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Xu J.,Southern California Research Center for and Cirrhosis | Xu J.,University of Southern California | Chi F.,Southern California Research Center for and Cirrhosis | Chi F.,University of Southern California | And 7 more authors.
Journal of Clinical Investigation | Year: 2015

Metabolic reprogramming is implicated in macrophage activation, but the underlying mechanisms are poorly understood. Here, we demonstrate that the NOTCH1 pathway dictates activation of M1 phenotypes in isolated mouse hepatic macrophages (HMacs) and in a murine macrophage cell line by coupling transcriptional upregulation of M1 genes with metabolic upregulation of mitochondrial oxidative phosphorylation and ROS (mtROS) to augment induction of M1 genes. Enhanced mitochondrial glucose oxidation was achieved by increased recruitment of the NOTCH1 intracellular domain (NICD1) to nuclear and mitochondrial genes that encode respiratory chain components and by NOTCH-dependent induction of pyruvate dehydrogenase phosphatase 1 (Pdp1) expression, pyruvate dehydrogenase activity, and glucose flux to the TCA cycle. As such, inhibition of the NOTCH pathway or Pdp1 knockdown abrogated glucose oxidation, mtROS, and M1 gene expression. Conditional NOTCH1 deficiency in the myeloid lineage attenuated HMac M1 activation and inflammation in a murine model of alcoholic steatohepatitis and markedly reduced lethality following endotoxin-mediated fulminant hepatitis in mice. In vivo monocyte tracking further demonstrated the requirement of NOTCH1 for the migration of blood monocytes into the liver and subsequent M1 differentiation. Together, these results reveal that NOTCH1 promotes reprogramming of mitochondrial metabolism for M1 macrophage activation. Source

Kholdani C.A.,Stanford University | Oudiz R.J.,LA Biomedical Research Institute | Fares W.H.,Yale University
Seminars in Respiratory and Critical Care Medicine | Year: 2015

The right heart failure (RHF) syndrome is a pathophysiologically complex state commonly associated with dysfunction of the right ventricle (RV). The normal RV is suited for its purposes of distributing venous blood to the low-resistance pulmonary circulation. Myriad stresses imposed upon it, though, can ultimately result in its failure, with the threat of cardiovascular collapse being the most dreaded outcome. Decreased cardiac output with increased central venous pressures are hemodynamic hallmarks of this highly morbid condition. Proper management of RHF is predicated on the accurate assessment of the key hemodynamic and clinical components signaling the syndrome that is the result of the failing RV. Appropriate use of diagnostic tools is paramount for understanding the key components of RV function: the preload state of the RV, its contractility, and the afterload burden placed on it. In making these assessments, it remains crucial to understand the limitations of these tools when managing RHF in the intensive care unit. An understanding of each of these components allows for the understanding of the physiology and the clinical presentation which can guide the use of therapies appropriately tailored to manage the condition. © 2015 by Thieme Medical Publishers, Inc. Source

Vaitheesvaran B.,Yeshiva University | Xu J.,University of Southern California | Yee J.,University of California at Los Angeles | Lu Q.-Y.,University of California at Los Angeles | And 5 more authors.
Metabolomics | Year: 2015

Cancer metabolism is characterized by increased macromolecular syntheses through coordinated increases in energy and substrate metabolism. The observation that cancer cells produce lactate in an environment of oxygen sufficiency (aerobic glycolysis) is a central theme of cancer metabolism known as the Warburg effect. Aerobic glycolysis in cancer metabolism is accompanied by increased pentose cycle and anaplerotic activities producing energy and substrates for macromolecular synthesis. How these processes are coordinated is poorly understood. Recent advances have focused on molecular regulation of cancer metabolism by oncogenes and tumor suppressor genes which regulate numerous enzymatic steps of central glucose metabolism. In the past decade, new insights in cancer metabolism have emerged through the application of stable isotopes particularly from 13C carbon tracing. Such studies have provided new evidence for system-wide changes in cancer metabolism in response to chemotherapy. Interestingly, experiments using metabolic inhibitors on individual biochemical pathways all demonstrate similar system-wide effects on cancer metabolism as in targeted therapies. Since biochemical reactions in the Warburg effect place competing demands on available precursors, high energy phosphates and reducing equivalents, the cancer metabolic system must fulfill the condition of balance of flux (homeostasis). In this review, the functions of the pentose cycle and of the tricarboxylic acid (TCA) cycle in cancer metabolism are analyzed from the balance of flux point of view. Anticancer treatments that target molecular signaling pathways or inhibit metabolism alter the invasive or proliferative behavior of the cancer cells by their effects on the balance of flux (homeostasis) of the cancer metabolic phenotype. © 2014, Springer Science+Business Media New York. Source

Zhang J.,University of California at Los Angeles | Khvorostov I.,University of California at Los Angeles | Hong J.S.,University of California at Los Angeles | Oktay Y.,University of California at Los Angeles | And 14 more authors.
EMBO Journal | Year: 2011

It has been assumed, based largely on morphologic evidence, that human pluripotent stem cells (hPSCs) contain underdeveloped, bioenergetically inactive mitochondria. In contrast, differentiated cells harbour a branched mitochondrial network with oxidative phosphorylation as the main energy source. A role for mitochondria in hPSC bioenergetics and in cell differentiation therefore remains uncertain. Here, we show that hPSCs have functional respiratory complexes that are able to consume O 2 at maximal capacity. Despite this, ATP generation in hPSCs is mainly by glycolysis and ATP is consumed by the F 1 F 0 ATP synthase to partially maintain hPSC mitochondrial membrane potential and cell viability. Uncoupling protein 2 (UCP2) plays a regulating role in hPSC energy metabolism by preventing mitochondrial glucose oxidation and facilitating glycolysis via a substrate shunting mechanism. With early differentiation, hPSC proliferation slows, energy metabolism decreases, and UCP2 is repressed, resulting in decreased glycolysis and maintained or increased mitochondrial glucose oxidation. Ectopic UCP2 expression perturbs this metabolic transition and impairs hPSC differentiation. Overall, hPSCs contain active mitochondria and require UCP2 repression for full differentiation potential. © 2011 European Molecular Biology Organization | All Rights Reserved. Source

Jang T.,University of California at Los Angeles | Jang T.,University of Washington | Jang T.,LA Biomedical Research Institute | Aubin C.,University of Washington | And 5 more authors.
European Journal of Emergency Medicine | Year: 2011

Background The diagnosis of patients with acute dyspnoea is challenging, as clinical history and physical examination are often nondiagnostic and inaccurate. Consequently, clinicians often rely on the results of chest radiography (CXR) to determine the initial intervention and guide further treatment. Objective The purpose of this study was to prospectively assess the sensitivity and specificity of ultrasonographic assessment of jugular venous distension (US-JVD) for identifying pulmonary oedema on CXR in dyspnoeic patients with suspected congestive heart failure. Measurements US-JVD was compared with initial CXR findings of pulmonary oedema as determined by radiology consultants blinded to all clinical information and US-JVD measurements. Results US-JVD had a sensitivity of 98.2% [95% confidence interval (CI), 89.2-99.9] and a specificity of 42.9% (95% CI, 30.7-55.9), a likelihood ratio positive of 1.7 (95% CI, 1.4-2.1), and likelihood ratio negative of 0.04 (95% CI, 0.006-0.3), for identifying dyspnoeic patients with pulmonary oedema on initial CXR. Conclusion US-JVD is a sensitive test for identifying pulmonary oedema on CXR in dyspnoeic patients with suspected congestive heart failure. European Journal of Emergency Medicine 18:41-45 © 2011 Wolters Kluwer Health | Lippincott Williams & Wilkins. Source

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