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      Inhibitory Effect of Idelalisib, a Selective Phosphatidylinositol 3-Kinase δ Inhibitor, on Adipogenesis in an In Vitro Model of Graves' Orbitopathy

      1 , 1 , 2 , 1
      Investigative Opthalmology & Visual Science
      Association for Research in Vision and Ophthalmology (ARVO)

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          Most cited references39

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          Graves' ophthalmopathy.

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            Akt signalling in health and disease.

            Akt (also known as protein kinase B or PKB) comprises three closely related isoforms Akt1, Akt2 and Akt3 (or PKBα/β/γ respectively). We have a very good understanding of the mechanisms by which Akt isoforms are activated by growth factors and other extracellular stimuli as well as by oncogenic mutations in key upstream regulatory proteins including Ras, PI3-kinase subunits and PTEN. There are also an ever increasing number of Akt substrates being identified that play a role in the regulation of the diverse array of biological effects of activated Akt; this includes the regulation of cell proliferation, survival and metabolism. Dysregulation of Akt leads to diseases of major unmet medical need such as cancer, diabetes, cardiovascular and neurological diseases. As a result there has been substantial investment in the development of small molecular Akt inhibitors that act competitively with ATP or phospholipid binding, or allosterically. In this review we will briefly discuss our current understanding of how Akt isoforms are regulated, the substrate proteins they phosphorylate and how this integrates with the role of Akt in disease. We will furthermore discuss the types of Akt inhibitors that have been developed and are in clinical trials for human cancer, as well as speculate on potential on-target toxicities, such as disturbances of heart and vascular function, metabolism, memory and mood, which should be monitored very carefully during clinical trial. Copyright © 2011 Elsevier Inc. All rights reserved.
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              An established preadipose cell line and its differentiation in culture. II. Factors affecting the adipose conversion.

              When cells of the established preadipose line 3T3-L1 enter a resting state, they accumulate triglyceride and convert to adipose cells. The adipose conversion is brought about by a large increase in the rate of triglyceride synthesis, as measured by the incorporation rate of labeled palmitate, acetate, and glucose. In a resting 3T3 subline which dose not undergo the adipose conversion, the rate of triglyceride synthesis from these precursors is very low, and similar to that of growing 3T3-L1 cells, before their adipose conversion begins. If 3T3-L1 cells incorporate bromodeoxyuridine during growth, triglyceride synthesis does not increase when the cells reach a stationary state, and triglycerides do not accumulate. As would be expected from their known actions on tissue adipose cells, lipogenic and lipolytic hormones and drugs affect the rate of synthesis and accumulation of triglyceride by 3T3-L1 cells, but in contrast to bromodeoxyuridine, these modulating agents do not seem to affect the proportion of cells which undergoes the adipose conversion. Insulin markedly increases the rate of synthesis and accumulation of triglyceride by fatty 3T3-L1 cells, and produces a related increase in cell protein content. Of 20 randomly selected clones isolated from the original 3T3 stock, 19 are able to convert to adipose cells. The probability of such a conversion varies greatly among the different clones, in most cases being much lower than for 3T3-L1; but once the conversion takes place, the adipose cells produced from all of the 19 clones appear similar. The adipose conversion would seem to depend on an on-off switch, which is on with a different probability in different clones. This probability is quasistably inherited by the clonal progeny.
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                Author and article information

                Journal
                Investigative Opthalmology & Visual Science
                Invest. Ophthalmol. Vis. Sci.
                Association for Research in Vision and Ophthalmology (ARVO)
                1552-5783
                September 04 2018
                September 05 2018
                : 59
                : 11
                : 4477
                Affiliations
                [1 ]Department of Ophthalmology, Severance Hospital, Institute of Vision Research, Yonsei University College of Medicine, Seoul, Korea
                [2 ]Department of Endocrinology, Severance Hospital, Institute of Endocrine Research, Yonsei University College of Medicine, Seoul, Korea
                Article
                10.1167/iovs.18-24509
                30193323
                e73dbf68-87a7-4f24-aceb-371f06cd90eb
                © 2018

                http://creativecommons.org/licenses/by-nc-nd/4.0/

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