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913 results on '"Johnson, Randall S."'

1. A century of the Warburg effect

Author

Thompson, Craig B., Vousden, Karen H., Johnson, Randall S., Koppenol, Willem H., Sies, Helmut, Lu, Zhimin, Finley, Lydia W. S., Frezza, Christian, Kim, Jiyeon, Hu, Zeping, and Bartman, Caroline R.

Published
2023
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2. Glutarate regulates T cell metabolism and anti-tumour immunity

Author

Minogue, Eleanor, Cunha, Pedro P., Wadsworth, Brennan J., Grice, Guinevere L., Sah-Teli, Shiv K., Hughes, Rob, Bargiela, David, Quaranta, Alessandro, Zurita, Javier, Antrobus, Robin, Velica, Pedro, Barbieri, Laura, Wheelock, Craig E., Koivunen, Peppi, Nathan, James A., Foskolou, Iosifina P., and Johnson, Randall S.

Published
2023
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6. Constitutive Glycolytic Metabolism Supports CD8+ T Cell Effector Memory Differentiation during Viral Infection

Author

Phan, Anthony T, Doedens, Andrew L, Palazon, Asis, Tyrakis, Petros A, Cheung, Kitty P, Johnson, Randall S, and Goldrath, Ananda W

Subjects
Biomedical and Clinical Sciences, Immunology, Prevention, Underpinning research, Aetiology, 1.1 Normal biological development and functioning, 2.1 Biological and endogenous factors, Infection, Animals, Arenaviridae Infections, CD8-Positive T-Lymphocytes, Cell Differentiation, Cell Separation, Disease Models, Animal, Flow Cytometry, Glycolysis, Immunologic Memory, Lymphocyte Activation, Lymphocytic choriomeningitis virus, Mice, Mice, Transgenic, Oxidative Phosphorylation
Abstract

Extensive metabolic changes accompany T cell activation, including a switch to glycolytic energy production and increased biosynthesis. Recent studies suggest that subsequent return to reliance on oxidative phosphorylation and increasing spare respiratory capacity are essential for the differentiation of memory CD8+ T cells. In contrast, we found that constitutive glycolytic metabolism and suppression of oxidative phosphorylation in CD8+ T cells, achieved by conditional deletion of hypoxia-inducible factor regulator Vhl, accelerated CD8+ memory cell differentiation during viral infection. Despite sustained glycolysis, CD8+ memory cells emerged that upregulated key memory-associated cytokine receptors and transcription factors and showed a heightened response to secondary challenge. In addition, increased glycolysis not only permitted memory formation, but it also favored the formation of long-lived effector-memory CD8+ T cells. These data redefine the role of cellular metabolism in memory cell differentiation, showing that reliance on glycolytic metabolism does not hinder formation of a protective memory population.

Published
2016

7. HIF1α Represses Cell Stress Pathways to Allow Proliferation of Hypoxic Fetal Cardiomyocytes

Author

Guimarães-Camboa, Nuno, Stowe, Jennifer, Aneas, Ivy, Sakabe, Noboru, Cattaneo, Paola, Henderson, Lindsay, Kilberg, Michael S, Johnson, Randall S, Chen, Ju, McCulloch, Andrew D, Nobrega, Marcelo A, Evans, Sylvia M, and Zambon, Alexander C

Subjects
Biochemistry and Cell Biology, Biological Sciences, Cancer, 2.1 Biological and endogenous factors, 1.1 Normal biological development and functioning, Aetiology, Underpinning research, Generic health relevance, Activating Transcription Factor 4, Animals, Biomarkers, Blotting, Western, Cell Proliferation, Cells, Cultured, Embryo, Mammalian, Female, Fetus, Flow Cytometry, Fluorescent Antibody Technique, Gene Expression Profiling, Hypoxia, Hypoxia-Inducible Factor 1, alpha Subunit, Immunoenzyme Techniques, Male, Mice, Mice, Knockout, Myocytes, Cardiac, Oligonucleotide Array Sequence Analysis, RNA, Messenger, Real-Time Polymerase Chain Reaction, Reverse Transcriptase Polymerase Chain Reaction, Signal Transduction, Tumor Suppressor Protein p53, Medical and Health Sciences, Developmental Biology, Biochemistry and cell biology
Abstract

Transcriptional mediators of cell stress pathways, including HIF1α, ATF4, and p53, are key to normal development and play critical roles in disease, including ischemia and cancer. Despite their importance, mechanisms by which pathways mediated by these transcription factors interact with one another are not fully understood. In addressing the controversial role of HIF1α in cardiomyocytes (CMs) during heart development, we discovered a mid-gestational requirement for HIF1α for proliferation of hypoxic CMs, involving metabolic switching and a complex interplay among HIF1α, ATF4, and p53. Loss of HIF1α resulted in activation of ATF4 and p53, the latter inhibiting CM proliferation. Bioinformatic and biochemical analyses revealed unexpected mechanisms by which HIF1α intersects with ATF4 and p53 pathways. Our results highlight previously undescribed roles of HIF1α and interactions among major cell stress pathways that could be targeted to enhance proliferation of CMs in ischemia and may have relevance to other diseases, including cancer.

Published
2015

9. Increased Adipocyte O2 Consumption Triggers HIF-1α, Causing Inflammation and Insulin Resistance in Obesity

Author

Lee, Yun Sok, Kim, Jung-whan, Osborne, Olivia, Oh, Da Young, Sasik, Roman, Schenk, Simon, Chen, Ai, Chung, Heekyung, Murphy, Anne, Watkins, Steven M, Quehenberger, Oswald, Johnson, Randall S, and Olefsky, Jerrold M

Subjects
Biochemistry and Cell Biology, Biological Sciences, Diabetes, Obesity, Nutrition, 2.1 Biological and endogenous factors, Cancer, Cardiovascular, Adenine Nucleotide Translocator 2, Adipocytes, Animals, Basic Helix-Loop-Helix Transcription Factors, Cell Hypoxia, Diet, High-Fat, Fatty Acids, Hypoxia-Inducible Factor 1, alpha Subunit, Inflammation, Insulin Resistance, Lactic Acid, Mice, Mice, Knockout, Nitric Oxide, Oxygen, Medical and Health Sciences, Developmental Biology, Biological sciences, Biomedical and clinical sciences
Abstract

Adipose tissue hypoxia and inflammation have been causally implicated in obesity-induced insulin resistance. Here, we report that, early in the course of high-fat diet (HFD) feeding and obesity, adipocyte respiration becomes uncoupled, leading to increased oxygen consumption and a state of relative adipocyte hypoxia. These events are sufficient to trigger HIF-1α induction, setting off the chronic adipose tissue inflammatory response characteristic of obesity. At the molecular level, these events involve saturated fatty acid stimulation of the adenine nucleotide translocase 2 (ANT2), an inner mitochondrial membrane protein, which leads to the uncoupled respiratory state. Genetic or pharmacologic inhibition of either ANT2 or HIF-1α can prevent or reverse these pathophysiologic events, restoring a state of insulin sensitivity and glucose tolerance. These results reveal the sequential series of events in obesity-induced inflammation and insulin resistance.

Published
2014

10. A 2-Hydroxybutyrate- mediated feedback loop regulates muscular fatigue

Author

Wadsworth, Brennan J, primary, Leiwe, Marina, additional, Minogue, Eleanor A, additional, Cunha, Pedro P, additional, Engman, Viktor, additional, Brombach, Carolin, additional, Asvestis, Christos, additional, Sah-Teli, Shiv K, additional, Marklund, Emilia, additional, Koivunen, Peppi, additional, Ruas, Jorge L, additional, Rundqvist, Helene, additional, Lanner, Johanna T, additional, and Johnson, Randall S, additional

Published
2023
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15. Metabolic basis to Sherpa altitude adaptation

Author

Horscroft, James A., Kotwica, Aleksandra O., Laner, Verena, West, James A., Hennis, Philip J., Levett, Denny Z. H., Howard, David J., Fernandez, Bernadette O., Burgess, Sarah L., Ament, Zsuzsanna, Gilbert-Kawai, Edward T., Vercueil, André, Landis, Blaine D., Mitchell, Kay, Mythen, Monty G., Branco, Cristina, Johnson, Randall S., Feelisch, Martin, Montgomery, Hugh E., Griffin, Julian L., Grocott, Michael P. W., Gnaiger, Erich, Martin, Daniel S., and Murray, Andrew J.

Published
2017

19. Oxygen levels at the time of activation determine T cell persistence and immunotherapeutic efficacy

Author

Cunha, Pedro P, primary, Minogue, Eleanor, additional, Krause, Lena CM, additional, Hess, Rita M, additional, Bargiela, David, additional, Wadsworth, Brennan J, additional, Barbieri, Laura, additional, Brombach, Carolin, additional, Foskolou, Iosifina P, additional, Bogeski, Ivan, additional, Velica, Pedro, additional, and Johnson, Randall S, additional

Published
2023
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22. Supplementary Figures and Tables S1 and S3 from Infiltration of Tumors Is Regulated by T cell–Intrinsic Nitric Oxide Synthesis

Author

Cunha, Pedro P., primary, Bargiela, David, primary, Minogue, Eleanor, primary, Krause, Lena C.M., primary, Barbieri, Laura, primary, Brombach, Carolin, primary, Gojkovic, Milos, primary, Marklund, Emilia, primary, Pietsch, Sandra, primary, Foskolou, Iosifina, primary, Branco, Cristina M., primary, Veliça, Pedro, primary, and Johnson, Randall S., primary

Published
2023
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24. Supplementary Table S2 from Infiltration of Tumors Is Regulated by T cell–Intrinsic Nitric Oxide Synthesis

Author

Cunha, Pedro P., primary, Bargiela, David, primary, Minogue, Eleanor, primary, Krause, Lena C.M., primary, Barbieri, Laura, primary, Brombach, Carolin, primary, Gojkovic, Milos, primary, Marklund, Emilia, primary, Pietsch, Sandra, primary, Foskolou, Iosifina, primary, Branco, Cristina M., primary, Veliça, Pedro, primary, and Johnson, Randall S., primary

Published
2023
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25. Data from Infiltration of Tumors Is Regulated by T cell–Intrinsic Nitric Oxide Synthesis

Author

Cunha, Pedro P., primary, Bargiela, David, primary, Minogue, Eleanor, primary, Krause, Lena C.M., primary, Barbieri, Laura, primary, Brombach, Carolin, primary, Gojkovic, Milos, primary, Marklund, Emilia, primary, Pietsch, Sandra, primary, Foskolou, Iosifina, primary, Branco, Cristina M., primary, Veliça, Pedro, primary, and Johnson, Randall S., primary

Published
2023
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30. Data from Loss of Fibroblast HIF-1α Accelerates Tumorigenesis

Author

Kim, Jung-whan, primary, Evans, Colin, primary, Weidemann, Alexander, primary, Takeda, Norihiko, primary, Lee, Yun Sok, primary, Stockmann, Christian, primary, Branco-Price, Cristina, primary, Brandberg, Filip, primary, Leone, Gustavo, primary, Ostrowski, Michael C., primary, and Johnson, Randall S., primary

Published
2023
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39. Lactate exposure shapes the metabolic and transcriptomic profile of CD8+ T cells

Author

Barbieri, Laura, Veliça, Pedro, Gameiro, Paulo A, Cunha, Pedro P, Foskolou, Iosifina P, Rullman, Eric, Bargiela, David, Johnson, Randall S, Rundqvist, Helene, Apollo - University of Cambridge Repository, and Foskolou, Iosifina P [0000-0003-1874-6356]

Subjects
lactate, Immunology, CD8-Positive T-Lymphocytes, CD8+ T cells, Sodium Lactate, Mice, Immunology and Allergy, Humans, Animals, Lactic Acid, Transcriptome, metabolism, oxygen, T-Lymphocytes, Cytotoxic
Abstract

Funder: Wellcome Trust, Funder: Cancer Research UK, Funder: Medical Research Council, INTRODUCTION: CD8+ T cells infiltrate virtually every tissue to find and destroy infected or mutated cells. They often traverse varying oxygen levels and nutrient-deprived microenvironments. High glycolytic activity in local tissues can result in significant exposure of cytotoxic T cells to the lactate metabolite. Lactate has been known to act as an immunosuppressor, at least in part due to its association with tissue acidosis. METHODS: To dissect the role of the lactate anion, independently of pH, we performed phenotypical and metabolic assays, high-throughput RNA sequencing, and mass spectrometry, on primary cultures of murine or human CD8+ T cells exposed to high doses of pH-neutral sodium lactate. RESULTS: The lactate anion is well tolerated by CD8+ T cells in pH neutral conditions. We describe how lactate is taken up by activated CD8+ T cells and can displace glucose as a carbon source. Activation in the presence of sodium lactate significantly alters the CD8+ T cell transcriptome, including the expression key effector differentiation markers such as granzyme B and interferon-gamma. DISCUSSION: Our studies reveal novel metabolic features of lactate utilization by activated CD8+ T cells, and highlight the importance of lactate in shaping the differentiation and activity of cytotoxic T cells.

Published
2023

41. Infiltration of Tumors Is Regulated by T cell–Intrinsic Nitric Oxide Synthesis

Author

Cunha, Pedro P., primary, Bargiela, David, additional, Minogue, Eleanor, additional, Krause, Lena C.M., additional, Barbieri, Laura, additional, Brombach, Carolin, additional, Gojkovic, Milos, additional, Marklund, Emilia, additional, Pietsch, Sandra, additional, Foskolou, Iosifina, additional, Branco, Cristina M., additional, Veliça, Pedro, additional, and Johnson, Randall S., additional

Published
2022
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42. Oxygen levels at the time of activation determine T cell persistence and immunotherapeutic efficacy

Author

Cunha, Pedro P., primary, Minogue, Eleanor, additional, Krause, Lena C. M., additional, Hess, Rita M., additional, Bargiela, David, additional, Wadsworth, Brennan J., additional, Barbieri, Laura, additional, Brombach, Carolin, additional, Foskolou, Iosifina P., additional, Bogeski, Ivan, additional, Veliça, Pedro, additional, and Johnson, Randall S., additional

Published
2022
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44. Hypoxia-inducible factor 2α regulates key neutrophil functions in humans, mice, and zebrafish

Author

Thompson, A.A. Roger, Elks, Philip M., Marriott, Helen M., Eamsamarng, Suttida, Higgins, Kathryn R., Lewis, Amy, Williams, Lynne, Parmar, Selina, Shaw, Gary, McGrath, Emmet E., Formenti, Federico, Van Eeden, Fredericus J., Kinnula, Vuokko L., Pugh, Christopher W., Sabroe, Ian, Dockrell, David H., Chilvers, Edwin R., Robbins, Peter A., Percy, Melanie J., Simon, M. Celeste, Johnson, Randall S., Renshaw, Stephen A., Whyte, Moira K.B., and Walmsley, Sarah R.

Published
2014
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45. Hypoxia determines survival outcomes of bacterial infection through HIF-1α–dependent reprogramming of leukocyte metabolism

Author

Thompson, A. A. Roger, Dickinson, Rebecca S., Murphy, Fiona, Thomson, John P., Marriott, Helen M., Tavares, Adriana, Willson, Joseph, Williams, Lynne, Lewis, Amy, Mirchandani, Ananda, Dos Santos Coelho, Patricia, Doherty, Catherine, Ryan, Eilise, Watts, Emily, Morton, Nicholas M., Forbes, Shareen, Stimson, Roland H., Hameed, Abdul G., Arnold, Nadine, Preston, Julie A., Lawrie, Allan, Finisguerra, Veronica, Mazzone, Massimiliano, Sadiku, Pranvera, Goveia, Jermaine, Taverna, Federico, Carmeliet, Peter, Foster, Simon J., Chilvers, Edwin R., Cowburn, Andrew S., Dockrell, David H., Johnson, Randall S., Meehan, Richard R., Whyte, Moira K. B., and Walmsley, Sarah R.

Published
2017
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47. S-2-hydroxyglutarate regulates CD8+ T-lymphocyte fate

Author

Tyrakis, Petros A., Palazon, Asis, Macias, David, Lee, Kian. L., Phan, Anthony. T., Velia, Pedro, You, Jia, Chia, Grace S., Sim, Jingwei, Doedens, Andrew, Abelanet, Alice, Evans, Colin E., Griffiths, John R., Poellinger, Lorenz, Goldrath, Ananda W., and Johnson, Randall S.

Subjects
Hydroxy acids -- Health aspects, Immunologic research, Immune response -- Research, T cells -- Genetic aspects -- Health aspects, Environmental issues, Science and technology, Zoology and wildlife conservation
Abstract

R-2-hydroxyglutarate accumulates to millimolar levels in cancer cells with gain-of-function isocitrate dehydrogenase 1/2 mutations. These levels of R-2-hydroxyglutarate affect 2-oxoglutarate-dependent dioxygenases. Both metabolite enantiomers, R- and S-2-hydroxyglutarate, are detectible in healthy individuals, yet their physiological function remains elusive. Here we show that 2-hydroxyglutarate accumulates in mouse CD8[sup.+] T cells in response to T-cell receptor triggering, and accumulates to millimolar levels in physiological oxygen conditions through a hypoxia-inducible factor 1-alpha (HIF-1)-dependent mechanism. S-2-hydroxyglutarate predominates over R-2-hydroxyglutarate in activated T cells, and we demonstrate alterations in markers of CD8[sup.+] T-cell differentiation in response to this metabolite. Modulation of histone and DNA demethylation, as well as HIF-1 stability, mediate these effects. S-2-hydroxyglutarate treatment greatly enhances the in vivo proliferation, persistence and anti-tumour capacity of adoptively transferred CD8[sup.+] T cells. Thus, S-2-hydroxyglutarate acts as an immunometabolite that links environmental context, through a metabolicepigenetic axis, to immune fate and function., Author(s): Petros A. Tyrakis [1, 2]; Asis Palazon [1]; David Macias [1]; Kian. L. Lee [3]; Anthony. T. Phan [4]; Pedro Velia [5]; Jia You [3]; Grace S. Chia [3]; [...]

Published
2016
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48. Hyperoxia Reprogrammes Microvascular Endothelial Cell Response to Hypoxia in an Organ-Specific Manner

Author

Reiterer, Moritz, Eakin, Amanda, Johnson, Randall S, Branco, Cristina M, Branco, Cristina M [0000-0001-6953-4922], and Apollo - University of Cambridge Repository

Subjects
Oxygen - metabolism, hypoxia, Endothelial Cells, General Medicine, Hypoxia - metabolism, Endothelial Cells - metabolism, Oxygen, Mice, microvascular endothelium, heterogeneity, hyperoxia, metabolism, Microvessels, Animals
Abstract

Organ function relies on microvascular networks to maintain homeostatic equilibrium, which varies widely in different organs and during different physiological challenges. The endothelium role in this critical process can only be evaluated in physiologically relevant contexts. Comparing the responses to oxygen flux in primary murine microvascular EC (MVEC) obtained from brain and lung tissue reveals that supra-physiological oxygen tensions can compromise MVEC viability. Brain MVEC lose mitochondrial activity and undergo significant alterations in electron transport chain (ETC) composition when cultured under standard, non-physiological atmospheric oxygen levels. While glycolytic capacity of both lung and brain MVEC are unchanged by environmental oxygen, the ability to trigger a metabolic shift when oxygen levels drop is greatly compromised following exposure to hyperoxia. This is particularly striking in MVEC from the brain. This work demonstrates that the unique metabolism and function of organ-specific MVEC (1) can be reprogrammed by external oxygen, (2) that this reprogramming can compromise MVEC survival and, importantly, (3) that ex vivo modelling of endothelial function is significantly affected by culture conditions. It further demonstrates that physiological, metabolic and functional studies performed in non-physiological environments do not represent cell function in situ, and this has serious implications in the interpretation of cell-based pre-clinical models.

Published
2022
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49. The two enantiomers of 2-hydroxyglutarate differentially regulate cytotoxic T cell function

Author

Foskolou, Iosifina P., primary, Cunha, Pedro P, additional, Minogue, Eleanor, additional, Nicolet, Benoit P, additional, Guislain, Aurelie, additional, Jorgensen, Christian, additional, Zandhuis, Nordin D, additional, Barbieri, Laura, additional, Bargiela, David, additional, Nathanael, Demitris, additional, Tyrakis, Petros, additional, Palazon, Asis, additional, Wolkers, Monika C, additional, and Johnson, Randall S, additional

Published
2022
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