases and the assembly of the cytolytic membrane attack complex (MAC, or C5b9). Zilucoplan fully prevented the in vitro activation of C5 clinical variants at R885 that have been previously reported to respond poorly to eculizumab treatment. Zilucoplan was further demonstrated to interfere with the formation of C5b6 and inhibit red blood cell (RBC) hemolysis induced by plasmin-mediated non-canonical C5 activation. Zilucoplan demonstrated greater permeability than a monoclonal C5 antibody in a reconstituted basement membrane model, providing a rationale for the rapid onset of action of zilucoplan observed in clinical studies. Our findings demonstrate that zilucoplan uses a dual mode of action to potently inhibit the activation of C5 and terminal complement pathway including wild-type and clinical R885 variants that do not respond to eculizumab treatment. These data may be relevant to the clinically demonstrated benefits of zilucoplan.

Evaluation of Antioxidant, Cytotoxic, Thrombolytic and Membrane Stabilizing Activities of Canna indica L. Leaves (Family: Cannaceae)

Canna indica L., a perennial plant known as Indian shot and African arrowroot, is a member of the family Cannaceae. Historically, this plant was used to treat menstrual cramps, diarrhea and dysentery. The purpose of this investigation was to assess the antioxidant, cytotoxic, thrombolytic and membrane stabilizing activities of the methanol extract of C. indica leaf and its organic soluble fractions. The DPPH free radical scavenging method and the total phenolic content determination were utilized to evaluate the antioxidant capacity, whereas the brine shrimp lethality bioassay was implemented to study the cytotoxic potential. The ability of the extractives to prevent the hemolysis of red blood cells (RBC) in response to the application of heat and hypotonic solutions was used to estimate of their membrane stabilizing potential. In all of these experiments, the methanolic leaf extract (ME) displayed moderate activity, while the petroleum ether soluble fraction (PSF) and the dichloromethane soluble fraction (DSF) demonstrated the most promising antioxidant and cytotoxic activities among the extractives. However, the strongest thrombolytic and membrane stabilizing activities were observed by the chloroform soluble fraction (CSF). Additional research may be necessary to determine which phytoconstituents are most likely to be responsible for the aforementioned qualities. Bangladesh Pharmaceutical Journal 26(2): 162-166, 2023 (July)

In vitro Antiplasmodial, Antioxidant, and Cytotoxicity Activity of Terminalia macroptera Traditionally Used in Cameroon Against Malaria

BackgroundThe alarming expansion of drug resistance, as well as the scarcity of effective antimalarial medications currently accessible, highlights the importance of finding novel antimalarial chemicals. This study was undertaken to evaluate the antiplasmodial efficacy, antioxidant, and cytotoxicity of Terminalia macroptera stem bark in order to justify it as an antimalarial agent for the local population. MethodologyAqueous and ethanol extracts of the stem bark were prepared using standard procedures. The antimalarial activity of the plant extract was investigated in culture using the fluorescence-based SYBR Green assay against chloroquine-sensitive (3D7) and chloroquine-resistant (Dd2) Plasmodium falciparum strains. The antioxidant activity was determined by measuring ferric reducing antioxidant power, 1,1-diphenyl-2-picrylhydrazyl, free radical scavenging, and nitric oxide radical scavenging. Cytotoxicity of the extracts was conducted against RAW 264.7 cell line and red blood cells. ResultsThe aqueous and ethanolic extracts of T macroptera were active with inhibitory concentration 50 (IC50) for 3D7 strains of 3.46 ± 0.48 and 4.10 ± 0.39μg/ml for the aqueous and ethanolic extracts, respectively. The same activity was obtained with the Dd2 strain with IC50 of 6.15 ± 1.46 and 7.47 ± 0.03μg/ml for the aqueous and ethanolic extracts, respectively. The aqueous extracts showed good free radical scavenging property. The IC50 of the aqueous extract was found to be 0.87, 8.49, 72.78, and 25.92μg/ml for 1,1-diphenyl-2-picrylhydrazyl, nitric oxide, H2O2, and ferric reducing antioxidant power, respectively. For the cytotoxicity test, aqueous and ethanolic extracts of T macroptera were non-toxic with a CC50 value of 292.55 ± 1.35 and 223.25 ± 2.75 µg/ml for ethanolic and aqueous, respectively. Regarding the cytotoxicity of the extracts on red blood cells (haemolysis), the two extracts showed very low toxicity compared to the positive control. Phytochemical screening of the plants extract revealed the presence of alkaloids, triterpenoids, anthocyanins, anthraquinons, saponins, flavonoids, and phenolics. ConclusionsThese findings suggest that extracts of T macroptera can serve as antimalarial agents. Further in vivo, antimalarial, antioxidant, and toxicity studies are required to scientifically validate the use of T macroptera as an antimalarial agent.

Dynamic photodamage of red blood cell induced by CisDiMPyP porphyrin.

It is well-known that oxidative damage in red blood cell (RBC) usually causes morphological changes and increased membrane rigidity. Although many studies have focused on investigating how RBC responds to a photodynamic stimulus, the intermediate steps between membrane damage and hemolysis are not reported. To give a comprehensive insight into changes of RBC membrane property under different oxidative damage levels, we employed the photoactivation of CisDiMPyP porphyrin that primarily generates singlet oxygen 1O2 as oxidant species. We found that there were distinguishable characteristic damages depending on the 1O2 flux over the membrane, in a way that each impact of photooxidative damage was categorized under three damage levels: mild (maintaining the membrane morphology and elasticity), moderate (membrane elongation and increased membrane elasticity) and severe (wrinkle-like deformation and hemolysis). When sodium azide (NaN3) was used as a singlet oxygen quencher, delayed cell membrane alterations and hemolysis were detected. The delay times showed that 1O2 indeed plays a key role that causes RBC photooxidation by CisDiMPyP. We suggest that the sequence of morphological changes (RBC discoid area expansion, wrinkle-like patterns, and hemolysis) under photooxidative damage occurs due to damage to the lipid membrane and cytoskeletal network proteins.

A brief history of crystalloids: the origin of the controversy.

Fluid resuscitation with crystalloids has been used in humans for more than 100 years. In patients with trauma, sepsis or shock of any etiology, they can help modify the clinical course of the illness. However, these solutions are medications which are not side-effect free. Recently, they have been questioned in terms of quantity (fluid overload) and their composition. The most frequently used crystalloids, both in high and low-income countries, are 0.9% normal saline (NS) and Ringer's lactate. The first descriptions of the use of sodium and water solutions in humans date from the cholera epidemic which spread throughout Europe in 1831. The composition of the fluids used by medical pioneers at that time differs greatly from the 0.9% NS used routinely today. The term "physiological solution" referred to fluids which did not cause red blood cell hemolysis in amphibians in in vitro studies years later. 0.9% NS has an acid pH, a more than 40% higher chloride concentration than plasma and a strong ion difference of zero, leading many researchers to consider it an unbalanced solution. In many observational studies and clinical trials, this 0.9% NS composition has been associated with multiple microcirculation and immune response complications, acute kidney injury, and worse clinical outcomes. Ringer's lactate has less sodium than plasma, as well as other electrolytes which can cause problems in patients with traumatic brain injury. This review provides a brief summary of the most important historical aspects of the origin of the most frequently used intravenous crystalloids today.

Atomic Force Microscopy and High-Resolution Spectrophotometry for Study of Anoxemia and Normoxemia in Model Experiment In Vitro.

The oxygen content in the blood may decrease under the influence of various physicochemical factors and different diseases. The state of hypoxemia is especially dangerous for critically ill patients. In this paper, we describe and analyze the changes in the characteristics of red blood cells (RBCs) with decreasing levels of oxygen in the RBC suspension from normoxemia to hypoxemia/anoxemia in an in vitro model experiment. The RBCs were stored in hypoxemia/anoxemia and normoxemia conditions in closed and open tubes correspondingly. For the quantitative study of RBC parameter changes, we used atomic force microscopy, digital spectrophotometry, and nonlinear curve fitting of the optical spectra. In both closed and open tubes, at the end of the storage period by day 29, only 2% of discocytes remained, and mainly irreversible types, such as microspherocytes and ghosts, were observed. RBC hemolysis occurred at a level of 25-30%. Addition of the storage solution, depending on the concentration, changed the influence of hypoxemia on RBCs. The reversibility of the change in hemoglobin derivatives was checked. Based on the experimental data and model approach, we assume that there is an optimal level of hypoxemia at which the imbalance between the oxidative and antioxidant systems, the rate of formation of reactive oxygen species, and, accordingly, the disturbances in RBCs, will be minimal.

Outcomes of therapeutic plasma exchange in severe autoimmune hemolytic anemia hospitalizations: An analysis of the National Inpatient Sample.

Autoimmune hemolytic anemia (AIHA) is characterized by humoral and/or cellular immune-mediated hemolysis of red blood cells. The role of therapeutic plasma exchange (TPE) in AIHA is unclear. We queried the National Inpatient Sample (NIS) for 2002-2019 to identify hospitalizations with the primary diagnosis of AIHA. We included hospitalizations with the highest severity subclass identified by All Patient Refined Disease Related Group (APR-DRG). We used multivariate regression analysis to compare in-hospital mortality and other relevant in-hospital outcomes between hospitalizations that received TPE and those that did not. We identified 255 weighted hospitalizations in the TPE group and 4973 in the control group. Those in the control group were older (median age 67 vs. 48 years, p < .001) and had a higher prevalence of most comorbidities. The TPE group had higher odds of all-cause in-hospital mortality (odds ratio [OR], 1.59; 95% confidence interval [CI], 1.19-2.11). They also had higher rates of many secondary outcomes, including requiring mechanical ventilation, developing circulatory shock, acute stroke, urinary tract infections, intracranial hemorrhage, acute kidney injury, and requiring new hemodialysis. No significant differences were noted in the rates of acute myocardial infarctions, bacterial pneumonia, sepsis/septicemia, thromboembolic events, and other bleeding events. Furthermore, the TPE group had a higher median length of hospital stay (19 vs. 9 days, p < .001). Hospitalizations with severe AIHA that received TPE had higher rates of adverse in-hospital outcomes.

Investigational Workout for the Diagnosis of Paroxysmal Nocturnal Hemoglobinuria

Paroxysmal nocturnal hemoglobinuria (PNH) is an acquired rare disease that affects both males and females characterized by the triad of intravascular hemolytic anemia, thrombosis, and bone marrow failure. Flow cytometry is the gold standard for the final diagnosis. This is a PNH case of a 42-year-old Indonesian woman who presented to the emergency department with sustained generalized fatigability, pallor, and jaundice with a history of multiple recurrent previous events managed by blood transfusions. The diagnosis was reached by laboratory studies that revealed hemolytic anemia and erythroid hyperplasia, which was confirmed by a clonal deficiency of CD59 red blood cells (RBCs) using flow cytometry. She was prescribed eculizumab. Hemolytic anemia and jaundice in patients with PNH can be caused by RBCs hemolysis due to the absence of CD55 and CD59 proteins caused by a genetic defect (PIG-A) on the X chromosome. That is why flow cytometry must be made for each patient suspected of having PNH.

Biovalorization of Fruit Wastes for Development of Biodegradable Antimicrobial Chitosan-Based Coatings for Fruits (Tomatoes and Grapes).

Organic wastes are generated from high consumption of fruits. In this paper, fruit residual wastes collected from fruit-juice centres were transformed into fine powder, and thereafter, proximate analysis along with SEM, EDX and XRD was done to get into the surface morphology, minerals and ash content of fine powder. Aqueous extract (AE) prepared from this powder was studied using gas chromatography-mass spectroscopy (GC-MS). The phytochemicals identified are N-hexadecanoic acid; 1,3-dioxane,2,4-dimethyl-, diglycerol, 4-ethyl-2-hydroxycyclopent-2-en-1-one, eicosanoic acid, etc. AE showed high antioxidant and a low MIC value (2mg/ml) against Pseudomonas aeruginosa MZ269380. AE having acceptance as nontoxic to biological system, formulation of chitosan (2%)-based coating was done with 1% AQ. Surface coatings of tomatoes and grapes showed significant inhibition of microbial growth even after 10days of storage at ambient temperature (25 ± 2°C). Colour, texture, firmness and aceptability of coated fruits showed no degradation compared to negative control. Additionally, the extracts showed insignificance haemolysis of goat RBC and damage of Calf Thymus DNA which exhibited its biocompatible nature. Biovalorization of fruit wastes yields useful phytochemicals and can be utilized in various sectors thereby finding a sustainable solution for disposal of fruit wastes.

Hemolysis and Metabolic Lesion of G6PD Deficient RBCs in Response to Dapsone Hydroxylamine in a Humanized Mouse Model.

Glucose 6-phosphate dehydrogenase (G6PD) deficiency is the most common enzymopathy in humans (~5% of all individuals). G6PD deficiency (G6PDd) is caused by an unstable enzyme and manifests most strongly in red blood cells (RBCs) that cannot synthesize new protein. G6PDd RBCs have decreased ability to mitigate oxidative stress due to lower levels of NADPH, as a result of a defective pentose phosphate pathway. Accordingly, oxidative drugs can result in hemolysis and potentially life-threatening anemia in G6PDd patients. Dapsone is a highly useful drug for treating a variety of pathologies but oral dapsone is contraindicated in patients with G6PDd due to oxidative stress-induced anemia. Dapsone must be metabolized to become hemolytic. Dapsone hydroxylamine (DDS-NOH) has been implicated as the major hemolytic dapsone metabolite, but this has never been tested on G6PDd RBCs with in vivo circulation as a metric. Moreover, the metabolic lesion caused by DDS-NOH is unknown. We report that RBCs from a novel humanized mouse expressing the human Mediterranean G6PD-deficient variant have increased sensitivity to DDS-NOH. In addition, we show that DDS-NOH damaged RBCs can either undergo sequestration (with subsequent return to circulation) or permanent removal in a dose-dependent manner, with G6PD-sufficient RBCs mostly being sequestered, and G6PDd RBCs mostly being permanently removed. Finally, we characterize the metabolic lesion caused by DDS-NOH in G6PDd RBCs and report a blockage in terminal glycolysis resulting in a cellular accumulation of pyruvate. These findings confirm DDS-NOH as a hemolytic metabolite and elucidate metabolic effects of DDS-NOH on G6PDd RBCs. Significance Statement These findings confirm that dapsone hydroxylamine, an active metabolite of dapsone, causes in vivo clearance of murine RBCs expressing a human variant of deficient G6PD, an enzymopathy that affects half a billion individuals (G6PD deficiency). Both cellular mechanisms of clearance (sequestration vs. destruction) and specific metabolic disturbances caused by dapsone hydroxylamine are elucidated, providing novel mechanistic understanding.

The Double-Edged Sword of Erythrocytes in Health and Disease via Their Adhesiveness.

Their widespread presence throughout the vasculature, coupled with their reactivity, and thereby to their potential to release reactive oxidative species, or to utilize their anti-oxidative capacities, has promoted much discussion of the role(s) of red blood cells (RBCs) in the progression of health or, alternatively, a wide range of disease states. Moreover, these role(s) have been linked to the development of adhesiveness and, in fact, thereby to the essential pathway to their eventual clearance, e.g., by macrophages in the spleen. These disparate roles coupled with the mechanisms involved are reviewed and given. Following an analysis, novel perspectives are provided; these perspectives can lead to novel assays for identifying the potential for RBC adhesiveness as suggested herein. We describe this paradigm, that involves RBC adhesiveness, hemolysis, and ghost formation, with examples including, inter alia, the progression of atherosclerosis and the suppression of tumor growth along with other disease states.

Analysis of the Polyphenolic Composition of Vaccinium L. Extracts and Their Protective Effect on Red Blood Cell Membranes

The blueberry fruit of the genus Vaccinium, including high blueberry, low blueberry, and wild bilberry, is consumed for its flavor and medicinal properties. The purpose of the experiments was to investigate the protective effect and mechanism of the interaction of blueberry fruit polyphenol extracts with the erythrocytes and their membranes. The content of polyphenolic compounds in the extracts was determined using the chromatographic UPLC–ESI–MS method. The effects of the extracts on red blood cell shape changes, hemolysis and osmotic resistance were examined. Changes in the order of packing and fluidity of the erythrocyte membrane and the lipid membrane model caused by the extracts were identified using fluorimetric methods. Erythrocyte membrane oxidation was induced by two agents: AAPH compound and UVC radiation. The results show that the tested extracts are a rich source of low molecular weight polyphenols that bind to the polar groups of the erythrocyte membrane, changing the properties of its hydrophilic area. However, they practically do not penetrate the hydrophobic part of the membrane and do not damage its structure. Research results suggest that the components of the extracts can defend the organism against oxidative stress if they are delivered to the organism in the form of dietary supplements.

Hybrid repair of left ventricle pseudoaneurysm utilizing a transapical and transseptal approach

Mitral valve endocarditis complicated by peri-mitral annular destruction requires surgical intervention. We present a case where surgery was not an option. A 45-year-old man who developed an enlarging left ventricle pseudoaneurysm, left ventricle to left atrium fistula and red blood cell hemolysis as sequalae of mitral valve endocarditis was not a surgical candidate. Patient underwent a hybrid repair of left ventricle pseudoaneurysm via a transapical and transseptal approach. The body of pseudoaneurysm was coiled trans-apically whereas the neck of pseudoaneurysm was reached and coiled via a transseptal approach. The left ventricle to left atrium fistula was closed via an Amplatz muscular ventricle septal occluder. The pseudoaneurysm was fully obliterated, patient symptoms improved and was discharged with stable hemoglobin levels.

Metabolic exhaustion and casein kinase 1α drive deguelin-induced premature red blood cell death

1. Deguelin (DGN), a retinoid isolated from many plants, exhibits a potent anticancer activity against a wide spectrum of tumour cells. There is a dearth of evidence, however, regarding the toxicity of DGN to red blood cells (RBCs). This is relevant given the prevalent chemotherapy-associated anaemia observed in cancer patients. 2. RBCs were exposed to 1-100 μM of DGN for 24 h at 37 °C. Haemolysis and related markers were photometrically measured while flow cytometry was employed to detect phosphatidylserine exposure through Annexin-V-FITC binding and light scatter properties. Additionally, cytosolic Ca2+ and reactive oxygen species were quantified using Fluo4/AM and H2DCFDA, respectively. DGN was also tested against specific signalling inhibitors in addition to vitamin C and ATP. 3. DGN caused a significant increase in Annexin-V-positive cells which was accompanied by cell shrinkage without Ca2+ elevation or oxidative stress. DGN also elicited dose-responsive haemolysis which was ameliorated by preventing KCl efflux and in the presence of sucrose, D4476, and ATP. In whole blood, DGN significantly reduced the reticulocyte count and increased platelet distribution width and large cell count. 4. DGN triggers premature RBC eryptosis and haemolysis through casein kinase 1α and ATP depletion, and exhibits a specific toxicity towards reticulocytes and platelets.

Investigating multifaceted action of ibuprofen derivatives towards cox isozymes and interleukin-6 (IL-6) site correlating with various target sites

The multifaceted action of new ibuprofen analogs has been investigated against inflammation, neurological and pro-inflammation factors. On the basis of ADMET (absorption, distribution, metabolism, excretion, and toxicity) analysis, molecular docking as well as molecular dynamics simulation, compound 3 was thought to have good anti-inflammatory activity. As the presence of structural interactions such as conventional hydrogen bonds and electrostatic interactions through the nitrogen atoms of the linker in compound 3 gave strong evidence of its potency. The major finding of the current work is that the presence of appropriate number of hetero atoms (NH, OH) in a compound makes it more efficient than the number of labile groups (i.e., hydroxyl groups). Additionally, the position of hetero atoms in a compound and orientation also play a vital role in its efficacy. It was also screened for in vitro anti-inflammatory activity by membrane stability method, where it has shown 90.8% protection of RBC hemolysis. Thus, compound 3 with effective structural features may have good anti-inflammatory activity. Communicated by Ramaswamy H. Sarma

Fatty Acid Conjugated Chalcones as Tubulin Polymerization Inhibitors: Design, Synthesis, QSAR, and Apoptotic and Antiproliferative Activity.

Cancer is often associated with an aberrant increase in tubulin and microtubule activity required for cell migration, invasion, and metastasis. A new series of fatty acid conjugated chalcones have been designed as tubulin polymerization inhibitors and anticancer candidates. These conjugates were designed to harness the beneficial physicochemical properties, ease of synthesis, and tubulin inhibitory activity of two classes of natural components. New lipidated chalcones were synthesized from 4-aminoacetophenone via N-acylation followed by condensation with different aromatic aldehydes. All new compounds showed strong inhibition of tubulin polymerization and antiproliferative activity against breast and lung cancer cell lines (MCF-7 and A549) at low or sub-micromolar concentrations. A significant apoptotic effect was shown using a flow cytometry assay that corresponded to cytotoxicity against cancer cell lines, as indicated by a 3-[4,5-dimethylthiazol-2-yl]-2,5 diphenyl tetrazolium bromide assay. Decanoic acid conjugates were more potent than longer lipid analogues, with the most active being more potent than the reference tubulin inhibitor, combretastatin-A4 and the anticancer drug, doxorubicin. None of the newly synthesized compounds caused any detectable cytotoxicity against the normal cell line (Wi-38) or hemolysis of red blood cells below 100 μM. It is unlikely that the new conjugates described would affect normal cells or interrupt with cell membranes due to their lipidic nature. A quantitative structure-activity relationship analysis was performed to determine the influence of 315 descriptors of the physicochemical properties of the new conjugates on their tubulin inhibitory activity. The obtained model revealed a strong correlation between the tubulin inhibitory activity of the investigated compounds and their dipole moment and degree of reactivity.

Silica nanoparticles trigger phosphatidylserine exposure in red blood cells and induce thrombosis risk

Silica nanoparticles (SiNPs) have attracted increasing attention for their health effects due to the increased risk of exposure to human bodies via diverse routes. Considering that SiNPs enter the circulatory system and inevitably encounter red blood cells (RBCs), it is necessary to investigate their risk of causing erythrocytotoxicity. In this study, three sizes of SiNPs (SiNP-60, SiNP-120, and SiNP-200) were tested for their effects on mouse RBCs. The results showed that SiNPs could induce hemolysis, morphological changes, and phosphatidylserine (PS) exposure in RBCs in a particulate size-related manner. Further investigations on the underlying mechanism indicated that SiNP-60 exposure increased intracellular reactive oxidative species (ROS) generation and subsequently caused the phosphorylation of p38 and ERK1/2 in RBCs. The addition of antioxidants or inhibitors of mitogen-activated protein kinase (MAPK) signaling significantly attenuated PS exposure in RBCs and ameliorated SiNP-induced erythrocytotoxicity. Moreover, ex vivo assays using platelet-rich plasma (PRP) showed that SiNP-60-induced PS exposure in RBCs could trigger thrombin-dependent platelet activation. The contrary evidence from the assays of PS blockage and thrombin inhibition further confirmed that SiNP-60-induced platelet activation was dependent on PS externalization in RBCs, concomitantly with thrombin formation. These findings revealed the procoagulant and prothrombotic effects of SiNPs through the regulation of PS externalization in RBCs, and may be of great help in bridging the knowledge gap on the potential cardiovascular hazards of particulate silica from both artificial and naturally occurring origins.

GBT021601 improves red blood cell health and the pathophysiology of sickle cell disease in a murine model.

The pathophysiologic mechanism of sickle cell disease (SCD) involves polymerization of deoxygenated haemoglobin S (HbS), leading to red blood cell (RBC) sickling, decreased RBC deformability, microvascular obstruction, haemolysis, anaemia and downstream clinical complications. Pharmacological increase in the concentration of oxygenated HbS in RBCs has been shown to be a novel approach to inhibit HbS polymerization and reduce RBC sickling and haemolysis. We report that GBT021601, a small molecule that increases HbS-oxygen affinity, inhibits HbS polymerization and prevents RBC sickling in blood from patients with SCD. Moreover, in a murine model of SCD (SS mice), GBT021601 reduces RBC sickling, improves RBC deformability, prolongs RBC half-life and restores haemoglobin levels to the normal range, while improving oxygen delivery and increasing tolerance to severe hypoxia. Notably, oral dosing of GBT021601 in animals results in higher levels of Hb occupancy than voxelotor and suggests the feasibility of once-daily dosing in humans. In summary, GBT021601 improves RBC health and normalizes haemoglobin in SS mice, suggesting that it may be useful for the treatment of SCD. These data are being used as a foundation for clinical research and development of GBT021601.

Hemolysis of red blood cells in blood vessels modeled via computational fluid dynamics.

The research aims to verify the universal relationship between vessel shape and the risk of hemolysis using a rheological model of blood reflecting the physiological processes related to blood for any blood vessel. Blood is a multi-component fluid, the rheology of which depends on many factors, such as the concentration of red blood cells and local shear stress, which significantly affect the process of hemolysis. Blood rheology models used so far cannot be used for all flows and geometries. Therefore, a new rheology model has been introduced suitable for modeling hemolytic flows observed in arteries with atherosclerotic lesions in the in vivo environment. The previously presented model also has advantages in modeling local viscosity in stenosis. Geometries of the blood vessels from computed tomography scans and simplified models of the actual arteries observed during medical procedures were used in the calculations. Population Balance Based Rheology model predicts the concentration of single, deagglomerated red blood cells and the concentration and size of red blood cell agglomerates, which affect blood rheology and hemolysis. Based on the simulations carried out, a correlation was found between the shape of the vessel cavity and the risk of hemolysis. Presented results can be used in the future to create a correlation between the shape of the atherosclerotic lesions and the risk of hemolysis in the blood to make an initial risk assessment for a given patient.

Hematological variations in healthy participants exposed 2 h to propylene glycol ethers under controlled conditions

Glycol ethers are solvents used in a plethora of occupational and household products exposing the users to potential toxic effects. Several glycol ethers derived from ethylene glycol induce hematological toxicity, such as anemia in workers. The exposure effects on blood cells of glycol ethers derived from propylene glycol are unknown in humans. The aim of our study was to evaluate blood parameters indicative of red blood cell (RBC) hemolysis and oxidative stress in participants exposed to propylene glycol (propylene glycol monobutyl ether (PGBE) and propylene glycol monomethyl ether (PGME)), two extensively used propylene glycol derivatives worldwide.Seventeen participants were exposed 2 h in a control inhalation exposure chamber to low PGME (35 ppm) and PGBE (15 ppm) air concentrations. Blood was regularly collected before, during (15, 30, 60, and 120 min), and 60 min after exposure for RBC and oxidative stress analyses. Urine was also collected for clinical effects related to hemolysis.Under the study conditions, our results showed that the blood parameters such as RBCs, hemoglobin concentration, and white blood cells tended to increase in response to PGME and PGBE exposures. These results raise questions about the possible effects in people regularly exposed to higher concentrations, such as workers.