The PI3K Pathway in Human Disease

Cell, Journal Year: 2017, Volume and Issue: 170(4), P. 605 - 635

Published: Aug. 1, 2017

Language: Английский

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mTOR- and HIF-1α–mediated aerobic glycolysis as metabolic basis for trained immunity

Science, Journal Year: 2014, Volume and Issue: 345(6204)

Published: Sept. 25, 2014

Epigenetic reprogramming of myeloid cells, also known as trained immunity, confers nonspecific protection from secondary infections. Using histone modification profiles human monocytes with the Candida albicans cell wall constituent β-glucan, together a genome-wide transcriptome, we identified induced expression genes involved in glucose metabolism. Trained display high consumption, lactate production, and ratio nicotinamide adenine dinucleotide (NAD(+)) to its reduced form (NADH), reflecting shift metabolism an increase glycolysis dependent on activation mammalian target rapamycin (mTOR) through dectin-1-Akt-HIF-1α (hypoxia-inducible factor-1α) pathway. Inhibition Akt, mTOR, or HIF-1α blocked monocyte induction whereas adenosine monophosphate-activated protein kinase activator metformin inhibited innate immune response fungal infection. Mice cell-specific defect were unable mount immunity against bacterial sepsis. Our results indicate that aerobic Akt-mTOR-HIF-1α pathway represents metabolic basis immunity.

Language: Английский

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Transcriptional control of effector and memory CD8+ T cell differentiation

Nature reviews. Immunology, Journal Year: 2012, Volume and Issue: 12(11), P. 749 - 761

Published: Oct. 19, 2012

Language: Английский

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Metabolic Pathways in Immune Cell Activation and Quiescence

Immunity, Journal Year: 2013, Volume and Issue: 38(4), P. 633 - 643

Published: April 1, 2013

Language: Английский

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Targeting PI3K/Akt/mTOR Signaling in Cancer

Frontiers in Oncology, Journal Year: 2014, Volume and Issue: 4

Published: April 14, 2014

The phosphatidylinositol-3-kinase (PI3K)/Akt and the mammalian target of Rapamycin (mTOR) signaling pathways are two crucial to many aspects cell growth survival, in physiological as well pathological conditions (e.g. cancer). Indeed, they so interconnected that, a certain sense, could be regarded single, unique pathway. In this paper, after general overview biological significance main components these pathways, we address present status development specific PI3K, Akt mTOR inhibitors, from already registered medicines novel compounds that just leaving laboratory bench.

Language: Английский

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Metabolic Regulation of T Lymphocytes

Annual Review of Immunology, Journal Year: 2013, Volume and Issue: 31(1), P. 259 - 283

Published: Jan. 9, 2013

T cell activation leads to dramatic shifts in metabolism protect against pathogens and orchestrate the action of other immune cells. Quiescent cells require predominantly ATP-generating processes, whereas proliferating effector high metabolic flux through growth-promoting pathways. Further, functionally distinct subsets energetic biosynthetic pathways support their specific functional needs. Pathways that control function are intimately linked, changes at both system levels have been shown enhance or suppress functions. As a result these findings, is now appreciated as key regulator specification fate. This review discusses role cellular development, activation, differentiation, highlight clinical relevance opportunities for therapeutic interventions may be used disrupt pathogenesis.

Language: Английский

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Targeting PI3K/mTOR Signaling in Cancer.

DOAJ (DOAJ: Directory of Open Access Journals), Journal Year: 2014, Volume and Issue: unknown

Published: Jan. 1, 2014

The phosphatidylinositol-3-kinase (PI3K)/Akt and the mammalian target of rapamycin (mTOR) signaling pathways are two crucial to many aspects cell growth survival, in physiological as well pathological conditions (e.g., cancer). Indeed, they so interconnected that, a certain sense, could be regarded single, unique pathway. In this paper, after general overview biological significance main components these pathways, we address present status development specific PI3K, Akt, mTOR inhibitors, from already registered medicines novel compounds that just leaving laboratory bench.

Language: Английский

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Glucose Metabolism Regulates T Cell Activation, Differentiation, and Functions

Frontiers in Immunology, Journal Year: 2015, Volume and Issue: 6

Published: Jan. 22, 2015

The adaptive immune system is equipped to eliminate both tumors and pathogenic microorganisms. It requires a series of complex coordinated signals drive the activation, proliferation differentiation appropriate T cell subsets. now established that changes in cellular activation are coupled profound metabolism. In addition, emerging evidence suggest specific metabolic alterations associated with distinct subsets may be ancillary their influential functions. "Warburg effect" originally used describe phenomenon which most cancer cells relied on aerobic glycolysis for growth key process sustain differentiation. Here we review how different aspects metabolism influence functions, focusing role regulators glucose such as HIF-1α. A thorough understanding function could provide insights into mechanisms involved inflammatory-mediated conditions, potential developing novel therapeutic approaches treat these diseases.

Language: Английский

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Inflammatory T Cell Responses Rely on Amino Acid Transporter ASCT2 Facilitation of Glutamine Uptake and mTORC1 Kinase Activation

Immunity, Journal Year: 2014, Volume and Issue: 40(5), P. 692 - 705

Published: May 1, 2014

Language: Английский

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Causes, consequences, and reversal of immune system aging

Journal of Clinical Investigation, Journal Year: 2013, Volume and Issue: 123(3), P. 958 - 965

Published: March 1, 2013

The effects of aging on the immune system are manifest at multiple levels that include reduced production B and T cells in bone marrow thymus diminished function mature lymphocytes secondary lymphoid tissues. As a result, elderly individuals do not respond to challenge as robustly young. An important goal research is define cellular changes occur molecular events underlie them. Considerable progress has been made this regard, information provided rationale for clinical trials rejuvenate system.

Language: Английский

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