Experimental hematology最新文献

Anemia in patients with sickle cell disease (SCD) increases 2,3-diphosphoglycerate (2,3-DPG), decreasing hemoglobin-oxygen (Hb-O₂) affinity to improve oxygen offloading and promote hemoglobin polymerization (sickling) of red blood cells (RBCs). We report the discovery of FT-4202, an investigational, selective pyruvate kinase type-R (PKR) activator with a multimodal mechanism of action and potential to increase ATP and decrease 2,3-DPG, resulting in increased Hb-O₂ affinity, decreased Hb polymerization, and improved RBC health. FT-4202 was identified via structure-enabled lead optimization medicinal chemistry using X-ray crystallography, molecular modeling, and thermal shift assays. FT-4202, an allosteric PKR activator, stabilizes the tetrameric enzyme and increases PKR activity in human and mouse RBCs in vitro. Seven-day oral administration of FT-4202 in Berkeley SCD mice reduced 2,3-DPG, increased Hb-O₂ affinity, and reduced RBC sickling versus control. There were no adverse in vitro safety findings. FT-4202 offers a therapeutic opportunity to modify the course of SCD.

Diversity in the granulocyte repertoire, including neutrophils, basophils, and eosinophils, has been reported in vertebrate species. Medaka fish (Oryzias latipes) have only neutrophils; however, the storage pool of granulopoiesis tissues and the molecular mechanism of granulopoiesis in medaka fish have not been explored. Granulocyte colony-stimulating factor (G-CSF) is a cytokine responsible for neutrophil differentiation, survival, and proliferation. We performed in silico analysis to molecularly characterize the medaka G-CSF and G-CSF receptor (G-CSFR) genes. This study showed that medaka G-CSF differs considerably from human and mouse G-CSF in terms of the primary protein structure; however, the predicted tertiary structure was largely conserved. Analyses of lipopolysaccharide stimulation and G-CSF knockout and overexpression in medaka revealed that G-CSF mobilizes neutrophils into the peripheral blood. The analysis of G-CSF-deficient medaka revealed that G-CSF is involved in erythropoiesis. These findings represent an important first step toward understanding granulocyte hematopoiesis in non-mammalian species.

Our study seeks to provide a theoretical foundation for the clinical use of Cold-stored platelets (CSPs) by interpreting ultrastructural images and quantitatively analyzing structural changes. CSPs, room temperature-stored platelets (RTPs), and delayed cold stored platelets(Delayed-CSPs) were continuously observed using scanning electron microscopy and transmission electron microscopy at 8 time points. Super-resolution fluorescence microscopy was employed to observe changes in platelet microtubules and mitochondrial structure and function, while platelet counts, metabolism, and relevant functional indicators were measured concurrently. Quantitative statistical analysis of platelet size, morphology, canalicular systems, and five organelles was performed under electron microscopy. CSPs stored for 1 day, platelet shape changed from circular or elliptical to spherical, with size decreasing from 2.8 × 2.2µm to 2.0 × 2.0µm. CSPs occurred wrinkling and reorganization of platelet microtubule proteins, with organelles aggregating towards the central region. CSPs stored for 14 days and Delayed-CSPs for 10 days exhibited numerous structurally intact and active cells. The structure-intact active cells in both group were 92% . RTPs stored for 5 and 7 days showed minimal changes in size, a normal microtubule skeleton, and were primarily in a resting state. However, RTPs stored for 10 and 14 days displayed swelling, irregular disintegration of the microtubule skeleton, and the presence of membranous structures and vacuolated cells,the structure-intact active cells was only 45% and 7%, respectively. Our findings confirmed that the maximum storage time of platelets was 5-7 days for RTPs, within 10 days for Delayed-CSPs, and 14 days for CSPs.