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      Autophagy Modulators: Mechanistic Aspects and Drug Delivery Systems

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          Abstract

          Autophagy modulation is considered to be a promising programmed cell death mechanism to prevent and cure a great number of disorders and diseases. The crucial step in designing an effective therapeutic approach is to understand the correct and accurate causes of diseases and to understand whether autophagy plays a cytoprotective or cytotoxic/cytostatic role in the progression and prevention of disease. This knowledge will help scientists find approaches to manipulate tumor and pathologic cells in order to enhance cellular sensitivity to therapeutics and treat them. Although some conventional therapeutics suffer from poor solubility, bioavailability and controlled release mechanisms, it appears that novel nanoplatforms overcome these obstacles and have led to the design of a theranostic-controlled drug release system with high solubility and active targeting and stimuli-responsive potentials. In this review, we discuss autophagy modulators-related signaling pathways and some of the drug delivery strategies that have been applied to the field of therapeutic application of autophagy modulators. Moreover, we describe how therapeutics will target various steps of the autophagic machinery. Furthermore, nano drug delivery platforms for autophagy targeting and co-delivery of autophagy modulators with chemotherapeutics/siRNA, are also discussed.

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          Analysis of nanoparticle delivery to tumours

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            AMP-activated protein kinase induces a p53-dependent metabolic checkpoint.

            Replicative cell division is an energetically demanding process that can be executed only if cells have sufficient metabolic resources to support a doubling of cell mass. Here we show that proliferating mammalian cells have a cell-cycle checkpoint that responds to glucose availability. The glucose-dependent checkpoint occurs at the G(1)/S boundary and is regulated by AMP-activated protein kinase (AMPK). This cell-cycle arrest occurs despite continued amino acid availability and active mTOR. AMPK activation induces phosphorylation of p53 on serine 15, and this phosphorylation is required to initiate AMPK-dependent cell-cycle arrest. AMPK-induced p53 activation promotes cellular survival in response to glucose deprivation, and cells that have undergone a p53-dependent metabolic arrest can rapidly reenter the cell cycle upon glucose restoration. However, persistent activation of AMPK leads to accelerated p53-dependent cellular senescence. Thus, AMPK is a cell-intrinsic regulator of the cell cycle that coordinates cellular proliferation with carbon source availability.
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              Dual role of 3-methyladenine in modulation of autophagy via different temporal patterns of inhibition on class I and III phosphoinositide 3-kinase.

              A group of phosphoinositide 3-kinase (PI3K) inhibitors, such as 3-methyladenine (3-MA) and wortmannin, have been widely used as autophagy inhibitors based on their inhibitory effect on class III PI3K activity, which is known to be essential for induction of autophagy. In this study, we systematically examined and compared the effects of these two inhibitors on autophagy under both nutrient-rich and deprivation conditions. To our surprise, 3-MA is found to promote autophagy flux when treated under nutrient-rich conditions with a prolonged period of treatment, whereas it is still capable of suppressing starvation-induced autophagy. We first observed that there are marked increases of the autophagic markers in cells treated with 3-MA in full medium for a prolonged period of time (up to 9 h). Second, we provide convincing evidence that the increase of autophagic markers is the result of enhanced autophagic flux, not due to suppression of maturation of autophagosomes or lysosomal function. More importantly, we found that the autophagy promotion activity of 3-MA is due to its differential temporal effects on class I and class III PI3K; 3-MA blocks class I PI3K persistently, whereas its suppressive effect on class III PI3K is transient. Because 3-MA has been widely used as an autophagy inhibitor in the literature, understanding the dual role of 3-MA in autophagy thus suggests that caution should be exercised in the application of 3-MA in autophagy study.
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                Author and article information

                Journal
                Biomolecules
                Biomolecules
                biomolecules
                Biomolecules
                MDPI
                2218-273X
                25 September 2019
                October 2019
                : 9
                : 10
                : 530
                Affiliations
                [1 ]Cellular and Molecular Research Center, Iran University of Medical Sciences, Tehran P.O. Box 1449614525, Iran; shima.tavakol@ 123456yahoo.com
                [2 ]Department of basic science, Faculty of Veterinary Medicine, University of Tabriz, Tabriz 1455742, Iran; dvm.milad73@ 123456yahoo.com
                [3 ]Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117597, Singapore; phsdes@ 123456nus.edu.sg (S.D.); phsyapc@ 123456nus.edu.sg (C.T.Y.)
                [4 ]Department of Biology, Science and Research Branch, Islamic Azad University, Tehran 1477893855, Iran; azarian.maryam@ 123456gmail.com
                [5 ]Departament de Bioquímica i Biologia Molecular, Institut de Biotecnologia i Biomedicina (IBB), Universitat Autónoma de Barcelona, 08193 Barcelona, Spain
                [6 ]Department of Hepatitis and AIDS, Pasteur Institute of Iran, Tehran 1316943551, Iran; asghar.abdoli7@ 123456gmail.com
                [7 ]Department of Molecular Genetics, Faculty of Biological Sciences, Tarbiat Modares University, Tehran 14115-111, Iran; motavaf.m@ 123456gmail.com
                [8 ]Department of Medical Nanotechnology, Faculty of Advanced Sciences & Technology, Pharmaceutical Sciences Branch, Islamic Azad University, (IAUPS), Tehran P.O. Box 1916893813, Iran; parand.pdrm@ 123456yahoo.com
                [9 ]Medical Physics Department, School of Medicine, Ahvaz Jundishapur University of Medical Sciences, Ahvaz 61357-15794, Iran; khanbabaie.mph@ 123456gmail.com
                [10 ]Neuroscience Research Center, Institute of Neuropharmacology, Kerman University of Medical Sciences, Kerman P.O. Box 7616911319, Iran; elham_gh_afshar@ 123456yahoo.com (E.G.A.); alimandegary@ 123456yahoo.com (A.M.); drpardakhti@ 123456yahoo.com (A.P.)
                [11 ]Pharmaceutics Research Center, Institute of Neuropharmacology, Kerman University of Medical Sciences, Kerman P.O. Box 1355576169, Iran
                [12 ]Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117 600, Singapore
                [13 ]Cancer Science Institute of Singapore, National University of Singapore, Singapore 1192288, Singapore
                Author notes
                [†]

                These authors contributed equally to this work.

                Author information
                https://orcid.org/0000-0001-6605-822X
                https://orcid.org/0000-0003-1669-4775
                https://orcid.org/0000-0002-4442-9605
                https://orcid.org/0000-0002-1065-9349
                https://orcid.org/0000-0002-1848-5961
                https://orcid.org/0000-0002-3754-5712
                Article
                biomolecules-09-00530
                10.3390/biom9100530
                6843293
                31557936
                e10e2694-5d36-468e-993d-291624379a9b
                © 2019 by the authors.

                Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

                History
                : 18 August 2019
                : 18 September 2019
                Categories
                Review

                autophagy,mtor,ampk,nanocarriers,combination therapy,cancer,sirna
                autophagy, mtor, ampk, nanocarriers, combination therapy, cancer, sirna

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