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      Pharmacological modulation of autophagy: therapeutic potential and persisting obstacles

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      Nature Reviews Drug Discovery

      Springer Nature

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          Abstract

          Dysregulated autography is associated with a variety of conditions, including cancer, neurodegenerative diseases, cardiovascular disorders and infectious diseases. However, despite significant efforts, no specific modulators of autophagy have yet been moved into the clinic. Here, Galluzzi et al. discuss the therapeutic potential of autophagy modulators and consider the key challenges that have limited their development.

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          Most cited references 290

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          mTOR signaling in growth control and disease.

          The mechanistic target of rapamycin (mTOR) signaling pathway senses and integrates a variety of environmental cues to regulate organismal growth and homeostasis. The pathway regulates many major cellular processes and is implicated in an increasing number of pathological conditions, including cancer, obesity, type 2 diabetes, and neurodegeneration. Here, we review recent advances in our understanding of the mTOR pathway and its role in health, disease, and aging. We further discuss pharmacological approaches to treat human pathologies linked to mTOR deregulation. Copyright © 2012 Elsevier Inc. All rights reserved.
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            Guidelines for the use and interpretation of assays for monitoring autophagy (3rd edition).

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              Resveratrol improves health and survival of mice on a high-calorie diet.

              Resveratrol (3,5,4'-trihydroxystilbene) extends the lifespan of diverse species including Saccharomyces cerevisiae, Caenorhabditis elegans and Drosophila melanogaster. In these organisms, lifespan extension is dependent on Sir2, a conserved deacetylase proposed to underlie the beneficial effects of caloric restriction. Here we show that resveratrol shifts the physiology of middle-aged mice on a high-calorie diet towards that of mice on a standard diet and significantly increases their survival. Resveratrol produces changes associated with longer lifespan, including increased insulin sensitivity, reduced insulin-like growth factor-1 (IGF-I) levels, increased AMP-activated protein kinase (AMPK) and peroxisome proliferator-activated receptor-gamma coactivator 1alpha (PGC-1alpha) activity, increased mitochondrial number, and improved motor function. Parametric analysis of gene set enrichment revealed that resveratrol opposed the effects of the high-calorie diet in 144 out of 153 significantly altered pathways. These data show that improving general health in mammals using small molecules is an attainable goal, and point to new approaches for treating obesity-related disorders and diseases of ageing.
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                Author and article information

                Journal
                Nature Reviews Drug Discovery
                Nat Rev Drug Discov
                Springer Nature
                1474-1776
                1474-1784
                May 19 2017
                May 19 2017
                :
                :
                Article
                10.1038/nrd.2017.22
                28529316
                © 2017
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