Mitapivat metabolically reprograms human β-thalassemic erythroblasts, increasing their responsiveness to oxidation.

β-thalassemia (β-thal) is a worldwide hereditary red cell disorder characterized by severe chronic anemia. Recently, the pyruvate kinase (PK) activator mitapivat has been shown to improve anemia and ineffective erythropoiesis in a mouse model of β-thal and in patients with non-transfusion-dependent thalassemia. Here, we showed that in vitro CD34+-derived erythroblasts from patients with β-thal (codb039) are characterized by persistent expression of 2 PK isoforms, PKR and PKM2, compared with healthy cells.

17(R)-Resolvin D1 protects against sickle cell-related inflammatory cardiomyopathy in humanized mice.

Cardiovascular disease has been recognized as the main cause of death in adults with sickle cell disease (SCD). Although the exact mechanism linking SCD to cardiomyopathy remains elusive, a possible role of subclinical acute transient myocardial ischemia during acute sickle cell-related vaso-occlusive crises (VOCs) has been suggested. We approached SCD cardiomyopathy by integrated omics using humanized SS mice exposed to hypoxia/reoxygenation (H/R; 10 hours hypoxia followed by 3 hours reoxygenation) stress, mimicking acute VOCs.

Nrf2 Plays a Key Role in Erythropoiesis during Aging.

Aging is characterized by increased oxidation and reduced efficiency of cytoprotective mechanisms. Nuclear factor erythroid-2-related factor (Nrf2) is a key transcription factor, controlling the expression of multiple antioxidant proteins. Here, we show that Nrf2 mice displayed an age-dependent anemia, due to the combined contributions of reduced red cell lifespan and ineffective erythropoiesis, suggesting a role of Nrf2 in erythroid biology during aging.

An oral carbon monoxide-releasing molecule protects against acute hyperhemolysis in sickle cell disease.

Acute hyperhemolysis is a severe life-threatening complication in patients with sickle cell disease (SCD) that may occur during delayed hemolytic transfusion reaction (DHTR), or vaso-occlusive crises associated with multiorgan failure. Here, we developed in vitro and in vivo animal models to mimic endothelial damage during the early phase of hyperhemolysis in SCD. We then used the carbon monoxide (CO)-releasing molecule CORM-401 and examined its effects against endothelial activation, damage, and inflammation inflicted by hemolysates containing red blood cell membrane-derived particles.

Epeleuton, a novel synthetic ω-3 fatty acid, reduces hypoxia/ reperfusion stress in a mouse model of sickle cell disease.

Inflammatory vasculopathy is critical in sickle cell disease (SCD)-associated organ damage. An imbalance between pro-inflammatory and pro-resolving mechanisms in response to different triggers such as hypoxia/reoxygenation or infections has been proposed to contribute to the progression of SCD. Administration of specialized pro-resolving lipid mediators may provide an effective therapeutic strategy to target inflammatory vasculopathy and to modulate inflammatory response.

Mitapivat reprograms the RBC metabolome and improves anemia in a mouse model of hereditary spherocytosis.

Hereditary spherocytosis (HS) is the most common, nonimmune, hereditary, chronic hemolytic anemia after hemoglobinopathies. The genetic defects in membrane function causing HS lead to perturbation of the RBC metabolome, with altered glycolysis. In mice genetically lacking protein 4.

Erythrocyte pyruvate kinase activation in red cell disorders.

Purpose Of Review: In red cells, pyruvate kinase is a key enzyme in the final step of glycolytic degradative process, which generates a constant energy supply via ATP production. This commentary discusses recent findings on pyruvate kinase activators as new therapeutic option in hereditary red cell disorders such as thalassemic syndromes or sickle cell disease (SCD).

Recent Findings: Mitapivat and etavopivat are two oral pyruvate kinase activators.

Treatment with recombinant ADAMTS13, alleviates hypoxia/reoxygenation-induced pathologies in a mouse model of human sickle cell disease.

Background: Sickle cell disease (SCD) is an inherited red blood cell disorder with a causative substitution in the beta-globin gene that encodes beta-globin in hemoglobin. Furthermore, the ensuing vasculopathy in the microvasculature involves heightened endothelial cell adhesion, inflammation, and coagulopathy, all of which contribute to vaso-occlusive crisis (VOC) and the sequelae of SCD. In particular, dysregulation of the von Willebrand factor (VWF) and a disintegrin and metalloproteinase with thrombospondin type 1 motif, member 13 (ADAMTS13) axis has been implicated in human SCD pathology.

Duality of Nrf2 in iron-overload cardiomyopathy.

Cardiomyopathy deeply affects quality of life and mortality of patients with b-thalassemia or with transfusion-dependent myelodysplastic syndromes. Recently, a link between Nrf2 activity and iron metabolism has been reported in liver ironoverload murine models. Here, we studied C57B6 mice as healthy control and nuclear erythroid factor-2 knockout (Nrf2-/-) male mice aged 4 and 12 months.

CD66bCD64CD115 cells in the human bone marrow represent neutrophil-committed progenitors.

Here we report the identification of human CD66bCD64CD115 neutrophil-committed progenitor cells (NCPs) within the SSCCD45CD34 and CD34 subsets in the bone marrow. NCPs were either CD45RA or CD45RA, and in vitro experiments showed that CD45RA acquisition was not mandatory for their maturation process. NCPs exclusively generated human CD66b neutrophils in both in vitro differentiation and in vivo adoptive transfer experiments.

Adaptative Up-Regulation of PRX2 and PRX5 Expression Characterizes Brain from a Mouse Model of Chorea-Acanthocytosis.

The peroxiredoxins (PRXs) constitute a ubiquitous antioxidant. Growing evidence in neurodegenerative disorders such as Parkinson's disease (PD) or Alzheimer's disease (AD) has highlighted a crucial role for PRXs against neuro-oxidation. Chorea-acanthocytosis/ disease (ChAc) is a devastating, life-shortening disorder characterized by acanthocytosis, neurodegeneration and abnormal proteostasis.

Dietary ω-3 Fatty Acid Supplementation Improves Murine Sickle Cell Bone Disease and Reprograms Adipogenesis.

Sickle cell disease (SCD) is a genetic disorder of hemoglobin, leading to chronic hemolytic anemia and multiple organ damage. Among chronic organ complications, sickle cell bone disease (SBD) has a very high prevalence, resulting in long-term disability, chronic pain and fractures. Here, we evaluated the effects of ω-3 (fish oil-based, FD)-enriched diet vs.

Targeting Lyn Kinase in Chorea-Acanthocytosis: A Translational Treatment Approach in a Rare Disease.

Chorea-acanthocytosis (ChAc) is a neurodegenerative disease caused by mutations in the gene. It is characterized by several neurological symptoms and the appearance of acanthocytes. Elevated tyrosine kinase Lyn activity has been recently identified as one of the key pathophysiological mechanisms in this disease, and therefore represents a promising drug target.

The pyruvate kinase activator mitapivat reduces hemolysis and improves anemia in a β-thalassemia mouse model.

Anemia in β-thalassemia is related to ineffective erythropoiesis and reduced red cell survival. Excess free heme and accumulation of unpaired α-globin chains impose substantial oxidative stress on β-thalassemic erythroblasts and erythrocytes, impacting cell metabolism. We hypothesized that increased pyruvate kinase activity induced by mitapivat (AG-348) in the Hbbth3/+ mouse model for β-thalassemia would reduce chronic hemolysis and ineffective erythropoiesis through stimulation of red cell glycolytic metabolism.

Tyrosine Phosphorylation Modulates Peroxiredoxin-2 Activity in Normal and Diseased Red Cells.

Peroxiredoxin-2 (Prx2) is the third most abundant cytoplasmic protein in red blood cells. Prx2 belongs to a well-known family of antioxidants, the peroxiredoxins (Prxs), that are widely expressed in mammalian cells. Prx2 is a typical, homodimeric, 2-Cys Prx that uses two cysteine residues to accomplish the task of detoxifying a vast range of organic peroxides, HO, and peroxynitrite.

Fyn specifically Regulates the activity of red cell glucose-6-phosphate-dehydrogenase.

Fyn is a tyrosine kinase belonging to the Src family (Src-Family-Kinase, SFK), ubiquitously expressed. Previously, we report that Fyn is important in stress erythropoiesis. Here, we show that in red cells Fyn specifically stimulates G6PD activity, resulting in a 3-fold increase enzyme catalytic activity (k) by phosphorylating tyrosine (Tyr)-401.

Oxidation Impacts the Intracellular Signaling Machinery in Hematological Disorders.

The dynamic coordination between kinases and phosphatases is crucial for cell homeostasis, in response to different stresses. The functional connection between oxidation and the intracellular signaling machinery still remains to be investigated. In the last decade, several studies have highlighted the role of reactive oxygen species (ROS) as modulators directly targeting kinases, phosphatases, and downstream modulators, or indirectly acting on cysteine residues on kinases/phosphatases resulting in protein conformational changes with modulation of intracellular signaling pathway(s).

Pathologic angiogenesis in the bone marrow of humanized sickle cell mice is reversed by blood transfusion.

Sickle cell disease (SCD) is a monogenic red blood cell (RBC) disorder with high morbidity and mortality. Here, we report, for the first time, the impact of SCD on the bone marrow (BM) vascular niche, which is critical for hematopoiesis. In SCD mice, we find a disorganized and structurally abnormal BM vascular network of increased numbers of highly tortuous arterioles occupying the majority of the BM cavity, as well as fragmented sinusoidal vessels filled with aggregates of erythroid and myeloid cells.

Emerging drugs in randomized controlled trials for sickle cell disease: are we on the brink of a new era in research and treatment?

: Sickle cell disease (SCD) is caused by a mutation in the HBB gene which is key for making a component of hemoglobin. The mutation leads to the formation of an abnormal hemoglobin molecule called sickle hemoglobin (HbS). SCD is a chronic, complex disease with a multiplicity of pathophysiological targets; it has high morbidity and mortality.