Neuronal Wiskott-Aldrich syndrome protein regulates Pseudomonas aeruginosa-induced lung vascular permeability through the modulation of actin cytoskeletal dynamics.

Pulmonary edema associated with increased vascular permeability is a severe complication of Pseudomonas (P.) aeruginosa-induced acute lung injury. The mechanisms underlying P aeruginosa-induced vascular permeability are not well understood.

Compromised Metabolic Reprogramming Is an Early Indicator of CD8 T Cell Dysfunction during Chronic Mycobacterium tuberculosis Infection.

The immunometabolic mechanisms underlying suboptimal T cell immunity in tuberculosis remain undefined. Here, we examine how chronic Mycobacterium tuberculosis (Mtb) and M. bovis BCG infections rewire metabolic circuits and alter effector functions in lung CD8 T cells.

Bioenergetics and translational metabolism: implications for genetics, physiology and precision medicine.

It is now becoming clear that human metabolism is extremely plastic and varies substantially between healthy individuals. Understanding the biochemistry that underlies this physiology will enable personalized clinical interventions related to metabolism. Mitochondrial quality control and the detailed mechanisms of mitochondrial energy generation are central to understanding susceptibility to pathologies associated with aging including cancer, cardiac and neurodegenerative diseases.

Over-the-counter mouthwash use, nitric oxide and hypertension risk.

Mouthwash is used by a large population. Short-term clinical trials have shown that antibacterial mouthwash deplete oral nitrate-reducing bacteria, and decrease systemic nitric oxide bioavailability. Our previous publication from the San Juan Overweight Adults Longitudinal Study (SOALS) was the first to show frequent over-the-counter mouthwash use was independently associated with increased risk of prediabetes/diabetes.

The Role of Metabolic Plasticity in Blood and Brain Stem Cell Pathophysiology.

Our understanding of intratumoral heterogeneity in cancer continues to evolve, with current models incorporating single-cell signatures to explore cell-cell interactions and differentiation state. The transition between stem and differentiation states in nonneoplastic cells requires metabolic plasticity, and this plasticity is increasingly recognized to play a central role in cancer biology. The insights from hematopoietic and neural stem cell differentiation pathways were used to identify cancer stem cells in leukemia and gliomas.

A precision medicine approach to defining the impact of doxorubicin on the bioenergetic-metabolite interactome in human platelets.

Non-invasive measures of the response of individual patients to cancer therapeutics is an emerging strategy in precision medicine. Platelets offer a potential dynamic marker for metabolism and bioenergetic responses in individual patients since they have active glycolysis and mitochondrial oxidative phosphorylation and can be easily isolated from a small blood sample. We have recently shown how the bioenergetic-metabolite interactome can be defined in platelets isolated from human subjects by measuring metabolites and bioenergetics in the same sample.

A murine neonatal model of necrotizing enterocolitis caused by anemia and red blood cell transfusions.

Necrotizing enterocolitis (NEC) is an idiopathic, inflammatory bowel necrosis of premature infants. Clinical studies have linked NEC with antecedent red blood cell (RBC) transfusions, but the underlying mechanisms are unclear. Here we report a neonatal murine model to investigate this association.

Erythrocyte and plasma oxidative stress appears to be compensated in patients with sickle cell disease during a period of relative health, despite the presence of known oxidative agents.

Sickle cell disease (SCD) is a monogenetic disease that results in the formation of hemoglobin S. Due to more rapid oxidation of hemoglobin S due to intracellular heme and adventitious iron in SCD, it has been thought that an inherent property of SCD red cells would be an imbalance in antioxidant defenses and oxidant production. Less deformable and fragile RBC in SCD results in intravascular hemolysis and release of free hemoglobin (PFHb) in the plasma, which might be expected to produce oxidative stress in the plasma.

Exercise Mediated Nrf2 Signaling Protects the Myocardium From Isoproterenol-Induced Pathological Remodeling.

Although exercise derived activation of Nrf2 signaling augments myocardial antioxidant signaling, the molecular mechanisms underlying the benefits of moderate exercise training (MET) in the heart remain elusive. Here we hypothesized that exercise training stabilizes Nrf2-dependent antioxidant signaling, which then protects the myocardium from isoproterenol-induced damage. The present study assessed the effects of 6 weeks of MET on the Nrf2/antioxidant function, glutathione redox state, and injury in the myocardium of C57/BL6J mice that received isoproterenol (ISO; 50 mg/kg/day for 7 days).

Enhanced Keap1-Nrf2 signaling protects the myocardium from isoproterenol-induced pathological remodeling in mice.

Nuclear factor (erythroid-derived 2)-like 2 (NFE2L2/Nrf2) is an inducible transcription factor that is essential for maintenance of redox signaling in response to stress. This suggests that if Nrf2 expression response could be enhanced for a defined physiological pro-oxidant stress then it would be protective. This has important implications for the therapeutic manipulation of the Keap1/Nrf2 signaling pathway which is now gaining a lot of attention.

Characterizing red blood cell age exposure in massive transfusion therapy: the scalar age of blood index (SBI).

Background: The mortality of trauma patients requiring massive transfusion to treat hemorrhagic shock approaches 17% at 24 hours and 26% at 30 days. The use of stored RBCs is limited to less than 42 days, so older RBCs are delivered first to rapidly bleeding trauma patients. Patients who receive a greater quantity of older RBCs may have a higher risk for mortality.

Phosgene inhalation causes hemolysis and acute lung injury.

Phosgene (Carbonyl Chloride, COCl) remains an important chemical intermediate in many industrial processes such as combustion of chlorinated hydrocarbons and synthesis of solvents (degreasers, cleaners). It is a sweet smelling gas, and therefore does not prompt escape by the victim upon exposure. Supplemental oxygen and ventilation are the only available management strategies.

Hydrogen sulfide inhibits calcification of heart valves; implications for calcific aortic valve disease.

Background And Purpose: Calcification of heart valves is a frequent pathological finding in chronic kidney disease and in elderly patients. Hydrogen sulfide (H S) may exert anti-calcific actions. Here we investigated H S as an inhibitor of valvular calcification and to identify its targets in the pathogenesis.

Hemoglobin β93 Cysteine Is Not Required for Export of Nitric Oxide Bioactivity From the Red Blood Cell.

Background: Nitrosation of a conserved cysteine residue at position 93 in the hemoglobin β chain (β93C) to form S-nitroso (SNO) hemoglobin (Hb) is claimed to be essential for export of nitric oxide (NO) bioactivity by the red blood cell (RBC) to mediate hypoxic vasodilation and cardioprotection.

Methods: To test this hypothesis, we used RBCs from mice in which the β93 cysteine had been replaced with alanine (β93A) in a number of ex vivo and in vivo models suitable for studying export of NO bioactivity.

Results: In an ex vivo model of cardiac ischemia/reperfusion injury, perfusion of a mouse heart with control RBCs (β93C) pretreated with an arginase inhibitor to facilitate export of RBC NO bioactivity improved cardiac recovery after ischemia/reperfusion injury, and the response was similar with β93A RBCs.

Mitochondrial localization, import, and mitochondrial function of the androgen receptor.

Nuclear localization of androgen receptor (AR) directs transcriptional regulation of a host of genes, referred to as genomic signaling. Additionally, nonnuclear or nongenomic activities of the AR have long been described, but understanding of these activities remains elusive. Here, we report that AR is imported into and localizes to mitochondria and has a novel role in regulating multiple mitochondrial processes.

Potential Role of H-Ferritin in Mitigating Valvular Mineralization.

Objective- Calcific aortic valve disease is a prominent finding in elderly and in patients with chronic kidney disease. We investigated the potential role of iron metabolism in the pathogenesis of calcific aortic valve disease. Approach and Results- Cultured valvular interstitial cells of stenotic aortic valve with calcification from patients undergoing valve replacement exhibited significant susceptibility to mineralization/osteoblastic transdifferentiation in response to phosphate.

Plasma xanthine oxidase activity is related to increased sodium and left ventricular hypertrophy in resistant hypertension.

Background: The extra-renal effects of aldosterone on left ventricular (LV) structure and function are exacerbated by increased dietary sodium in persons with hypertension. Previous studies demonstrated endothelial dysfunction and increased oxidative stress with high salt diet in normotensive salt-resistant subjects. We hypothesized that increased xanthine oxidase (XO), a product of endothelial cells, is related to 24-h urinary sodium and to LV hypertrophy and function in patients with resistant hypertension (RHTN).

The role of redox-dependent mechanisms in heme release from hemoglobin and erythrocyte hemolysates.

Toxicity mediated by free heme has emerged as an important element of end organ injuries and adverse outcomes in critically ill disease states. Free heme is thought to be derived from oxidative denaturation of free hemoglobin, secondary to red cell hemolysis. In this study, we evaluated the ability of oxidants (HO, nitrite, peroxynitrite and hypochlorous acid) formed during inflammation to cause heme release from purified hemoglobin and hemolysates, at pH 7.

Older Blood Is Associated With Increased Mortality and Adverse Events in Massively Transfused Trauma Patients: Secondary Analysis of the PROPPR Trial.

Study Objective: The transfusion of older packed RBCs may be harmful in critically ill patients. We seek to determine the association between packed RBC age and mortality among trauma patients requiring massive packed RBC transfusion.

Methods: We analyzed data from the Pragmatic, Randomized Optimal Platelet and Plasma Ratios trial.

Microanatomic Distribution of Myeloid Heme Oxygenase-1 Protects against Free Radical-Mediated Immunopathology in Human Tuberculosis.

Heme oxygenase-1 (HO-1) is a cytoprotective enzyme that controls inflammatory responses and redox homeostasis; however, its role during pulmonary tuberculosis (TB) remains unclear. Using freshly resected human TB lung tissue, we examined the role of HO-1 within the cellular and pathological spectrum of TB. Flow cytometry and histopathological analysis of human TB lung tissues showed that HO-1 is expressed primarily in myeloid cells and that HO-1 levels in these cells were directly proportional to cytoprotection.

Maternal perinatal calorie restriction temporally regulates the hepatic autophagy and redox status in male rat.

Intrauterine growth restriction (IUGR) leads to adult obesity, cardiovascular disease, and non-alcoholic fatty liver disease/steatohepatitis. Animal models have shown that combined intrauterine and early postnatal calorie restriction (IPCR) ameliorates these sequelae in adult life. The mechanism by which IPCR protects against adult onset disease is not understood.

Mitochondrial - nuclear genetic interaction modulates whole body metabolism, adiposity and gene expression in vivo.

We hypothesized that changes in the mitochondrial DNA (mtDNA) would significantly influence whole body metabolism, adiposity and gene expression in response to diet. Because it is not feasible to directly test these predictions in humans we used Mitochondrial-Nuclear eXchange mice, which have reciprocally exchanged nuclear and mitochondrial genomes between different Mus musculus strains. Results demonstrate that nuclear-mitochondrial genetic background combination significantly alters metabolic efficiency and body composition.