{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,24]],"date-time":"2026-07-24T10:54:53Z","timestamp":1784890493267,"version":"3.55.0"},"reference-count":17,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"1","license":[{"start":{"date-parts":[[2015,9,1]],"date-time":"2015-09-01T00:00:00Z","timestamp":1441065600000},"content-version":"tdm","delay-in-days":608,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["lww.com","ovid.com"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2014,1]]},"abstract":"<jats:title>\n                           <jats:bold>Abstract<\/jats:bold>\n                        <\/jats:title>\n          <jats:sec>\n            <jats:title\/>\n            <jats:p>\n                                 <jats:bold>Recent investigations have demonstrated a complex interrelationship between autophagy and cell death. A common mechanism of cell death in liver injury is tumor necrosis factor (TNF) cytotoxicity. To better delineate the in vivo function of autophagy in cell death, we examined the role of autophagy in TNF-induced hepatic injury. Atg7\u0394hep mice with a hepatocyte-specific knockout of the autophagy gene<\/jats:bold>\n                                 <jats:bold>\n                                    atg7\n                                 <\/jats:bold>\n                                 <jats:bold>were generated and cotreated with D-galactosamine (GalN) and lipopolysaccharide (LPS). GalN\/LPS-treated Atg7\u0394hep mice had increased serum alanine aminotransferase levels, histological injury, numbers of TUNEL (terminal deoxynucleotide transferase-mediated deoxyuridine triphosphate nick end-labeling)-positive cells and mortality as compared with littermate controls. Loss of hepatocyte autophagy similarly sensitized to GalN\/TNF liver injury. GalN\/LPS injury in knockout animals did not result from altered production of TNF or other cytokines. Atg7\u0394hep mice had accelerated activation of the mitochondrial death pathway and caspase-3 and \u22127 cleavage. Increased cell death did not occur from direct mitochondrial toxicity or a lack of mitophagy, but rather from increased activation of initiator caspase-8 causing Bid cleavage. GalN blocked LPS induction of hepatic autophagy, and increased autophagy from beclin 1 overexpression prevented GalN\/LPS injury. Autophagy, therefore, mediates cellular resistance to TNF toxicity in vivo by blocking activation of caspase-8 and the mitochondrial death pathway, suggesting that autophagy is a therapeutic target in TNF-dependent tissue injury.<\/jats:bold>\n                              <\/jats:p>\n          <\/jats:sec>","DOI":"10.1002\/hep.26572","type":"journal-article","created":{"date-parts":[[2013,6,14]],"date-time":"2013-06-14T16:11:51Z","timestamp":1371226311000},"page":"340-343","update-policy":"https:\/\/doi.org\/10.1097\/lww.0000000000001000","source":"Crossref","is-referenced-by-count":28,"title":["Induction of autophagy, a promising approach for treating liver injury"],"prefix":"10.1097","volume":"59","author":[{"given":"Wen-Xing","family":"Ding","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"276","reference":[{"key":"R1-36-20250213","doi-asserted-by":"crossref","first-page":"1102","DOI":"10.1038\/ncb1007-1102","article-title":"Autophagosome formation: core machinery and adaptations.","volume":"9","author":"Xie","year":"2007","journal-title":"Nat Cell Biol"},{"key":"R2-36-20250213","doi-asserted-by":"crossref","first-page":"425","DOI":"10.1083\/jcb.200412022","article-title":"Impairment of starvation-induced and constitutive autophagy in Atg7-deficient mice.","volume":"169","author":"Komatsu","year":"2005","journal-title":"J Cell Biol"},{"key":"R3-36-20250213","doi-asserted-by":"crossref","first-page":"438","DOI":"10.1093\/toxsci\/kfs133","article-title":"Liver-specific loss of Atg5 causes persistent activation of Nrf2 and protects against acetaminophen-induced liver injury.","volume":"127","author":"Ni","year":"2012","journal-title":"Toxicol Sci"},{"key":"R4-36-20250213","doi-asserted-by":"crossref","first-page":"R1202","DOI":"10.1152\/ajpregu.2000.278.5.R1202","article-title":"LPS-induced liver injury in D-galactosamine-sensitized mice requires secreted TNF-alpha and the TNF-p55 receptor.","volume":"278","author":"Nowak","year":"2000","journal-title":"Am J Physiol Regul Integr Comp Physiol"},{"key":"R5-36-20250213","doi-asserted-by":"crossref","first-page":"491","DOI":"10.2174\/1566524033479555","article-title":"Death receptor activation-induced hepatocyte apoptosis and liver injury.","volume":"3","author":"Yin","year":"2003","journal-title":"Curr Mol Med"},{"key":"R6-36-20250213","doi-asserted-by":"crossref","first-page":"445","DOI":"10.1111\/j.1582-4934.2004.tb00469.x","article-title":"Dissection of the multiple mechanisms of TNF-alpha-induced apoptosis in liver injury.","volume":"8","author":"Ding","year":"2004","journal-title":"J Cell Mol 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p62-dependent aggregation of caspase-8 mediate extrinsic apoptosis signaling.","volume":"137","author":"Jin","year":"2009","journal-title":"Cell"},{"key":"R12-36-20250213","doi-asserted-by":"crossref","first-page":"891","DOI":"10.4161\/auto.6.7.13038","article-title":"Autophagic degradation of active caspase-8: a crosstalk mechanism between autophagy and apoptosis.","volume":"6","author":"Hou","year":"2010","journal-title":"Autophagy"},{"key":"R13-36-20250213","doi-asserted-by":"crossref","first-page":"3158","DOI":"10.1128\/MCB.05460-11","article-title":"Inhibition of protein degradation induces apoptosis through a microtubule-associated protein 1 light chain 3-mediated activation of caspase-8 at intracellular membranes.","volume":"31","author":"Pan","year":"2011","journal-title":"Mol Cell Biol"},{"key":"R14-36-20250213","doi-asserted-by":"crossref","first-page":"12455","DOI":"10.1074\/jbc.M111.309104","article-title":"Autophagosomal membrane serves as platform for intracellular death-inducing signaling complex (iDISC)-mediated caspase-8 activation and apoptosis.","volume":"287","author":"Young","year":"2012","journal-title":"J Biol Chem"},{"key":"R15-36-20250213","doi-asserted-by":"crossref","first-page":"1095","DOI":"10.1038\/emboj.2012.32","article-title":"A lysosome-to-nucleus signalling mechanism senses and regulates the lysosome via mTOR and TFEB.","volume":"31","author":"Settembre","year":"2012","journal-title":"EMBO J"},{"key":"R16-36-20250213","doi-asserted-by":"crossref","first-page":"456","DOI":"10.1126\/science.1196371","article-title":"Phosphorylation of ULK1 (hATG1) by AMP-activated protein kinase connects energy sensing to mitophagy.","volume":"331","author":"Egan","year":"2011","journal-title":"Science"},{"key":"R17-36-20250213","doi-asserted-by":"crossref","first-page":"290","DOI":"10.1016\/j.cell.2012.12.016","article-title":"Differential regulation of distinct Vps34 complexes by AMPK in nutrient stress and 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