{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,26]],"date-time":"2026-08-26T17:57:51Z","timestamp":1787767071350,"version":"build-2784847793"},"reference-count":57,"publisher":"SAGE Publications","issue":"2","license":[{"start":{"date-parts":[[2019,10,29]],"date-time":"2019-10-29T00:00:00Z","timestamp":1572307200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.sagepub.com\/page\/policies\/text-and-data-mining-license"}],"content-domain":{"domain":["journals.sagepub.com"],"crossmark-restriction":true},"short-container-title":["Hum Exp Toxicol"],"published-print":{"date-parts":[[2020,2]]},"abstract":"<jats:p>Mono(2-ethylhexyl) phthalate (MEHP) is the main metabolite of di(2-ethylhexyl) phthalate (DEHP) in organisms and is commonly used as a plasticizer. Exposure to DEHP impairs the function of islet beta cells (INS-1 cells), which is related to insulin resistance and type 2 diabetes. At present, some research data have also confirmed that MEHP has a certain damage effect on INS-1 cells. In our experiment, we found that MEHP would lead to the increase of reactive oxygen species (ROS) and the upregulation of autophagy. And downregulated ROS production by N-acetyl-L-cysteine could also reduce autophagy. In addition, MEHP-induced lysosomal membrane permeability (LMP) subsequently released cathepsin D. Additionally, MEHP induced the collapse of mitochondrial transmembrane potential and release of cytochrome c. Addition of autophagy inhibitor 3-methyladenine relieved MEHP-induced apoptosis as assessed by the expression of cleaved caspase 3, cleaved caspase 9, and terminal deoxynucleotidyl transferase dUTP nick end labeling assay, indicating that MEHP-induced apoptosis was autophagy dependent. Cathepsin D inhibitor, pepstatin A, suppressed MEHP-induced mitochondria release of cytochrome c and apoptosis as well. Meanwhile, pyrroloquinoline quinone (PQQ), a new B vitamin, improved the above phenomenon. Taken together, our results indicate that MEHP induces autophagy-dependent apoptosis in INS-1 cells by lysosomal\u2013mitochondrial axis. PQQ improved this process by downregulating ROS and provided a degree of protection. Our study provides a new perspective for MEHP on the cytotoxic mechanism and PQQ protection in INS-1 cells.<\/jats:p>","DOI":"10.1177\/0960327119882983","type":"journal-article","created":{"date-parts":[[2019,10,29]],"date-time":"2019-10-29T22:59:07Z","timestamp":1572389947000},"page":"194-211","update-policy":"https:\/\/doi.org\/10.1177\/sage-journals-update-policy","source":"Crossref","is-referenced-by-count":13,"title":["Pyrroloquinoline quinone protected autophagy-dependent apoptosis induced by mono(2-ethylhexyl) phthalate in INS-1 cells"],"prefix":"10.1177","volume":"39","author":[{"given":"L","family":"Shi","sequence":"first","affiliation":[{"name":"Department of Nutrition and Food Safety, College of Public Health, Dalian Medical University, Dalian, People\u2019s Republic of China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"L","family":"Jiang","sequence":"additional","affiliation":[{"name":"Preventive Medicine Laboratory, College of Public Health, Dalian Medical University, Dalian, People\u2019s Republic of China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"X","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Nutrition and Food Safety, College of Public Health, Dalian Medical University, Dalian, People\u2019s Republic of China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"G","family":"Yang","sequence":"additional","affiliation":[{"name":"Department of Nutrition and Food Safety, College of Public Health, Dalian Medical University, Dalian, People\u2019s Republic of China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"C","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Nutrition and Food Safety, College of Public Health, Dalian Medical University, Dalian, People\u2019s Republic of China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"X","family":"Yao","sequence":"additional","affiliation":[{"name":"Department of Occupational and Environmental Health, College of Public Health, Dalian Medical University, Dalian, People\u2019s Republic of China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"X","family":"Wu","sequence":"additional","affiliation":[{"name":"Department of Otorhinolaryngology Head and Neck Surgery, The Second Affiliated Hospital of Dalian Medical University, Dalian, People\u2019s Republic of China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M","family":"Fu","sequence":"additional","affiliation":[{"name":"Department of Otorhinolaryngology Head and Neck Surgery, The Second Affiliated Hospital of Dalian Medical University, Dalian, People\u2019s Republic of China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"X","family":"Sun","sequence":"additional","affiliation":[{"name":"Department of Occupational and Environmental Health, College of Public Health, Dalian Medical University, Dalian, People\u2019s Republic of China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4687-1851","authenticated-orcid":false,"given":"X","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Nutrition and Food Safety, College of Public Health, Dalian Medical University, Dalian, People\u2019s Republic of China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"179","published-online":{"date-parts":[[2019,10,29]]},"reference":[{"key":"bibr1-0960327119882983","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2605.2005.00567.x"},{"key":"bibr2-0960327119882983","doi-asserted-by":"publisher","DOI":"10.1016\/j.ijheh.2007.07.011"},{"key":"bibr3-0960327119882983","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2605.2005.00607.x"},{"key":"bibr4-0960327119882983","doi-asserted-by":"publisher","DOI":"10.1016\/j.taap.2013.01.020"},{"key":"bibr5-0960327119882983","doi-asserted-by":"publisher","DOI":"10.1016\/j.fct.2011.04.001"},{"key":"bibr6-0960327119882983","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0109039"},{"key":"bibr7-0960327119882983","doi-asserted-by":"publisher","DOI":"10.1016\/j.envpol.2017.03.037"},{"key":"bibr8-0960327119882983","doi-asserted-by":"publisher","DOI":"10.1038\/nri2925"},{"key":"bibr9-0960327119882983","doi-asserted-by":"publisher","DOI":"10.1038\/280843a0"},{"key":"bibr10-0960327119882983","doi-asserted-by":"publisher","DOI":"10.1007\/s12038-012-9195-5"},{"key":"bibr11-0960327119882983","doi-asserted-by":"publisher","DOI":"10.3181\/00379727-197-43218"},{"key":"bibr12-0960327119882983","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbrc.2012.10.055"},{"key":"bibr13-0960327119882983","doi-asserted-by":"publisher","DOI":"10.1042\/bj3070331"},{"key":"bibr14-0960327119882983","doi-asserted-by":"publisher","DOI":"10.1038\/422832a"},{"key":"bibr15-0960327119882983","first-page":"980","volume":"255","author":"Hamagishi Y","year":"1990","journal-title":"J Pharmacol Exp Ther"},{"key":"bibr16-0960327119882983","doi-asserted-by":"publisher","DOI":"10.1111\/j.1440-1746.1993.tb01525.x"},{"key":"bibr17-0960327119882983","first-page":"421","volume":"43","author":"Zhu B","year":"2004","journal-title":"J Am Coll Cardiol"},{"key":"bibr18-0960327119882983","doi-asserted-by":"publisher","DOI":"10.1248\/bpb.31.1321"},{"key":"bibr19-0960327119882983","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0121939"},{"key":"bibr20-0960327119882983","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2007.12.018"},{"key":"bibr21-0960327119882983","doi-asserted-by":"publisher","DOI":"10.1016\/j.biocel.2004.04.009"},{"key":"bibr22-0960327119882983","doi-asserted-by":"publisher","DOI":"10.1038\/nature06639"},{"key":"bibr23-0960327119882983","doi-asserted-by":"publisher","DOI":"10.1089\/cbr.2014.1704"},{"key":"bibr24-0960327119882983","doi-asserted-by":"publisher","DOI":"10.1038\/nrm2239"},{"key":"bibr25-0960327119882983","doi-asserted-by":"publisher","DOI":"10.1002\/cam4.1276"},{"key":"bibr26-0960327119882983","doi-asserted-by":"publisher","DOI":"10.1159\/000080503"},{"key":"bibr27-0960327119882983","doi-asserted-by":"publisher","DOI":"10.1007\/s12272-013-0024-7"},{"key":"bibr28-0960327119882983","doi-asserted-by":"publisher","DOI":"10.3858\/emm.2012.44.2.030"},{"key":"bibr29-0960327119882983","volume-title":"Physiology of the lysosome","author":"Saftig P.","year":"2006"},{"key":"bibr30-0960327119882983","first-page":"3012","volume":"15","author":"Zhang Z","year":"2018","journal-title":"Exp Ther Med"},{"key":"bibr31-0960327119882983","doi-asserted-by":"publisher","DOI":"10.3390\/diseases4040031"},{"key":"bibr32-0960327119882983","doi-asserted-by":"publisher","DOI":"10.1248\/bpb.28.1083"},{"key":"bibr33-0960327119882983","doi-asserted-by":"publisher","DOI":"10.4161\/cbt.13.1.18871"},{"key":"bibr34-0960327119882983","doi-asserted-by":"publisher","DOI":"10.1262\/jrd.2015-019"},{"key":"bibr35-0960327119882983","doi-asserted-by":"publisher","DOI":"10.1038\/cddis.2013.263"},{"key":"bibr36-0960327119882983","doi-asserted-by":"publisher","DOI":"10.2147\/OTT.S148108"},{"key":"bibr37-0960327119882983","doi-asserted-by":"publisher","DOI":"10.1007\/s10495-009-0452-5"},{"key":"bibr38-0960327119882983","doi-asserted-by":"publisher","DOI":"10.1016\/j.ymeth.2014.11.021"},{"key":"bibr39-0960327119882983","doi-asserted-by":"publisher","DOI":"10.1080\/10408440600779065"},{"key":"bibr40-0960327119882983","doi-asserted-by":"publisher","DOI":"10.1289\/ehp.7932"},{"key":"bibr41-0960327119882983","doi-asserted-by":"publisher","DOI":"10.1111\/1753-0407.12325"},{"key":"bibr42-0960327119882983","doi-asserted-by":"publisher","DOI":"10.1016\/j.envres.2015.01.010"},{"key":"bibr43-0960327119882983","doi-asserted-by":"publisher","DOI":"10.4161\/oxim.2.3.8608"},{"key":"bibr44-0960327119882983","doi-asserted-by":"publisher","DOI":"10.1007\/s11746-998-0032-9"},{"key":"bibr45-0960327119882983","doi-asserted-by":"publisher","DOI":"10.1023\/A:1011020225433"},{"key":"bibr46-0960327119882983","doi-asserted-by":"publisher","DOI":"10.1177\/074823379901500801"},{"key":"bibr47-0960327119882983","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.171.6.3010"},{"key":"bibr48-0960327119882983","doi-asserted-by":"publisher","DOI":"10.1016\/j.reprotox.2010.04.008"},{"key":"bibr49-0960327119882983","doi-asserted-by":"publisher","DOI":"10.1016\/j.cellsig.2013.11.028"},{"key":"bibr50-0960327119882983","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCRESAHA.108.175448"},{"key":"bibr51-0960327119882983","doi-asserted-by":"publisher","DOI":"10.1016\/j.critrevonc.2017.02.004"},{"key":"bibr52-0960327119882983","doi-asserted-by":"publisher","DOI":"10.4161\/auto.24132"},{"key":"bibr53-0960327119882983","doi-asserted-by":"publisher","DOI":"10.1371\/journal.ppat.1003328"},{"key":"bibr54-0960327119882983","doi-asserted-by":"publisher","DOI":"10.1046\/j.1432-1327.1998.2520001.x"},{"key":"bibr55-0960327119882983","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.cellbio.15.1.269"},{"key":"bibr56-0960327119882983","doi-asserted-by":"publisher","DOI":"10.1016\/j.cbi.2017.01.015"},{"key":"bibr57-0960327119882983","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbrc.2008.11.045"}],"container-title":["Human &amp; Experimental Toxicology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/journals.sagepub.com\/doi\/pdf\/10.1177\/0960327119882983","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/journals.sagepub.com\/doi\/full-xml\/10.1177\/0960327119882983","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/journals.sagepub.com\/doi\/pdf\/10.1177\/0960327119882983","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,4,29]],"date-time":"2026-04-29T07:49:11Z","timestamp":1777448951000},"score":1,"resource":{"primary":{"URL":"https:\/\/journals.sagepub.com\/doi\/10.1177\/0960327119882983"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,10,29]]},"references-count":57,"journal-issue":{"issue":"2","published-print":{"date-parts":[[2020,2]]}},"alternative-id":["10.1177\/0960327119882983"],"URL":"https:\/\/doi.org\/10.1177\/0960327119882983","relation":{},"ISSN":["0960-3271","1477-0903"],"issn-type":[{"value":"0960-3271","type":"print"},{"value":"1477-0903","type":"electronic"}],"subject":[],"published":{"date-parts":[[2019,10,29]]}}}