A Comprehensive Review of Autophagy and Its Various Roles in Infectious, Non-Infectious, and Lifestyle Diseases: Current Knowledge and Prospects for Disease Prevention, Novel Drug Design, and Therapy
Identifieur interne : 000A71 ( Pmc/Checkpoint ); précédent : 000A70; suivant : 000A72A Comprehensive Review of Autophagy and Its Various Roles in Infectious, Non-Infectious, and Lifestyle Diseases: Current Knowledge and Prospects for Disease Prevention, Novel Drug Design, and Therapy
Auteurs : Rekha Khandia [Inde] ; Maryam Dadar [Iran] ; Ashok Munjal [Inde] ; Kuldeep Dhama [Inde] ; Kumaragurubaran Karthik [Inde] ; Ruchi Tiwari [Inde] ; Mohd. Iqbal Yatoo [Inde] ; Hafiz M. N. Iqbal [Mexique] ; Karam Pal Singh [Inde] ; Sunil K. Joshi [États-Unis] ; Wanpen Chaicumpa [Thaïlande]Source :
- Cells [ 2073-4409 ] ; 2019.
Abstract
Autophagy (self-eating) is a conserved cellular degradation process that plays important roles in maintaining homeostasis and preventing nutritional, metabolic, and infection-mediated stresses. Autophagy dysfunction can have various pathological consequences, including tumor progression, pathogen hyper-virulence, and neurodegeneration. This review describes the mechanisms of autophagy and its associations with other cell death mechanisms, including apoptosis, necrosis, necroptosis, and autosis. Autophagy has both positive and negative roles in infection, cancer, neural development, metabolism, cardiovascular health, immunity, and iron homeostasis. Genetic defects in autophagy can have pathological consequences, such as static childhood encephalopathy with neurodegeneration in adulthood, Crohn’s disease, hereditary spastic paraparesis, Danon disease, X-linked myopathy with excessive autophagy, and sporadic inclusion body myositis. Further studies on the process of autophagy in different microbial infections could help to design and develop novel therapeutic strategies against important pathogenic microbes. This review on the progress and prospects of autophagy research describes various activators and suppressors, which could be used to design novel intervention strategies against numerous diseases and develop therapeutic drugs to protect human and animal health.
Url:
DOI: 10.3390/cells8070674
PubMed: 31277291
PubMed Central: 6678135
Affiliations:
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PMC:6678135Le document en format XML
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<author><name sortKey="Iqbal, Hafiz M N" sort="Iqbal, Hafiz M N" uniqKey="Iqbal H" first="Hafiz M. N." last="Iqbal">Hafiz M. N. Iqbal</name>
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<author><name sortKey="Dadar, Maryam" sort="Dadar, Maryam" uniqKey="Dadar M" first="Maryam" last="Dadar">Maryam Dadar</name>
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<author><name sortKey="Karthik, Kumaragurubaran" sort="Karthik, Kumaragurubaran" uniqKey="Karthik K" first="Kumaragurubaran" last="Karthik">Kumaragurubaran Karthik</name>
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<author><name sortKey="Tiwari, Ruchi" sort="Tiwari, Ruchi" uniqKey="Tiwari R" first="Ruchi" last="Tiwari">Ruchi Tiwari</name>
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<author><name sortKey="Yatoo, Mohd Iqbal" sort="Yatoo, Mohd Iqbal" uniqKey="Yatoo M" first="Mohd. Iqbal" last="Yatoo">Mohd. Iqbal Yatoo</name>
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<author><name sortKey="Iqbal, Hafiz M N" sort="Iqbal, Hafiz M N" uniqKey="Iqbal H" first="Hafiz M. N." last="Iqbal">Hafiz M. N. Iqbal</name>
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<country xml:lang="fr">Mexique</country>
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<author><name sortKey="Singh, Karam Pal" sort="Singh, Karam Pal" uniqKey="Singh K" first="Karam Pal" last="Singh">Karam Pal Singh</name>
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<author><name sortKey="Joshi, Sunil K" sort="Joshi, Sunil K" uniqKey="Joshi S" first="Sunil K." last="Joshi">Sunil K. Joshi</name>
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<author><name sortKey="Chaicumpa, Wanpen" sort="Chaicumpa, Wanpen" uniqKey="Chaicumpa W" first="Wanpen" last="Chaicumpa">Wanpen Chaicumpa</name>
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<front><div type="abstract" xml:lang="en"><p>Autophagy (self-eating) is a conserved cellular degradation process that plays important roles in maintaining homeostasis and preventing nutritional, metabolic, and infection-mediated stresses. Autophagy dysfunction can have various pathological consequences, including tumor progression, pathogen hyper-virulence, and neurodegeneration. This review describes the mechanisms of autophagy and its associations with other cell death mechanisms, including apoptosis, necrosis, necroptosis, and autosis. Autophagy has both positive and negative roles in infection, cancer, neural development, metabolism, cardiovascular health, immunity, and iron homeostasis. Genetic defects in autophagy can have pathological consequences, such as static childhood encephalopathy with neurodegeneration in adulthood, Crohn’s disease, hereditary spastic paraparesis, Danon disease, X-linked myopathy with excessive autophagy, and sporadic inclusion body myositis. Further studies on the process of autophagy in different microbial infections could help to design and develop novel therapeutic strategies against important pathogenic microbes. This review on the progress and prospects of autophagy research describes various activators and suppressors, which could be used to design novel intervention strategies against numerous diseases and develop therapeutic drugs to protect human and animal health.</p>
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<pmc article-type="review-article"><pmc-dir>properties open_access</pmc-dir>
<front><journal-meta><journal-id journal-id-type="nlm-ta">Cells</journal-id>
<journal-id journal-id-type="iso-abbrev">Cells</journal-id>
<journal-id journal-id-type="publisher-id">cells</journal-id>
<journal-title-group><journal-title>Cells</journal-title>
</journal-title-group>
<issn pub-type="epub">2073-4409</issn>
<publisher><publisher-name>MDPI</publisher-name>
</publisher>
</journal-meta>
<article-meta><article-id pub-id-type="pmid">31277291</article-id>
<article-id pub-id-type="pmc">6678135</article-id>
<article-id pub-id-type="doi">10.3390/cells8070674</article-id>
<article-id pub-id-type="publisher-id">cells-08-00674</article-id>
<article-categories><subj-group subj-group-type="heading"><subject>Review</subject>
</subj-group>
</article-categories>
<title-group><article-title>A Comprehensive Review of Autophagy and Its Various Roles in Infectious, Non-Infectious, and Lifestyle Diseases: Current Knowledge and Prospects for Disease Prevention, Novel Drug Design, and Therapy</article-title>
</title-group>
<contrib-group><contrib contrib-type="author"><name><surname>Khandia</surname>
<given-names>Rekha</given-names>
</name>
<xref ref-type="aff" rid="af1-cells-08-00674">1</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Dadar</surname>
<given-names>Maryam</given-names>
</name>
<xref ref-type="aff" rid="af2-cells-08-00674">2</xref>
</contrib>
<contrib contrib-type="author"><contrib-id contrib-id-type="orcid" authenticated="true">https://orcid.org/0000-0001-6294-1584</contrib-id>
<name><surname>Munjal</surname>
<given-names>Ashok</given-names>
</name>
<xref ref-type="aff" rid="af1-cells-08-00674">1</xref>
<xref rid="c1-cells-08-00674" ref-type="corresp">*</xref>
</contrib>
<contrib contrib-type="author"><contrib-id contrib-id-type="orcid" authenticated="true">https://orcid.org/0000-0001-7469-4752</contrib-id>
<name><surname>Dhama</surname>
<given-names>Kuldeep</given-names>
</name>
<xref ref-type="aff" rid="af3-cells-08-00674">3</xref>
<xref rid="c1-cells-08-00674" ref-type="corresp">*</xref>
</contrib>
<contrib contrib-type="author"><contrib-id contrib-id-type="orcid" authenticated="true">https://orcid.org/0000-0002-9215-6306</contrib-id>
<name><surname>Karthik</surname>
<given-names>Kumaragurubaran</given-names>
</name>
<xref ref-type="aff" rid="af4-cells-08-00674">4</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Tiwari</surname>
<given-names>Ruchi</given-names>
</name>
<xref ref-type="aff" rid="af5-cells-08-00674">5</xref>
</contrib>
<contrib contrib-type="author"><contrib-id contrib-id-type="orcid" authenticated="true">https://orcid.org/0000-0002-4501-7354</contrib-id>
<name><surname>Yatoo</surname>
<given-names>Mohd. Iqbal</given-names>
</name>
<xref ref-type="aff" rid="af6-cells-08-00674">6</xref>
</contrib>
<contrib contrib-type="author"><contrib-id contrib-id-type="orcid" authenticated="true">https://orcid.org/0000-0003-4855-2720</contrib-id>
<name><surname>Iqbal</surname>
<given-names>Hafiz M.N.</given-names>
</name>
<xref ref-type="aff" rid="af7-cells-08-00674">7</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Singh</surname>
<given-names>Karam Pal</given-names>
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<xref ref-type="aff" rid="af3-cells-08-00674">3</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Joshi</surname>
<given-names>Sunil K.</given-names>
</name>
<xref ref-type="aff" rid="af8-cells-08-00674">8</xref>
<xref rid="c1-cells-08-00674" ref-type="corresp">*</xref>
</contrib>
<contrib contrib-type="author"><contrib-id contrib-id-type="orcid" authenticated="true">https://orcid.org/0000-0001-6973-8255</contrib-id>
<name><surname>Chaicumpa</surname>
<given-names>Wanpen</given-names>
</name>
<xref ref-type="aff" rid="af9-cells-08-00674">9</xref>
</contrib>
</contrib-group>
<aff id="af1-cells-08-00674"><label>1</label>
Department of Genetics, Barkatullah University, Bhopal 462 026, Madhya Pradesh, India</aff>
<aff id="af2-cells-08-00674"><label>2</label>
Razi Vaccine and Serum Research Institute, Agricultural Research, Education and Extension Organization (AREEO), Karaj 31975/148, Iran</aff>
<aff id="af3-cells-08-00674"><label>3</label>
Division of Pathology, ICAR-Indian Veterinary Research Institute, Izatnagar, Bareilly 243 122, Uttar Pradesh, India</aff>
<aff id="af4-cells-08-00674"><label>4</label>
Central University Laboratory, Tamil Nadu Veterinary and Animal Sciences University, Madhavaram Milk Colony, Chennai, Tamil Nadu 600051, India</aff>
<aff id="af5-cells-08-00674"><label>5</label>
Department of Veterinary Microbiology and Immunology, College of Veterinary Sciences, UP Pandit Deen Dayal Upadhayay Pashu Chikitsa Vigyan Vishwavidyalay Evum Go-Anusandhan Sansthan (DUVASU), Mathura, Uttar Pradesh 281 001, India</aff>
<aff id="af6-cells-08-00674"><label>6</label>
Sher-E-Kashmir University of Agricultural Sciences and Technology of Kashmir, Shalimar, Srinagar 190025, Jammu and Kashmir, India</aff>
<aff id="af7-cells-08-00674"><label>7</label>
Tecnologico de Monterrey, School of Engineering and Sciences, Campus Monterrey, Ave. Eugenio Garza Sada 2501, Monterrey, N. L., CP 64849, Mexico</aff>
<aff id="af8-cells-08-00674"><label>8</label>
Department of Pediatrics, Division of Hematology, Oncology and Bone Marrow Transplantation, University of Miami School of Medicine, Miami, FL 33136, USA</aff>
<aff id="af9-cells-08-00674"><label>9</label>
Center of Research Excellence on Therapeutic Proteins and Antibody Engineering, Department of Parasitology, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok 10700, Thailand</aff>
<author-notes><corresp id="c1-cells-08-00674"><label>*</label>
Correspondence: <email>ak.munjal@bubhopal.ac.in</email>
(A.M.); <email>kdhama@rediffmail.com</email>
(K.D.); <email>sunil.joshi@med.miami.edu</email>
(S.K.J.)</corresp>
</author-notes>
<pub-date pub-type="epub"><day>03</day>
<month>7</month>
<year>2019</year>
</pub-date>
<pub-date pub-type="collection"><month>7</month>
<year>2019</year>
</pub-date>
<volume>8</volume>
<issue>7</issue>
<elocation-id>674</elocation-id>
<history><date date-type="received"><day>01</day>
<month>4</month>
<year>2019</year>
</date>
<date date-type="accepted"><day>04</day>
<month>6</month>
<year>2019</year>
</date>
</history>
<permissions><copyright-statement>© 2019 by the authors.</copyright-statement>
<copyright-year>2019</copyright-year>
<license license-type="open-access"><license-p>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 (<ext-link ext-link-type="uri" xlink:href="http://creativecommons.org/licenses/by/4.0/">http://creativecommons.org/licenses/by/4.0/</ext-link>
).</license-p>
</license>
</permissions>
<abstract><p>Autophagy (self-eating) is a conserved cellular degradation process that plays important roles in maintaining homeostasis and preventing nutritional, metabolic, and infection-mediated stresses. Autophagy dysfunction can have various pathological consequences, including tumor progression, pathogen hyper-virulence, and neurodegeneration. This review describes the mechanisms of autophagy and its associations with other cell death mechanisms, including apoptosis, necrosis, necroptosis, and autosis. Autophagy has both positive and negative roles in infection, cancer, neural development, metabolism, cardiovascular health, immunity, and iron homeostasis. Genetic defects in autophagy can have pathological consequences, such as static childhood encephalopathy with neurodegeneration in adulthood, Crohn’s disease, hereditary spastic paraparesis, Danon disease, X-linked myopathy with excessive autophagy, and sporadic inclusion body myositis. Further studies on the process of autophagy in different microbial infections could help to design and develop novel therapeutic strategies against important pathogenic microbes. This review on the progress and prospects of autophagy research describes various activators and suppressors, which could be used to design novel intervention strategies against numerous diseases and develop therapeutic drugs to protect human and animal health.</p>
</abstract>
<kwd-group><kwd>autophagy mechanism</kwd>
<kwd>autophagy-associated diseases</kwd>
<kwd>macroautophagy</kwd>
<kwd>chaperone-mediated autophagy</kwd>
<kwd>apoptosis</kwd>
<kwd>necroptosis</kwd>
<kwd>necrosis</kwd>
<kwd>iron homeostasis</kwd>
<kwd>autophagy inhibition</kwd>
<kwd>AKT/mTOR signaling pathway</kwd>
<kwd>autosis</kwd>
</kwd-group>
</article-meta>
</front>
<floats-group><fig id="cells-08-00674-f001" orientation="portrait" position="float"><label>Figure 1</label>
<caption><p>Different types of autophagy. Macroautophagy, microautophagy, and chaperone-mediated autophagy.</p>
</caption>
<graphic xlink:href="cells-08-00674-g001"></graphic>
</fig>
<fig id="cells-08-00674-f002" orientation="portrait" position="float"><label>Figure 2</label>
<caption><p>In chaperone-mediated autophagy (CMA), (<bold>1</bold>
) KFERQ motif that is present in 30% of soluble cytosolic proteins (<bold>2</bold>
) is recognized by cytosolic chaperone protein HSPA8/HSC70, which is present in a complex with other chaperone proteins. (<bold>3</bold>
) Such recognized proteins bound to lysosomal receptor protein LAMP-2A. (<bold>4</bold>
) Binding of the substrate with the LAMP-2A leads to oligomerization of receptors. (<bold>5</bold>
) With the help of HSP90, the substrate is then unfolded and translocated through LAMP-2A-enriched translocation complex. (<bold>6</bold>
) After reaching inside the lysosomes, the proteins are degraded (<bold>7</bold>
), and the LAMP-2A receptors are disassembled.</p>
</caption>
<graphic xlink:href="cells-08-00674-g002"></graphic>
</fig>
<fig id="cells-08-00674-f003" orientation="portrait" position="float"><label>Figure 3</label>
<caption><p>Process of autophagosome formation. (<bold>1</bold>
) Autophagy is inhibited by mTOR. (<bold>2</bold>
) Various kinds of stress (hypoxia, oxidative stress, pathogen infection, endoplasmic reticulum stress or nutrient starvation conditions) inhibit mTOR, and the process of autophagy is initiated. (<bold>3</bold>
) Assembly of ULK complex occurs, and the complex includes ULK-1, autophagy-related protein 13 (Atg13), Atg101 and FAK-<bold>F</bold>
amily <bold>I</bold>
nteracting <bold>P</bold>
rotein (FIP200). (<bold>4</bold>
) The complex phosphorylates AMBRA1. (<bold>5</bold>
) AMBRA1 activates PI3K complex encompassing Atg15, vacuolar protein sorting 15 (VPS15), VPS34, Beclin-1 and AMBRA1 which helps in nucleation. (<bold>6</bold>
) Atg5-Atg12-Atg16 complex is recruited to phagophore and prevent premature fusion of vesicle to the lysosome. (<bold>7</bold>
) LC3 is conjugated with PE by the ubiquitin-like system and (<bold>8</bold>
) transformed into LC3-II with the help of Atg4, Atg7, and Atg3. (<bold>9</bold>
) LC3-II is present on both the inner and outer surfaces of the autophagosome. (<bold>10</bold>
) Atg 9 further elongates the membrane and forms intraluminal vesicles; also required for local acidification. (<bold>11</bold>
) Atg5-Atg12-Atg16 complex is dissociated from the complete autophagosome (<bold>12</bold>
).</p>
</caption>
<graphic xlink:href="cells-08-00674-g003"></graphic>
</fig>
<fig id="cells-08-00674-f004" orientation="portrait" position="float"><label>Figure 4</label>
<caption><p>Anti-bacterial role of autophagy. (<bold>1</bold>
) Bcl-xL regulates the autophagy, and in Bcl-xL knockout cells, <italic>Streptococcus pyogenes</italic>
infection is promoted. (<bold>2</bold>
) <italic>Shigella flexneri</italic>
invasion in non-phagocytic cells is dependent upon the type-III secretion system (T3SS) effector proteins. Following internalization nucleotide-binding oligomerization domain (NOD)-like receptors (NLRs) detect bacterial peptidoglycans and trigger pro-inflammatory immune response. Bacterial sensing inside the cell either by NLRs or sequestosome-1-like receptors (SLRs) recruits autophagy proteins including unc-51-like kinase (ULK) 1/2 with lipid kinase complexed with Beclin 1 and Atg16L1 to initiate membrane nucleation of the phagophore to engulf invading bacteria. (<bold>3</bold>
) Group A <italic>Streptococcus</italic>
species inhibits autophagy directly by suppressing the fusion of autophagosomes. (<bold>4</bold>
) <italic>Bacillus amyloliquefaciens</italic>
was found to stimulate autophagy by elevating the expression of Beclin 1 and Atg5-Atg12-Atg16 complex.</p>
</caption>
<graphic xlink:href="cells-08-00674-g004"></graphic>
</fig>
<fig id="cells-08-00674-f005" orientation="portrait" position="float"><label>Figure 5</label>
<caption><p>Proviral and anti-viral actions of autophagy.</p>
</caption>
<graphic xlink:href="cells-08-00674-g005"></graphic>
</fig>
<fig id="cells-08-00674-f006" orientation="portrait" position="float"><label>Figure 6</label>
<caption><p>Autophagy in tumor suppression. (<bold>1</bold>
) The Atg5- or Atg7-deficient mice showed liver tumors, indicating that defective autophagy can affect the suppression of tumorigenesis. (<bold>2</bold>
) Beclin 1 inhibits the growth of tumor in cell lines such as the breast cancer cell line, MCF-7, in which the expression of Beclin 1 was lower than in normal epithelial breast cells. (<bold>3</bold>
) UVRAG protein could suppress tumorigenicity and proliferation of colon cancer cells in humans. (<bold>4</bold>
) mTOR is implicated in cancer and its substrates include the eukaryotic initiation factor 4E (eIF4E)-binding proteins (4E-BPs) and the ribosomal S6 kinases (S6Ks) 1 and 2, which promote cell cycle progression. The mTOR, which is inhibited by rapamycin, induces autophagy. (<bold>5</bold>
) A novel anti-cancer molecule, HA15, which targets HSPA5/BIP was shown to induce endoplasmic reticulum stress and increase the unfolded protein response, resulting in cancer cell death through autophagy and apoptosis.</p>
</caption>
<graphic xlink:href="cells-08-00674-g006"></graphic>
</fig>
<fig id="cells-08-00674-f007" orientation="portrait" position="float"><label>Figure 7</label>
<caption><p>Compounds that inhibit and activate autophagy. Autophagy inhibitors: 3-methyladenine inhibits PI3K. Bafilomycin A1 causes dissociation of the Beclin 1-Vps34 complex and prevents the formation of autolysosome. Chloroquine/hydroxychloroquine, NH<sub>4</sub>
Cl, and leupeptin rapidly neutralizing the acidic environment of the lysosome and are used to block lysosomal degradation of substrates. Leupeptin inhibits cysteine, serine and threonine peptidases, and hence blocking protein degradation at the last step of autophagy. Autophagy activators: rapamycin inhibits the mTOR. RAD001 and AP23573 are rapamycin derivatives having comparatively higher safely with minimum dose toxicities. Trehalose causes LC3-I to LC3-II conversion in an mTOR-independent pathway. Valproic acid increases LC3-II and Beclin 1 concentrations.</p>
</caption>
<graphic xlink:href="cells-08-00674-g007"></graphic>
</fig>
<table-wrap id="cells-08-00674-t001" orientation="portrait" position="float"><object-id pub-id-type="pii">cells-08-00674-t001_Table 1</object-id>
<label>Table 1</label>
<caption><p>Potential role of autophagy in ameliorating/deteriorating diseases and homeostasis.</p>
</caption>
<table frame="hsides" rules="groups"><thead><tr><th align="center" valign="middle" style="border-top:solid thin;border-bottom:solid thin" rowspan="1" colspan="1">S. No.</th>
<th align="center" valign="middle" style="border-top:solid thin;border-bottom:solid thin" rowspan="1" colspan="1">Activity Associated with Autophagy</th>
<th align="center" valign="middle" style="border-top:solid thin;border-bottom:solid thin" rowspan="1" colspan="1">Effect of Autophagy</th>
<th align="center" valign="middle" style="border-top:solid thin;border-bottom:solid thin" rowspan="1" colspan="1">Modus Operandi of Related Activity and Example/Proof of Concept</th>
<th align="center" valign="middle" style="border-top:solid thin;border-bottom:solid thin" rowspan="1" colspan="1">Reference(s)</th>
</tr>
</thead>
<tbody><tr><td rowspan="28" align="center" valign="middle" style="border-bottom:solid thin" colspan="1">1</td>
<td rowspan="28" align="center" valign="middle" style="border-bottom:solid thin" colspan="1">Viral infection</td>
<td rowspan="8" align="center" valign="middle" style="border-bottom:solid thin" colspan="1">Anti-viral activity</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Endogenous viral antigen presentation on MHC class-1 in Herpes simplex virus type 1 (HSV-1) infection</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">English et al., 2009 [<xref rid="B236-cells-08-00674" ref-type="bibr">236</xref>
]</td>
</tr>
<tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Delivery of viral antigens to Toll-like receptors (TLRs)- in Vesicular stomatitis virus (VSV) infection; Pattern recognition receptor Toll-7 mediated PI3K-Akt-signaling </td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Shelly et al., 2009 [<xref rid="B239-cells-08-00674" ref-type="bibr">239</xref>
], Nakamoto et al., 2012 [<xref rid="B240-cells-08-00674" ref-type="bibr">240</xref>
]</td>
</tr>
<tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Sirtuin 1, a NAD(+)-dependent deacetylase mediated dendritic cell and autophagy induction - Respiratory syncytial virus (RSV)</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Owczarczyk et al., 2015 [<xref rid="B242-cells-08-00674" ref-type="bibr">242</xref>
]</td>
</tr>
<tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Autophagy by salicylamide derivates- anti-viral activity against - Cytopathic bovine viral diarrhea virus (cp-BVDV) flavivirus</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Needs et al., 2016 [<xref rid="B243-cells-08-00674" ref-type="bibr">243</xref>
]</td>
</tr>
<tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Inhibition of Sindbis virus replication by overexpression of Beclin 1</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Liang et al., 1998 [<xref rid="B176-cells-08-00674" ref-type="bibr">176</xref>
]</td>
</tr>
<tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Enhanced autophagy by 1α,25-dihydroxycholecalciferol reduces HIV replication</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Campbell and Spector, 2012 [<xref rid="B220-cells-08-00674" ref-type="bibr">220</xref>
]</td>
</tr>
<tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">During foot and mouth disease virus infection, Atg5-Atg12 enhances NF-κB and IRF3 pathways</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Fan et al., 2017 [<xref rid="B244-cells-08-00674" ref-type="bibr">244</xref>
]</td>
</tr>
<tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Targeting glycoproteins E1 and E2 and non-structural proteins of Chikungunya virus (CHKV) </td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Subudhi et al., 2018 [<xref rid="B397-cells-08-00674" ref-type="bibr">397</xref>
]</td>
</tr>
<tr><td rowspan="20" align="center" valign="middle" style="border-bottom:solid thin" colspan="1">Pro-viral activity</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Rapamycin, chloroquine and small interfering RNAs target Atg5 and Beclin 1- virus production is hampered in New Castle disease virus (NCDV)</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Sun et al., 2014 [<xref rid="B259-cells-08-00674" ref-type="bibr">259</xref>
]</td>
</tr>
<tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Induction of early stages of autophagy and inhibition of later destructive stages – to conquer suppression of new virion production- HIV</td>
<td rowspan="2" align="center" valign="middle" style="border-bottom:solid thin" colspan="1">Kyei et al., 2009 [<xref rid="B261-cells-08-00674" ref-type="bibr">261</xref>
]</td>
</tr>
<tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Nef-mediated inhibition of maturation of autophagosome- HIV </td>
</tr>
<tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">NS4A-induced autophagy in epithelial cells induces virus replication – Flavivirus</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">McLean et al., 2011 [<xref rid="B269-cells-08-00674" ref-type="bibr">269</xref>
]</td>
</tr>
<tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Limitation of autophagosomal by 3-methyladenine or small-interfering RNAs- diminished replication of virus- FMDV</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">O’Donnell et al., 2011 [<xref rid="B272-cells-08-00674" ref-type="bibr">272</xref>
]</td>
</tr>
<tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Virus-induced autophagy-mediated impairment of innate immune response- Hepatitis C virus (HCV)</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Shrivastava et al., 2011 [<xref rid="B252-cells-08-00674" ref-type="bibr">252</xref>
]</td>
</tr>
<tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Diminished viral clearance by IFN-α /RBV-based antiviral therapy-HCV</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Dash et al., 2016 [<xref rid="B274-cells-08-00674" ref-type="bibr">274</xref>
]</td>
</tr>
<tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Inhibition of RLR-mediated type-I IFN-independent signaling resulting in antibody-dependent enhancement (ADE) of Dengue virus (DENV)</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Huang et al., 2016 [<xref rid="B275-cells-08-00674" ref-type="bibr">275</xref>
]</td>
</tr>
<tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Adenoviral infection may be privileged by autophagy via an increase in ATP; Atg12-Atg5 complex is significantly upregulated. </td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Jiang et al., 2008 [<xref rid="B277-cells-08-00674" ref-type="bibr">277</xref>
]</td>
</tr>
<tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Activation of the phosphatidylinositol 3 kinase/Akt/mTOR pathway and inhibition of autophagy- induce cellular entry of –Human Papilloma virus (HPV) type 16. </td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Surviladze et al., 2013 [<xref rid="B283-cells-08-00674" ref-type="bibr">283</xref>
]</td>
</tr>
<tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Replication of Infectious Spleen and Kidney Necrosis virus (ISKNV) is increased when autophagy is induced</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Li et al., 2017 [<xref rid="B246-cells-08-00674" ref-type="bibr">246</xref>
]</td>
</tr>
<tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Human nuclear ribonucleoprotein K (hnRNP-K) and ubiquilin 4 (UBQLN4) help in viral replication. NDP52 human autophagy receptor interacts with CHIKV nsP2 and acts as proviral factor</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Wong and Chu, 2018 [<xref rid="B37-cells-08-00674" ref-type="bibr">37</xref>
]</td>
</tr>
<tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Classical swine fever virus replication is negatively regulated through mTORC1</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Luo et al., 2018 [<xref rid="B33-cells-08-00674" ref-type="bibr">33</xref>
]</td>
</tr>
<tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Autophagosomal targeting of ribosomal proteins by influenza A virus (IAV)</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Becker et al., 2018 [<xref rid="B32-cells-08-00674" ref-type="bibr">32</xref>
]</td>
</tr>
<tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Autophagy of endothelial cells of umbilical vein by Zika virus (ZIKV) helps in replication</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Peng et al., 2018 [<xref rid="B35-cells-08-00674" ref-type="bibr">35</xref>
]</td>
</tr>
<tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Necrosis of cells through severe acute respiratory syndrome-coronavirus (SARS-CoV) open reading frame-3a for multiplication</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Yue et al., 2018 [<xref rid="B36-cells-08-00674" ref-type="bibr">36</xref>
]</td>
</tr>
<tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">ER stress by DENV infection helps in autophagy and replication, both in vitro and <italic>in vivo</italic>
</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Lee et al., 2018 [<xref rid="B38-cells-08-00674" ref-type="bibr">38</xref>
]</td>
</tr>
<tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Non-structural protein of virus affects mitochondrial membrane in Crimean-Congo Hemorrhagic fever causing apoptosis</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Barnwal et al., 2016 [<xref rid="B40-cells-08-00674" ref-type="bibr">40</xref>
]</td>
</tr>
<tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">MDA5 protein inhibition by paramyxovirus V proteins</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Mandhana et al., 2018 [<xref rid="B41-cells-08-00674" ref-type="bibr">41</xref>
]</td>
</tr>
<tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Altering nonstructural proteins of West Nile virus (WNV) affects LC3 modification and aggregation </td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Martín-Acebes et al., 2015 [<xref rid="B43-cells-08-00674" ref-type="bibr">43</xref>
]</td>
</tr>
<tr><td rowspan="10" align="center" valign="middle" style="border-bottom:solid thin" colspan="1">2</td>
<td rowspan="10" align="center" valign="middle" style="border-bottom:solid thin" colspan="1">Bacterial infection</td>
<td rowspan="4" align="center" valign="middle" style="border-bottom:solid thin" colspan="1">Anti-bacterial activity</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">In Bcl-xL knockout cells, <italic>Streptococcus pyogenes</italic>
infection is promoted </td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Nakajima et al., 2017 [<xref rid="B53-cells-08-00674" ref-type="bibr">53</xref>
]</td>
</tr>
<tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">NOD proteins interaction with Atg16L1 and initiation of anti-bacterial autophagosome biogenesis</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Sorbara et al., 2013 [<xref rid="B212-cells-08-00674" ref-type="bibr">212</xref>
]</td>
</tr>
<tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Protection from <italic>Caenorhabditis elegans</italic>
infection by transcription factor HLH-30/TFEB-mediated autophagy</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Chen et al., 2017 [<xref rid="B215-cells-08-00674" ref-type="bibr">215</xref>
]</td>
</tr>
<tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Inhibition of <italic>Mycobacterium tuberculosis</italic>
in human macrophages by SMAD specific E3 ubiquitin protein ligase 1 (SMURF1)</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Franco et al., 2017 [<xref rid="B398-cells-08-00674" ref-type="bibr">398</xref>
]</td>
</tr>
<tr><td rowspan="6" align="center" valign="middle" style="border-bottom:solid thin" colspan="1">Pro-bacterial activity</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Effector Ats-1 is used to enhance autophagosomes formation containing LC3, Beclin 1, Atg8 and Atg6, without lysosomal marker by <italic>Anaplasma phagocytophilum</italic>
</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Niu et al., 2012 [<xref rid="B222-cells-08-00674" ref-type="bibr">222</xref>
]</td>
</tr>
<tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1"><italic>Yersinia-</italic>
containing vacuoles (YCVs) contains autophagy markers but not acidified</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Moreau et al., 2010 [<xref rid="B224-cells-08-00674" ref-type="bibr">224</xref>
]</td>
</tr>
<tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1"><italic>Coxiella</italic>
-replicative vacuoles contains LC3, Beclin 1, and Rab24</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Vázquez and Colombo, 2010 [<xref rid="B226-cells-08-00674" ref-type="bibr">226</xref>
]</td>
</tr>
<tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Inside BCVs, replication of <italic>Brucella</italic>
requires ULK1, Beclin 1, and Atg14L </td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Starr et al., 2012 [<xref rid="B227-cells-08-00674" ref-type="bibr">227</xref>
]</td>
</tr>
<tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Secreted phospholipases C (PLCs; PlcA and PlcB) and a surface protein (ActA) help <italic>Listeria monocytogenes</italic>
multiplication </td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Mitchell et al., 2018 [<xref rid="B50-cells-08-00674" ref-type="bibr">50</xref>
]</td>
</tr>
<tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1"><italic>Shigella</italic>
gatekeeper protein MxiC regulate type III secretion </td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Roehrich et al., 2017 [<xref rid="B52-cells-08-00674" ref-type="bibr">52</xref>
] </td>
</tr>
<tr><td rowspan="17" align="center" valign="middle" style="border-bottom:solid thin" colspan="1">3</td>
<td rowspan="17" align="center" valign="middle" style="border-bottom:solid thin" colspan="1">Tumor</td>
<td rowspan="9" align="center" valign="middle" style="border-bottom:solid thin" colspan="1">Tumor suppression</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Monoallelic loss of Atg6/Beclin 1 gene – correlated with human prostate, breast, and ovarian cancers </td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Choi et al., 2013 [<xref rid="B285-cells-08-00674" ref-type="bibr">285</xref>
]</td>
</tr>
<tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Beclin 1 overexpression inhibits tumor progression </td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Liang et al., 1999 [<xref rid="B286-cells-08-00674" ref-type="bibr">286</xref>
]</td>
</tr>
<tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Inhibition of necrosis and chronic inflammation through inhibiting- high mobility group box 1 protein (HMGB1) </td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Tang et al., 2010 [<xref rid="B288-cells-08-00674" ref-type="bibr">288</xref>
]</td>
</tr>
<tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Autophagy deficiency- leads to benign hepatoma cell death </td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Takamura et al., 2011 [<xref rid="B291-cells-08-00674" ref-type="bibr">291</xref>
]</td>
</tr>
<tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Autophagy induced by PTEN and TSC, the tumor suppressor protein</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Feng et al., 2005 [<xref rid="B301-cells-08-00674" ref-type="bibr">301</xref>
]; Tsuchihara et al., 2009 [<xref rid="B302-cells-08-00674" ref-type="bibr">302</xref>
]</td>
</tr>
<tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">In mice tumor model, inactivation of Beclin 1 and Atg5 affects autophagy </td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Levine, 2007 [<xref rid="B292-cells-08-00674" ref-type="bibr">292</xref>
]</td>
</tr>
<tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Heterozygous disturbance of Beclin 1 lead to development of cancer</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Qu et al., 2003 [<xref rid="B289-cells-08-00674" ref-type="bibr">289</xref>
]; Yue et al., 2003 [<xref rid="B293-cells-08-00674" ref-type="bibr">293</xref>
]</td>
</tr>
<tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">UV radiation resistance associated gene (UVRAG) can suppress tumorigenicity and proliferation of colon cancer </td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Liang et al., 2006 [<xref rid="B295-cells-08-00674" ref-type="bibr">295</xref>
]</td>
</tr>
<tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Pogostone stimulate autophagy and apoptosis through PI3K/Akt/mTOR axis and have anti-colorectal tumor activities</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Cao et al., 2017 [<xref rid="B303-cells-08-00674" ref-type="bibr">303</xref>
]</td>
</tr>
<tr><td rowspan="8" align="center" valign="middle" style="border-bottom:solid thin" colspan="1">Tumor induction</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Autophagy alleviates stressed condition – in hypoxic conditions, metabolic stress, shortage of energy, damaged mitochondria and other organelles</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Sato et al., 2007 [<xref rid="B306-cells-08-00674" ref-type="bibr">306</xref>
]</td>
</tr>
<tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Increased autophagy-associated protein LC3 and BNIP3- linked to colorectal and gastric cancers; Elevated expression of NIP3 (a pro-apoptotic member of the Bcl-2 family of cell death factor) in gastric carcinomas</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Lee et al., 2007a [<xref rid="B309-cells-08-00674" ref-type="bibr">309</xref>
]</td>
</tr>
<tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Autophagy inhibition leads to cell death in tumors acting like an RAS-activated tumor</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Guo et al., 2011 [<xref rid="B312-cells-08-00674" ref-type="bibr">312</xref>
]</td>
</tr>
<tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">In the absence of autophagy -accumulation of ubiquitinylated protein aggregates and higher p62 level- responsible for liver tumor </td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Takamura et al., 2011 [<xref rid="B291-cells-08-00674" ref-type="bibr">291</xref>
]</td>
</tr>
<tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Activation of autophagy and peroxisome proliferator-activated receptor gamma (PPARγ) protect colon cancer cells against apoptosis</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Tylichová et al., 2017 [<xref rid="B310-cells-08-00674" ref-type="bibr">310</xref>
]</td>
</tr>
<tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">In RAS-activated tumors, inhibition of autophagy leads to increased cancer cell death</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Guo et al., 2011 [<xref rid="B312-cells-08-00674" ref-type="bibr">312</xref>
]</td>
</tr>
<tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Post-chemotherapy, increased autophagy may cause cancer cells to go into dormancy and proliferate later</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">White et al., 2010 [<xref rid="B315-cells-08-00674" ref-type="bibr">315</xref>
]</td>
</tr>
<tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Proteasome 26S subunit, non-ATPase 10 (PSMD10) or gankyrin induced autophagy in hepatocellular carcinoma causes tumor progression</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Luo et al., 2016 [<xref rid="B318-cells-08-00674" ref-type="bibr">318</xref>
]</td>
</tr>
<tr><td rowspan="11" align="center" valign="middle" style="border-bottom:solid thin" colspan="1">4</td>
<td rowspan="11" align="center" valign="middle" style="border-bottom:solid thin" colspan="1">Neuronal health</td>
<td rowspan="4" align="center" valign="middle" style="border-bottom:solid thin" colspan="1">Brain development</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Clear protein aggregates / old organelles in old neurons</td>
<td rowspan="2" align="center" valign="middle" style="border-bottom:solid thin" colspan="1">Hara et al., 2006 [<xref rid="B319-cells-08-00674" ref-type="bibr">319</xref>
]</td>
</tr>
<tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Atg5 mutation confined to neural tissue leads to impaired growth, progressive motor and behavioral deficits, prominent neurodegeneration and axonal swelling</td>
</tr>
<tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Absence of Atg59 and Atg710- leads to neuronal degeneration</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Liao et al., 2007 [<xref rid="B100-cells-08-00674" ref-type="bibr">100</xref>
]</td>
</tr>
<tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Upon ethanol exposure, autophagy dysregulation in cortical microvessels affects cortical vascular development </td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Girault et al., 2017 [<xref rid="B322-cells-08-00674" ref-type="bibr">322</xref>
]</td>
</tr>
<tr><td rowspan="7" align="center" valign="middle" style="border-bottom:solid thin" colspan="1">Neurodegeneration</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Dysregulated autophagy results in accumulation of damaged and toxic molecules- leads to Alzheimer’s, Parkinson’s and Huntington’s diseases </td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Sahni et al., 2014 [<xref rid="B327-cells-08-00674" ref-type="bibr">327</xref>
]</td>
</tr>
<tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Anomalies in endosomal-lysosomal pathway and accumulation of autophagosomes- lead to Alzheimer’s, Parkinson’s and Huntington’s diseases</td>
<td rowspan="2" align="center" valign="middle" style="border-bottom:solid thin" colspan="1">Pickford et al., 2008 [<xref rid="B330-cells-08-00674" ref-type="bibr">330</xref>
]</td>
</tr>
<tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Beclin 1 deficiency- leads to deposition of β-amyloid protein and neurodegeneration</td>
</tr>
<tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Atg7 mutation in mice causes accumulate ubiquitin and results in neurodegeneration and death</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Komatsu et al., 2006 [<xref rid="B334-cells-08-00674" ref-type="bibr">334</xref>
]; Nixon, 2013 [<xref rid="B31-cells-08-00674" ref-type="bibr">31</xref>
] </td>
</tr>
<tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Embryos of Ambra1-deficient mice possess defects in the neuronal tube </td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Fimia et al., 2007 [<xref rid="B335-cells-08-00674" ref-type="bibr">335</xref>
]</td>
</tr>
<tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Mutations in the phosphatase and tensin homolog (PTEN)-induced kinase 1 (PINK1) and Parkin genes result in defective mitophagy which leads to Parkinson’s disease </td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Whitworth and Pallanck, 2017 [<xref rid="B339-cells-08-00674" ref-type="bibr">339</xref>
]</td>
</tr>
<tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Beta-propeller protein causes neurodegeneration</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Stige et al., 2018 [<xref rid="B399-cells-08-00674" ref-type="bibr">399</xref>
]</td>
</tr>
<tr><td rowspan="3" align="center" valign="middle" style="border-bottom:solid thin" colspan="1">5</td>
<td rowspan="3" align="center" valign="middle" style="border-bottom:solid thin" colspan="1">Iron availability in body</td>
<td rowspan="2" align="center" valign="middle" style="border-bottom:solid thin" colspan="1">Homeostasis</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Iron in the form of ferritin complex- redox-active iron is sequestered in lysosome </td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Kurz et al., 2011 [<xref rid="B382-cells-08-00674" ref-type="bibr">382</xref>
]; Krishan et al., 2015 [<xref rid="B384-cells-08-00674" ref-type="bibr">384</xref>
]</td>
</tr>
<tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Knockdown of nuclear receptor co-activator 4 (NCOA4), which is responsible for directing ferritin to autophagosome, increases iron-responsive element-binding protein 2 (IRP2)- prevent cell death by exogenous reactive oxygen species</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Berndt, 2014 [<xref rid="B386-cells-08-00674" ref-type="bibr">386</xref>
]</td>
</tr>
<tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Ferritinophagy</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Iron storage protein called ferritin is degraded in the lysosome; thus, resulting in a form of selective macroautophagy </td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Hamaï and Mehrpour, 2017 [<xref rid="B379-cells-08-00674" ref-type="bibr">379</xref>
]</td>
</tr>
<tr><td rowspan="2" align="center" valign="middle" style="border-bottom:solid thin" colspan="1">6</td>
<td rowspan="2" align="center" valign="middle" style="border-bottom:solid thin" colspan="1">Chronic inflammatory bowel disease</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Anti-effect</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Reduction in TNF-α induced apoptosis in gut epithelium </td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Pott and Maloy, 2018 [<xref rid="B400-cells-08-00674" ref-type="bibr">400</xref>
]</td>
</tr>
<tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Pro-effect</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Goblet cell function, cytokine production or NOD2, ATG16L1, and IRGM gene regulation affect pathogenesis of inflammatory bowel disease</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Iida et al., 2017 [<xref rid="B401-cells-08-00674" ref-type="bibr">401</xref>
]</td>
</tr>
<tr><td rowspan="4" align="center" valign="middle" style="border-bottom:solid thin" colspan="1">7</td>
<td rowspan="4" align="center" valign="middle" style="border-bottom:solid thin" colspan="1">Lifestyle diseases</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Obesity </td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Causes biochemical disturbance, ER stress, mitochondrial dysfunction induces obesity-cardiac disorders</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Che et al., 2018 [<xref rid="B388-cells-08-00674" ref-type="bibr">388</xref>
]</td>
</tr>
<tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Diabetes mellitus</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Affects beta-cells of pancreas, insulin target tissues, glucose metabolism</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Bhattacharya et al., 2018 [<xref rid="B389-cells-08-00674" ref-type="bibr">389</xref>
]</td>
</tr>
<tr><td rowspan="2" align="center" valign="middle" style="border-bottom:solid thin" colspan="1">Cardiovascular disease</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Perturbations in autophagic machinery in cardiomyocytes and other cardiovascular cell types</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Schiattarella and Hill, 2015 [<xref rid="B377-cells-08-00674" ref-type="bibr">377</xref>
]</td>
</tr>
<tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Autophagy through PARP1 modulation of FoxO3a transcription in cardiomyocytes </td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Wang et al., 2018a [<xref rid="B378-cells-08-00674" ref-type="bibr">378</xref>
]</td>
</tr>
</tbody>
</table>
</table-wrap>
<table-wrap id="cells-08-00674-t002" orientation="portrait" position="float"><object-id pub-id-type="pii">cells-08-00674-t002_Table 2</object-id>
<label>Table 2</label>
<caption><p>Details of applied/granted patents for treating ailments related to autophagy dysfunction.</p>
</caption>
<table frame="hsides" rules="groups"><thead><tr><th align="center" valign="middle" style="border-top:solid thin;border-bottom:solid thin" rowspan="1" colspan="1">S. No.</th>
<th align="center" valign="middle" style="border-top:solid thin;border-bottom:solid thin" rowspan="1" colspan="1">Targeted Ailment</th>
<th align="center" valign="middle" style="border-top:solid thin;border-bottom:solid thin" rowspan="1" colspan="1">Title of Patent</th>
<th align="center" valign="middle" style="border-top:solid thin;border-bottom:solid thin" rowspan="1" colspan="1">Patent Number</th>
<th align="center" valign="middle" style="border-top:solid thin;border-bottom:solid thin" rowspan="1" colspan="1">Modus Operandi</th>
<th align="center" valign="middle" style="border-top:solid thin;border-bottom:solid thin" rowspan="1" colspan="1">Inventers</th>
<th align="center" valign="middle" style="border-top:solid thin;border-bottom:solid thin" rowspan="1" colspan="1">Date of Publication</th>
<th align="center" valign="middle" style="border-top:solid thin;border-bottom:solid thin" rowspan="1" colspan="1">Status</th>
<th align="center" valign="middle" style="border-top:solid thin;border-bottom:solid thin" rowspan="1" colspan="1">Reference(s) </th>
</tr>
</thead>
<tbody><tr><td rowspan="5" align="center" valign="middle" style="border-bottom:solid thin" colspan="1">1.</td>
<td rowspan="5" align="center" valign="middle" style="border-bottom:solid thin" colspan="1">Tumor treatment</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Inhibition of autophagy genes in cancer chemotherapy </td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">US 8076308 </td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Compositions comprise a siRNA directed against an Atg gene to inhibit its expression </td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Gorski SM, Qadir MA </td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">13.12.11</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Granted </td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Gorski and Qadir 2011 [<xref rid="B402-cells-08-00674" ref-type="bibr">402</xref>
]</td>
</tr>
<tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Dimeric quinacrine derivatives as autophagy inhibitors for cancer therapy </td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">WO 2016168721 </td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Chloroquine compounds and derivatives mediated inhibition of lysosome </td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Amaravadi RK, Winkler J.</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">20.10.16</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Application</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Amaravadi and Winkler, 2016 [<xref rid="B403-cells-08-00674" ref-type="bibr">403</xref>
]</td>
</tr>
<tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Anti-cervical cancer compound and method of use thereof </td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">US 9339488 </td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Griffipavixanthone, a novel cytotoxic Bixanthone from <italic>Garcinia griffithii</italic>
and <italic>G. pavifolia</italic>
selectively kill cervical cancer cells via inducing autophagy</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">XU H, Zhang H, Lao Y, Wang X, Chen K, Yang D, Chen S, Lin C, Bian Z, Lu A, Chan ASC, </td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">17.05.16</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Grant </td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Xu et al., 2016 [<xref rid="B404-cells-08-00674" ref-type="bibr">404</xref>
]</td>
</tr>
<tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Substituted thioxanthenone autophagy inhibitors</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">US 9926326</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Inhibition of autophagy through autophagy inhibitors developed from substitution of chemical groups, can help in treatment of cancers</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Carew J, Phillips JG</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">27.03.18</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Grant</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Carew and Phillips, 2018 [<xref rid="B405-cells-08-00674" ref-type="bibr">405</xref>
]</td>
</tr>
<tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Method for inhibiting growth of ovarian cancer cells</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">US20180050012</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Method of inhibition of ovarian cancer cells by 4-acetyl-antroquinonol B or its salt</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Huang CC, Tzeng YM, Yeh CT, Wu THA</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">22.02.18</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Application</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Huang et al., 2018 [<xref rid="B25-cells-08-00674" ref-type="bibr">25</xref>
]</td>
</tr>
<tr><td rowspan="8" align="center" valign="middle" style="border-bottom:solid thin" colspan="1">2.</td>
<td rowspan="8" align="center" valign="middle" style="border-bottom:solid thin" colspan="1">Neuroprotection </td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Autophagy enhancer for treatment of neurodegenerative diseases </td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">US 9005677 </td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Onjisaponin B derived and isolated from <italic>Radix polygalae</italic>
enhances autophagy </td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Law YK, Wu AG, Wong KW, Liu L</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">14.04.15 </td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Grant</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Law et al., 2015 [<xref rid="B406-cells-08-00674" ref-type="bibr">406</xref>
]</td>
</tr>
<tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Autophagy enhancing compounds, peptides and peptidomimetic compounds for use in the treatment of neuronal diseases </td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">WO 2012076555 </td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Pharmaceutical compositions enhancing autophagy in acute focal brain lesions</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">D’amelio M, Molinari M, Viscomi MT, Cecconi F</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">14.06.12</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Application</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">D’amelio et al., 2012 [<xref rid="B407-cells-08-00674" ref-type="bibr">407</xref>
]</td>
</tr>
<tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Highly potent peptides to control cancer and neurodegenerative diseases </td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">WO 2010011952 </td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Inhibition of autophagy by administering a FLIP protein interfering with the formation of the LC3-Atg4-Atg7-Atg3 conjugation complex </td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1"> Jung JU, Lee JS</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">24.06.10 </td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Application</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Jung and Lee, 2010 [<xref rid="B408-cells-08-00674" ref-type="bibr">408</xref>
]</td>
</tr>
<tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Methods for reducing neurodegeneration </td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1"> EP 2717695 </td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Inhibiting the expression of mTOR in canine</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Middleton RP, Zanghi BM</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">02.11.16</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Grant</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Middleton and Zanghi, 2016 [<xref rid="B409-cells-08-00674" ref-type="bibr">409</xref>
]</td>
</tr>
<tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Regulating autophagy</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">WO2008122038A1</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Regulating autophagy helps in prevention and treatment of neurodeneration or other diseases</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Bradner JE , Shen JP, Perlstein EO, Rubinsztein D, Sarkar S, Wood SLS</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">09.10.08</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Application</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Bradner et al., 2008 [<xref rid="B410-cells-08-00674" ref-type="bibr">410</xref>
]</td>
</tr>
<tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Method for modulating autophagy and applications thereof</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">WO2017098467A1</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Autophagy modulators (pyridines; hydrogenated derivatives) regulate all types of autophagy by increasing or decreasing autophagic flux</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Manjithaya R, Mishra P, Santhi Natesan S, Bats S, Ammanathan V, Chavalmane A</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">15.06.17</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Application</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Manjithaya et al., 2017 [<xref rid="B411-cells-08-00674" ref-type="bibr">411</xref>
]</td>
</tr>
<tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">mTOR-independent activator of TFEB for autophagy enhancement and uses thereof </td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">US 9351946 </td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Small molecules enhance autophagy and lysosome biogenesis by activating the gene TFEB</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Li M, Song J, Zeng Y, Liu L</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">31.05.16</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">grant</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Li et al., 2016 [<xref rid="B412-cells-08-00674" ref-type="bibr">412</xref>
]</td>
</tr>
<tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Combination product with autophagy modulator </td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">WO 2016131945 </td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Autophagy modulator directly or indirectly acting on a complex involved in autophagy such as ULKl/2-Atgl3- FIP200 complex, Atg9 complex, STING complex, class III PI3K complex, ubiquitin-like conjugation systems Atg5-Atgl2, LC3, fusion complex, SNARE protein and transcription factor EB</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Zaupa C, Hortelano J, Silvestre N, Spindler A</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">25.08.16</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Application</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Zaupa et al., 2016 [<xref rid="B413-cells-08-00674" ref-type="bibr">413</xref>
]</td>
</tr>
<tr><td rowspan="4" align="center" valign="middle" style="border-bottom:solid thin" colspan="1">3.</td>
<td rowspan="4" align="center" valign="middle" style="border-bottom:solid thin" colspan="1">Viral inhibitor</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Treatment of hepatitis C virus-related diseases using hydroxychloroquine or a combination of hydroxychloroquine and an anti-viral agent </td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">US 8987302 </td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Chloroquine cause pH-dependent inhibition of degradation of cargo delivered to the lysosome</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Halfon P</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">24.03.15</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Grant</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Halfon, 2015 [<xref rid="B414-cells-08-00674" ref-type="bibr">414</xref>
]</td>
</tr>
<tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Enhancing the anti-tumor, anti-viral, and anti-protozoan effects of 2-amino-n-[4-[5-phenanthren-2-yl-3-(trifluoromethyl)pyrazol-1-yl] phenyl]acetamide (osu-03012) and other pharmaceutical drugs </td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">WO 2016069854 </td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Drug OSU-03012 (AR-12) in combination with multikinase inhibitor</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Dent P, Zukiwski A, Proniuk S </td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">06.05.16</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Application</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Dent et al., 2016 [<xref rid="B415-cells-08-00674" ref-type="bibr">415</xref>
]</td>
</tr>
<tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Autophagy-inducing peptide</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">CA2864145C</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Autophagy-inducing peptide derived from beclin-1 (residues 269-283) has antiviral role against West Nile Virus, chikungunya virus, HIV and Ebola viru</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Levine BC, Sanae Shoji-Kawata S, Lichtarge O, Wilkins AD</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">14.02.17</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Grant</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Levine et al., 2017 [<xref rid="B416-cells-08-00674" ref-type="bibr">416</xref>
]</td>
</tr>
<tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Combination treatment of RAS-positive diseases with PDE-delta inhibitor and direct autophagy inhibitor</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">US 9861623B1</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Potentiating the apoptotic activity of deltarasin, a PDE-delta inhibitor by 3-methyladenine, a direct autophagy inhibitor for treatment of RAS positive cases</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Liu L, Ward D, Leung ELH, Yao XJ, Wong VKW, Luo LX</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">09.01.18</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Grant</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Liu et al., 2018 [<xref rid="B417-cells-08-00674" ref-type="bibr">417</xref>
]</td>
</tr>
<tr><td rowspan="4" align="center" valign="middle" style="border-bottom:solid thin" colspan="1">4.</td>
<td rowspan="4" align="center" valign="middle" style="border-bottom:solid thin" colspan="1">Iron homeostasis</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Compositions and methods for modulating nuclear receptor coactivator 4 (NCOA4) -mediated autophagic targeting of ferritin </td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">WO 2015149006</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Modulation of the level and activity of nuclear receptor coactivator 4 (NCOA4)</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Kimmelman AC, Mancias JD, Harper JW</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">26.11.15</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Application</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Kimmelman et al., 2015 [<xref rid="B418-cells-08-00674" ref-type="bibr">418</xref>
]</td>
</tr>
<tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">MicroRNA that regulate autophagy </td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">JPWO 2015037656A1</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">miRNA-mediated targeting the WDR45 gene and ATP13A2 gene</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Hidenao S, Jun U, Koichi W</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">02.03.15</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Application</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Hidenao et al., 2015 [<xref rid="B419-cells-08-00674" ref-type="bibr">419</xref>
]</td>
</tr>
<tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Use of hepcidin as a regulator of iron homeostasis</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">US7169758B2</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Hepcidin, a key regulator of the entry of iron into the circulation can be used for disorders of iron overload</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Nicolas G, Vaulont S, Kahn A</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">30.01.07</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Grant</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Nicolas et al., 2007 [<xref rid="B420-cells-08-00674" ref-type="bibr">420</xref>
]</td>
</tr>
<tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Erythroferrone and erfe polypeptides and methods of regulating iron metabolism</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">CA2890040A1</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Hepcidin concentration can be regulated by herein polypeptides called as erythroferrone and erfe polypeptides</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Ganz T, Nemeth E, Kautz L</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">08.05.14</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Application</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Ganz et al., 2014 [<xref rid="B421-cells-08-00674" ref-type="bibr">421</xref>
]</td>
</tr>
</tbody>
</table>
</table-wrap>
<table-wrap id="cells-08-00674-t003" orientation="portrait" position="float"><object-id pub-id-type="pii">cells-08-00674-t003_Table 3</object-id>
<label>Table 3</label>
<caption><p>Diseases due to genetic defects in autophagy genes.</p>
</caption>
<table frame="hsides" rules="groups"><thead><tr><th align="center" valign="middle" style="border-top:solid thin;border-bottom:solid thin" rowspan="1" colspan="1">S. No. </th>
<th align="center" valign="middle" style="border-top:solid thin;border-bottom:solid thin" rowspan="1" colspan="1">Name of disorder</th>
<th align="center" valign="middle" style="border-top:solid thin;border-bottom:solid thin" rowspan="1" colspan="1">Type of disorder</th>
<th align="center" valign="middle" style="border-top:solid thin;border-bottom:solid thin" rowspan="1" colspan="1">Mutant gene</th>
<th align="center" valign="middle" style="border-top:solid thin;border-bottom:solid thin" rowspan="1" colspan="1">Outcome of pathological condition</th>
<th align="center" valign="middle" style="border-top:solid thin;border-bottom:solid thin" rowspan="1" colspan="1">Symptoms </th>
<th align="center" valign="middle" style="border-top:solid thin;border-bottom:solid thin" rowspan="1" colspan="1">Reference(s)</th>
</tr>
</thead>
<tbody><tr><td rowspan="2" align="center" valign="middle" style="border-bottom:solid thin" colspan="1">1</td>
<td rowspan="2" align="center" valign="middle" style="border-bottom:solid thin" colspan="1">Static encephalopathy of childhood with neurodegeneration in adulthood (SENDA)</td>
<td rowspan="2" align="center" valign="middle" style="border-bottom:solid thin" colspan="1">Neurodegenerative disorder</td>
<td rowspan="2" align="center" valign="middle" style="border-bottom:solid thin" colspan="1"><italic>WIPI4</italic>
located at Xp11.23</td>
<td rowspan="2" align="center" valign="middle" style="border-bottom:solid thin" colspan="1"><italic>WIPI4</italic>
, homologous to yeast Atg18, is recruited to autophagosome formation site, severely reduced in affected individuals.<break></break>
<break></break>
Iron accumulation in brain</td>
<td align="center" valign="middle" rowspan="1" colspan="1">In childhood- early-onset of spastic paraplegia and mental retardation </td>
<td rowspan="2" align="center" valign="middle" style="border-bottom:solid thin" colspan="1">Ozawa et al. 2014 [<xref rid="B445-cells-08-00674" ref-type="bibr">445</xref>
]; Haack et al., 2012 [<xref rid="B423-cells-08-00674" ref-type="bibr">423</xref>
]; Saitsu et al., 2013 [<xref rid="B424-cells-08-00674" ref-type="bibr">424</xref>
]</td>
</tr>
<tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">In adult age- symptoms of parkinsonism and dystonia</td>
</tr>
<tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">2</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Crohn’s disease</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Inflammatory bowel disease</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1"><italic>Atg16L1</italic>
</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Inhibited LC3 conjugations to phosphatidylethanolamine (PE)</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Abdominal pain, diarrhea, vomiting, and weight loss</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Fujita et al., 2009 [<xref rid="B430-cells-08-00674" ref-type="bibr">430</xref>
]</td>
</tr>
<tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">3</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Hereditary spastic paraparesis (HSP)</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Increased muscle spasticity </td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">A recessive mutation in <italic>TECPR2</italic>
</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Autophagosome accumulation due to impaired fusion with lysosome </td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Lower extremity weakness and spasticity</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Vantaggiato et al., 2013 [<xref rid="B433-cells-08-00674" ref-type="bibr">433</xref>
]; Oz-Levi et al., 2012 [<xref rid="B432-cells-08-00674" ref-type="bibr">432</xref>
]</td>
</tr>
<tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">4</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Danon disease</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Cardiomyopathy and intellectual dysfunction</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Lysosome-associated membrane protein 2 (LAMP-2B isoform)</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Accumulation of autophagic vacuoles in liver, kidney, pancreas, and cardiac and skeletal muscles</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Weakening of skeletal muscles</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">D’souza et al., 2014 [<xref rid="B446-cells-08-00674" ref-type="bibr">446</xref>
]; Rothaug et al., 2015 [<xref rid="B435-cells-08-00674" ref-type="bibr">435</xref>
]; Ng et al., 2016 [<xref rid="B436-cells-08-00674" ref-type="bibr">436</xref>
]</td>
</tr>
<tr><td rowspan="2" align="center" valign="middle" style="border-bottom:solid thin" colspan="1">5</td>
<td rowspan="2" align="center" valign="middle" style="border-bottom:solid thin" colspan="1">X-linked myopathy with excessive autophagy (XMEA)</td>
<td rowspan="2" align="center" valign="middle" style="border-bottom:solid thin" colspan="1">Skeletal myopathy</td>
<td rowspan="2" align="center" valign="middle" style="border-bottom:solid thin" colspan="1"><italic>VMA21</italic>
</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Elevated levels of CPK </td>
<td rowspan="2" align="center" valign="middle" style="border-bottom:solid thin" colspan="1">Weakness in proximal muscles of the legs</td>
<td rowspan="2" align="center" valign="middle" style="border-bottom:solid thin" colspan="1">Ruggieri et al., 2015 [<xref rid="B440-cells-08-00674" ref-type="bibr">440</xref>
]; Dowling et al., 2015 [<xref rid="B439-cells-08-00674" ref-type="bibr">439</xref>
]</td>
</tr>
<tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Interrupted sarcolemma membrane homeostasis<break></break>
<break></break>
Impaired autophagy and lysosomal function <break></break>
<break></break>
Vps15 knockouts exhibit muscle pathology similar to the XMEA, indicative of role of aberrant autophagy in XMEA disease.</td>
</tr>
<tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">6</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Sporadic inclusion body myositis (sIBM)</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Progressive muscle disorder</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">MYH2</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Muscle tissues exhibits both inflammatory and degenerative changes.<break></break>
Impaired autophagy with inhibited lysosomal protein degradation.</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Progressive quadriceps femoris and deep finger flexors weakness and atrophy</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Mastaglia, 2009 [<xref rid="B444-cells-08-00674" ref-type="bibr">444</xref>
]; Nogalska et al., 2010 [<xref rid="B442-cells-08-00674" ref-type="bibr">442</xref>
]</td>
</tr>
<tr><td rowspan="2" align="center" valign="middle" style="border-bottom:solid thin" colspan="1">7</td>
<td rowspan="2" align="center" valign="middle" style="border-bottom:solid thin" colspan="1">Vici syndrome</td>
<td rowspan="2" align="center" valign="middle" style="border-bottom:solid thin" colspan="1">Callosal agenesis, cataracts, hypopigmentation, cardiomyopathy, psychomotor retardation, and immunodeficiency with cleft lip and palate</td>
<td rowspan="2" align="center" valign="middle" style="border-bottom:solid thin" colspan="1">Recessive mutations in EPG5</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Deficiency blocks the maturation of autophagosomes into degradative autolysosomes resulting in accumulation of non-degradative autolysosomes.</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Psychomotor abnormalities</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Cullup et al., 2013 [<xref rid="B447-cells-08-00674" ref-type="bibr">447</xref>
]</td>
</tr>
<tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Defect in the endocytic pathway<break></break>
<break></break>
Epg5 deficiency blocks the maturation of autophagosomes into degradative autolysosomes</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Facial dysmorphism and cataracts</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Zhao et al., 2013 [<xref rid="B448-cells-08-00674" ref-type="bibr">448</xref>
]</td>
</tr>
<tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">8</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Lysosomal storage disorder Niemann-Pick type C (NPC)</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Neurodegeneration and liver dysfunction</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">NPC1 or NPC2</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Compromised autophagy with accumulation of autophagosomes as evidenced by elevated LC3-II levels and LC3 positive vesicles in the NPC1 mutant cells <break></break>
<break></break>
Cholesterol accumulation</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Increased death of brain and liver cells</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Sarkar et al., 2013 [<xref rid="B449-cells-08-00674" ref-type="bibr">449</xref>
]</td>
</tr>
<tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">9</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Pompe disease</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Pathology of the neuromuscular junction</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Lysosomal acid α-glucosidase</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Accumulation of glycogen in the nervous system </td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Muscle atrophy, weakness, loss of muscle function and cardio-respiratory failure </td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Todd et al., 2015 [<xref rid="B450-cells-08-00674" ref-type="bibr">450</xref>
]</td>
</tr>
<tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">10</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Cancer</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">High percentage of human breast cancers and ovarian cancer </td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Monoallelic deletion of <italic>BECN1</italic>
</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Activation of inflammasome leading to the maturation of inflammatory cytokines like IL-1β and IL-18</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Cell necrosis, chronic inflammation and ultimate tumorigenesis</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Sun et al., 2013 [<xref rid="B451-cells-08-00674" ref-type="bibr">451</xref>
]</td>
</tr>
<tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">11</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Myelodysplastic syndromes / acute myeloid leukemia (AML)</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Accumulation of damaged mitochondria </td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Atg7</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Increased levels of ROS</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Bone marrow cells are characterized by mitochondrial abnormalities and increased cell death</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Watson et al., 2011 [<xref rid="B452-cells-08-00674" ref-type="bibr">452</xref>
]</td>
</tr>
<tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">12</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Autoimmune/Autoinflammatory diseases</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Immune dysfunction</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Atg5</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Disturbance in autophagic vesicle formation, immune cell development and function, mitochondrial ROS, antimicrobial immunity [(retinoic acid receptor responder 3 (RARRES3) and mitochondrial anti-viral signalling protein (MAVS)]</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Autoimmune diseases, susceptibility to infections, e.g., HIV, bacteria</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Ye et al., 2018 [<xref rid="B453-cells-08-00674" ref-type="bibr">453</xref>
]</td>
</tr>
<tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">13</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Autoimmune thyroid diseases</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Autoimmune thyroid diseases and Graves’ disease</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">IRGM</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Lymphocytic infiltration in thyroid, antibodies to antigens including thyroid-stimulating hormone receptor (TSHR), thyroid antigens including thyroglobulin (Tg), and thyroid peroxidase (TPO), anti-TSHR autoantibodies</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Graves’ disease, hyperthyroidism </td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Yao et al., 2018 [<xref rid="B454-cells-08-00674" ref-type="bibr">454</xref>
]</td>
</tr>
<tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">14</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Paget disease of bone (PDB)</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Osteoclast size, number and activity increase causing bone cleavage, cytoplasmic inclusions with protein aggregates responsible for autophagy</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Atg2B, Atg5</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Focal bone disorder affecting the skeleton segmentally, bone defects, softening, breakage</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Bone defects, softening, breakage, pain</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Usategui-Martín et al., 2015 [<xref rid="B455-cells-08-00674" ref-type="bibr">455</xref>
]</td>
</tr>
<tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">15</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Celiac disease in children</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Chronic systemic autoimmune disease of the small intestine, gluten induced damage resulting in celiac sprue and gluten-sensitive enteropathy</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Atg7 and Beclin 1</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Chronic systemic autoimmune disorder, enteropathy</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Diarrhea, dehydration, indigestion, decreased appetite, stomach-ache and bloating, poor growth, and weight loss</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Comincini et al., 2017 [<xref rid="B456-cells-08-00674" ref-type="bibr">456</xref>
]</td>
</tr>
<tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">16</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Huntington disease</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Neurodegenerative disorder, CAG trinucleotide repeats in the 5′ coding region of the IT15 (Interesting Transcript 15) gene of 4th chromosome </td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">IT15 </td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Neurodegeneration, deformity in autosomal-lysosome degradation, neurodegenerative proteinopathy, accumulation of toxic materials</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Depression, apathy, irritability, suicidal behaviours, involuntary movements/chorea, progressive dementia, severe weight loss</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Barboza and Ghisi, 2018 [<xref rid="B457-cells-08-00674" ref-type="bibr">457</xref>
]</td>
</tr>
<tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">17</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Cardiac disease</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Cardiac autophagy disorder</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Beclin 1, microRNAs (miRNAs)</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Over or under expression of genes regulating cardiac autophagy (Beclin 1), miRNAs regulate cardiac autophagy by suppressing the expression of autophagy-related genes in a targeted manner</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Signs of cardiovascular disease- like heart attack, pain, fainting, dysrhythmia </td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Shirakabe et al., 2016 [<xref rid="B458-cells-08-00674" ref-type="bibr">458</xref>
]; Sun et al., 2018 [<xref rid="B459-cells-08-00674" ref-type="bibr">459</xref>
]</td>
</tr>
</tbody>
</table>
</table-wrap>
</floats-group>
</pmc>
<affiliations><list><country><li>Inde</li>
<li>Iran</li>
<li>Mexique</li>
<li>Thaïlande</li>
<li>États-Unis</li>
</country>
</list>
<tree><country name="Inde"><noRegion><name sortKey="Khandia, Rekha" sort="Khandia, Rekha" uniqKey="Khandia R" first="Rekha" last="Khandia">Rekha Khandia</name>
</noRegion>
<name sortKey="Dhama, Kuldeep" sort="Dhama, Kuldeep" uniqKey="Dhama K" first="Kuldeep" last="Dhama">Kuldeep Dhama</name>
<name sortKey="Karthik, Kumaragurubaran" sort="Karthik, Kumaragurubaran" uniqKey="Karthik K" first="Kumaragurubaran" last="Karthik">Kumaragurubaran Karthik</name>
<name sortKey="Munjal, Ashok" sort="Munjal, Ashok" uniqKey="Munjal A" first="Ashok" last="Munjal">Ashok Munjal</name>
<name sortKey="Singh, Karam Pal" sort="Singh, Karam Pal" uniqKey="Singh K" first="Karam Pal" last="Singh">Karam Pal Singh</name>
<name sortKey="Tiwari, Ruchi" sort="Tiwari, Ruchi" uniqKey="Tiwari R" first="Ruchi" last="Tiwari">Ruchi Tiwari</name>
<name sortKey="Yatoo, Mohd Iqbal" sort="Yatoo, Mohd Iqbal" uniqKey="Yatoo M" first="Mohd. Iqbal" last="Yatoo">Mohd. Iqbal Yatoo</name>
</country>
<country name="Iran"><noRegion><name sortKey="Dadar, Maryam" sort="Dadar, Maryam" uniqKey="Dadar M" first="Maryam" last="Dadar">Maryam Dadar</name>
</noRegion>
</country>
<country name="Mexique"><noRegion><name sortKey="Iqbal, Hafiz M N" sort="Iqbal, Hafiz M N" uniqKey="Iqbal H" first="Hafiz M. N." last="Iqbal">Hafiz M. N. Iqbal</name>
</noRegion>
</country>
<country name="États-Unis"><noRegion><name sortKey="Joshi, Sunil K" sort="Joshi, Sunil K" uniqKey="Joshi S" first="Sunil K." last="Joshi">Sunil K. Joshi</name>
</noRegion>
</country>
<country name="Thaïlande"><noRegion><name sortKey="Chaicumpa, Wanpen" sort="Chaicumpa, Wanpen" uniqKey="Chaicumpa W" first="Wanpen" last="Chaicumpa">Wanpen Chaicumpa</name>
</noRegion>
</country>
</tree>
</affiliations>
</record>
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