{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,16]],"date-time":"2026-10-16T01:17:45Z","timestamp":1792113465127,"version":"4.4.0"},"reference-count":82,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2022,4,23]],"date-time":"2022-04-23T00:00:00Z","timestamp":1650672000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Ministry of Science and Technology, Taipei, Taiwan","award":["MOST 110-2320-B-303-004-"],"award-info":[{"award-number":["MOST 110-2320-B-303-004-"]}]},{"name":"Ministry of Science and Technology, Taipei, Taiwan","award":["MOST 109-2320-B-039-039"],"award-info":[{"award-number":["MOST 109-2320-B-039-039"]}]},{"name":"Taoyuan General Hospital, Ministry of Health and Welfare, Taiwan","award":["Grants No. PTH10658"],"award-info":[{"award-number":["Grants No. PTH10658"]}]},{"name":"Taoyuan General Hospital, Ministry of Health and Welfare, Taiwan","award":["Grants No. PTH109018"],"award-info":[{"award-number":["Grants No. PTH109018"]}]},{"name":"Far Eastern Memorial Hospital, New Taipei City, Taiwan","award":["Grant no. FEMH-2019-C-022"],"award-info":[{"award-number":["Grant no. FEMH-2019-C-022"]}]},{"DOI":"10.13039\/501100012544","name":"China Medical University, Taiwan","doi-asserted-by":"publisher","award":["CMU110-S-36"],"award-info":[{"award-number":["CMU110-S-36"]}],"id":[{"id":"10.13039\/501100012544","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Ketamine-associated cystitis is characterized by suburothelial inflammation and urothelial cell death. Norketamine (NK), the main metabolite of ketamine, is abundant in urine following ketamine exposure. NK has been speculated to exert toxic effects in urothelial cells, similarly to ketamine. However, the molecular mechanisms contributing to NK-induced urothelial cytotoxicity are almost unclear. Here, we aimed to investigate the toxic effects of NK and the potential mechanisms underlying NK-induced urothelial cell injury. In this study, NK exposure significantly reduced cell viability and induced apoptosis in human urinary bladder epithelial-derived RT4 cells that NK (0.01\u20130.5 mM) exhibited greater cytotoxicity than ketamine (0.1\u20133 mM). Signals of mitochondrial dysfunction, including mitochondrial membrane potential (MMP) loss and cytosolic cytochrome c release, were found to be involved in NK-induced cell apoptosis and death. NK exposure of cells also triggered the expression of endoplasmic reticulum (ER) stress-related proteins including GRP78, CHOP, XBP-1, ATF-4 and -6, caspase-12, PERK, eIF-2\u03b1, and IRE-1. Pretreatment with 4-phenylbutyric acid (an ER stress inhibitor) markedly prevented the expression of ER stress-related proteins and apoptotic events in NK-exposed cells. Additionally, NK exposure significantly activated JNK, ERK1\/2, and p38 signaling and increased intracellular calcium concentrations ([Ca2+]i). Pretreatment of cells with both PD98059 (an ERK1\/2 inhibitor) and BAPTA\/AM (a cell-permeable Ca2+ chelator), but not SP600125 (a JNK inhibitor) and SB203580 (a p38 inhibitor), effectively suppressed NK-induced mitochondrial dysfunction, ER stress-related signals, and apoptotic events. The elevation of [Ca2+]i in NK-exposed cells could be obviously inhibited by BAPTA\/AM, but not PD98059. Taken together, these findings suggest that NK exposure exerts urothelial cytotoxicity via a [Ca2+]i-regulated ERK1\/2 activation, which is involved in downstream mediation of the mitochondria-dependent and ER stress-triggered apoptotic pathway, consequently resulting in urothelial cell death. Our findings suggest that regulating [Ca2+]i\/ERK signaling pathways may be a promising strategy for treatment of NK-induced urothelial cystitis.<\/jats:p>","DOI":"10.3390\/ijms23094666","type":"journal-article","created":{"date-parts":[[2022,4,23]],"date-time":"2022-04-23T08:14:06Z","timestamp":1650701646000},"page":"4666","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":15,"title":["Norketamine, the Main Metabolite of Ketamine, Induces Mitochondria-Dependent and ER Stress-Triggered Apoptotic Death in Urothelial Cells via a Ca2+-Regulated ERK1\/2-Activating Pathway"],"prefix":"10.3390","volume":"23","author":[{"given":"Jhe-Wei","family":"Lin","sequence":"first","affiliation":[{"name":"Department of Physiology, School of Medicine, College of Medicine, China Medical University, Taichung 404, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yi-Chun","family":"Lin","sequence":"additional","affiliation":[{"name":"Department of Infectious Diseases, Taoyuan General Hospital, Ministry of Health and Welfare, Taoyuan 330, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3868-085X","authenticated-orcid":false,"given":"Jui-Ming","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Urology, Taoyuan General Hospital, Ministry of Health and Welfare, Taoyuan 330, Taiwan"},{"name":"Department of Obstetrics and Gynecology, Tri-Service General Hospital, National Defense Medical Center, Taipei 114, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9976-1197","authenticated-orcid":false,"given":"Shing-Hwa","family":"Liu","sequence":"additional","affiliation":[{"name":"Institute of Toxicology, College of Medicine, National Taiwan University, Taipei 100, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kai-Min","family":"Fang","sequence":"additional","affiliation":[{"name":"Department of Otolaryngology, Far Eastern Memorial Hospital, New Taipei City 220, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2877-9215","authenticated-orcid":false,"given":"Ren-Jun","family":"Hsu","sequence":"additional","affiliation":[{"name":"Department of Pathology and Graduate Institute of Pathology and Parasitology, Tri-Service General Hospital, Taipei 114, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0122-0043","authenticated-orcid":false,"given":"Chun-Fa","family":"Huang","sequence":"additional","affiliation":[{"name":"School of Chinese Medicine, College of Chinese Medicine, China Medical University, Taichung 404, Taiwan"},{"name":"Department of Nursing, College of Medical and Health Science, Asia University, Taichung 413, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kai-Yao","family":"Chang","sequence":"additional","affiliation":[{"name":"Department of Emergency, Taichung Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Taichung 427, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kuan-I","family":"Lee","sequence":"additional","affiliation":[{"name":"Department of Emergency, Taichung Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Taichung 427, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kai-Chih","family":"Chang","sequence":"additional","affiliation":[{"name":"Center for Digestive Medicine, Department of Internal Medicine, China Medical University Hospital, Taichung 404, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chin-Chuan","family":"Su","sequence":"additional","affiliation":[{"name":"Department of Otorhinolaryngology, Head and Neck Surgery, Changhua Christian Hospital, Changhua County 500, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ya-Wen","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Physiology, School of Medicine, College of Medicine, China Medical University, Taichung 404, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,4,23]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1111\/j.1360-0443.2011.03576.x","article-title":"Ketamine use: A review","volume":"107","author":"Morgan","year":"2012","journal-title":"Addiction"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"93","DOI":"10.1159\/000338098","article-title":"Ketamine-Associated Urinary Tract Dysfunction: An Underrecognized Clinical Entity","volume":"89","author":"Lai","year":"2012","journal-title":"Urol. 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