Red blood cell urate levels are linked to hemolysis in vitro and post-transfusion as a function of donor sex, population and genetic polymorphisms in SLC2A9 and ABCG2.

Background: Storage of packed red blood cells (RBCs) for transfusion leads to biochemical and morphological changes, increasing hemolysis risk. Urate levels in blood bags at donation contribute to the molecular heterogeneity and hemolytic propensity of stored RBCs. However, studies to date have been underpowered to investigate at scale the contribution of donor demographics and genetics to the heterogeneity in urate levels across donations.

Early adipose tissue wasting in a novel preclinical model of human lung cancer cachexia.

Cancer cachexia (CC), a syndrome of skeletal muscle and adipose tissue wasting, reduces responsiveness to therapies and increases mortality. There are no approved treatments for CC, which may relate to discordance between pre-clinical models and human CC. To address the need for clinically relevant models, we generated tamoxifen-inducible, epithelial cell specific ( ) mice.

Differentiating erythroblasts adapt to mechanical stimulation by upregulation of cholesterol biosynthesis via S1P/SREBP-induced HMGCR expression.

Understanding how mechanical stress affects erythropoiesis is crucial to produce transfusable erythrocytes in fluid-turbulent bioreactors. We investigated the effects of shear-stress on differentiating CD49dCD235a primary human erythroblasts (EBL) at molecular, cellular, and functional level. Shear-stress, at differentiation onset, enhanced EBL maturation and induced upregulation of genes regulating cholesterol/lipids biosynthesis, causing changes in cell lipid composition.

Sex Differences in Tryptophan Metabolism via the Kynurenine Pathway in Acute Ischemic Stroke.

Purpose: Females are at increased lifetime risk of stroke and experience worse outcomes compared with males. Tryptophan metabolism through the kynurenine pathway, resulting in decreased tryptophan concentrations, is associated with poor outcomes (larger infarct volume, higher National Institutes of Health Stroke Scale [NIHSS] score, and increased early mortality). This metabolic pathway activity varies by sex in healthy adults.

The influence of a human macronutrient-matched diet on phenotypes in old mice.

Preclinical rodent models are essential research tools for improving understanding of physiological aging processes in humans. However, the translatability of findings obtained leveraging rodent models to humans is limited, likely due in part to differences in macronutrient composition of the diets. Here, we investigated the impact of a 3-month diet intervention in old male C57BL/6JN mice in which the macronutrient composition was aligned with that of a midlife/older adult in the United States, compared to a traditional rodent diet, and assessed various phenotypes that are typically altered with aging.

Arginine metabolism is a biomarker of red blood cell and human aging.

Increasing global life expectancy motivates investigations of molecular mechanisms of aging and age-related diseases. This study examines age-associated changes in red blood cells (RBCs), the most numerous host cell in humans. Four cohorts, including healthy individuals and patients with sickle cell disease, were analyzed to define age-dependent changes in RBC metabolism.

Copper drives remodeling of metabolic state and progression of clear cell renal cell carcinoma.

Copper (Cu) is a cofactor of cytochrome c oxidase (CuCOX), indispensable for aerobic mitochondrial respiration. This study reveals that advanced clear cell renal cell carcinomas (ccRCCs) accumulate Cu, allocating it to CuCOX. Using a range of orthogonal approaches, including metabolomics, lipidomics, isotope-labeled glucose and glutamine flux analysis, and transcriptomics across tumor samples, cell lines, xenografts, and PDX models, combined with genetic and pharmacological interventions, we explored Cu's role in ccRCC.

Increased cholesterol synthesis drives neurotoxicity in patient stem cell-derived model of multiple sclerosis.

Senescent neural progenitor cells have been identified in brain lesions of people with progressive multiple sclerosis (PMS). However, their role in disease pathobiology and contribution to the lesion environment remains unclear. By establishing directly induced neural stem/progenitor cell (iNSC) lines from PMS patient fibroblasts, we studied their senescent phenotype in vitro.

Cysteamine dioxygenase (ADO) governs cancer cell mitochondrial redox homeostasis through proline metabolism.

2-Aminoethanethiol dioxygenase (ADO) is a thiol dioxygenase that sulfinylates cysteamine and amino-terminal cysteines in polypeptides. The pathophysiological roles of ADO remain largely unknown. Here, we demonstrate that ADO expression represents a vulnerability in cancer cells, as ADO depletion led to loss of proliferative capacity and survival in cancer cells and reduced xenograft growth.

Spermidine metabolism regulates leukemia stem and progenitor cell function through KAT7 expression in patient-derived mouse models.

Acute myeloid leukemia (AML) is a devastating disease initiated and maintained by a rare subset of cells called leukemia stem cells (LSCs). LSCs are responsible for driving disease relapse, making the development of new therapeutic strategies to target LSCs urgently needed. The use of mass spectrometry-based metabolomics profiling has enabled the discovery of unique and targetable metabolic properties in LSCs.

Biological and genetic determinants of glycolysis: Phosphofructokinase isoforms boost energy status of stored red blood cells and transfusion outcomes.

Mature red blood cells (RBCs) lack mitochondria and thus exclusively rely on glycolysis to generate adenosine triphosphate (ATP) during aging in vivo or storage in blood banks. Here, we leveraged 13,029 volunteers from the Recipient Epidemiology and Donor Evaluation Study to identify associations between end-of-storage levels of glycolytic metabolites and donor age, sex, and ancestry-specific genetic polymorphisms in regions encoding phosphofructokinase 1, platelet (detected in mature RBCs); hexokinase 1 (HK1); and ADP-ribosyl cyclase 1 and 2 (CD38/BST1). Gene-metabolite associations were validated in fresh and stored RBCs from 525 Diversity Outbred mice and via multi-omics characterization of 1,929 samples from 643 human RBC units during storage.

Sex Differences in the Blood Metabolome During Acute Response to Ischemic Stroke.

Females suffer greater lifetime risk of stroke and greater morbidity and mortality from stroke compared with males. This study's objective was to identify differences in metabolomic profiling of females and males with stroke and which differences were associated with neurological outcome. Females and males with acute ischemic stroke enrolled in the Emergency Medicine Specimen Bank at a comprehensive stroke center provided whole blood samples upon arrival for mass spectrometry-based metabolomics.

A Multimodal Drug-Diet-Immunotherapy Combination Restrains Melanoma Progression and Metastasis.

The genetic landscape of cancer cells can lead to specific metabolic dependencies for tumor growth. Dietary interventions represent an attractive strategy to restrict the availability of key nutrients to tumors. In this study, we identified that growth of a subset of melanoma was severely restricted by a rationally designed combination therapy of a stearoyl-CoA desaturase (SCD) inhibitor with an isocaloric low-oleic acid diet.

Prevalence and clinical implications of heightened plastic chemical exposure in pediatric patients undergoing cardiopulmonary bypass.

Background: Phthalate chemicals are used to manufacture plastic medical products, including many components of cardiopulmonary bypass (CPB) circuits. We aimed to quantify iatrogenic phthalate exposure in pediatric patients undergoing cardiac surgery and examine the link between phthalate exposure and postoperative outcomes.

Study Design And Methods: The study included pediatric patients undergoing (n=122) unique cardiac surgeries at Children's National Hospital.

Effect of leukoreduction on the omics phenotypes of canine packed red blood cells during refrigerated storage.

Background: Red blood cell (RBC) storage promotes biochemical and morphological alterations, collectively referred to as storage lesions (SLs). Studies in humans have identified leukoreduction (LR) as a critical processing step that mitigates SLs. To date no study has evaluated the impact of LR on metabolic SLs in canine blood units using omics technologies.

Genetic regulation of carnitine metabolism controls lipid damage repair and aging RBC hemolysis in vivo and in vitro.

Recent large-scale multiomics studies suggest that genetic factors influence the chemical individuality of donated blood. To examine this concept, we performed metabolomics analyses of 643 blood units from volunteers who donated units of packed red blood cells (RBCs) on 2 separate occasions. These analyses identified carnitine metabolism as the most reproducible pathway across multiple donations from the same donor.

Mitochondrial complex I activity in microglia sustains neuroinflammation.

Sustained smouldering, or low-grade activation, of myeloid cells is a common hallmark of several chronic neurological diseases, including multiple sclerosis. Distinct metabolic and mitochondrial features guide the activation and the diverse functional states of myeloid cells. However, how these metabolic features act to perpetuate inflammation of the central nervous system is unclear.

Effect of leukoreduction on the metabolism of equine packed red blood cells during refrigerated storage.

Background: Understanding of the biochemical and morphological lesions associated with storage of equine blood is limited.

Objective: To demonstrate the temporal sequences of lipid and metabolic profiles of equine fresh and stored (up to 42 days) and leukoreduced packed red blood cells (LR-pRBC) and non-leukoreduced packed RBC (nLR-pRBC).

Animals: Packed RBC units were obtained from 6 healthy blood donor horses enrolled in 2 blood banks.

An iron rheostat controls hematopoietic stem cell fate.

Mechanisms governing the maintenance of blood-producing hematopoietic stem and multipotent progenitor cells (HSPCs) are incompletely understood, particularly those regulating fate, ensuring long-term maintenance, and preventing aging-associated stem cell dysfunction. We uncovered a role for transitory free cytoplasmic iron as a rheostat for adult stem cell fate control. We found that HSPCs harbor comparatively small amounts of free iron and show the activation of a conserved molecular response to limited iron-particularly during mitosis.