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In this study, we have investigated the role of Ca<jats:sup>2+<\/jats:sup> in hesperidin\u2010induced paraptotic cell death in HepG2 cells. Increase in mitochondrial Ca<jats:sup>2+<\/jats:sup> level was observed in hesperidin treated HepG2 cells but not in normal liver cancer cells. Inhibition of inositol\u20101,4,5\u2010triphosphate receptor (IP<jats:sub>3<\/jats:sub>R) and ryanodine receptor also block the mitochondrial Ca<jats:sup>2+<\/jats:sup> accumulation suggesting that the release of Ca<jats:sup>2+<\/jats:sup> from the endoplasmic reticulum (ER) may probably lead to the increase in mitochondrial Ca<jats:sup>2+<\/jats:sup> level. Pretreatment with ruthenium red (RuRed), a Ca<jats:sup>2+<\/jats:sup> uniporter inhibitor inhibited the hesperidin\u2010induced mitochondrial Ca<jats:sup>2+<\/jats:sup> overload, swelling of mitochondria, and cell death in HepG2 cells. It has also been demonstrated that mitochondrial Ca<jats:sup>2+<\/jats:sup> influxes act upstream of ROS and mitochondrial superoxide production. The increased ROS production further leads to mitochondrial membrane loss in hesperidin treated HepG2 cells. Taken together our results show that IP<jats:sub>3<\/jats:sub>R and ryanodine receptor mediated release of Ca<jats:sup>2+<\/jats:sup> from the ER and its subsequent influx through the uniporter into mitochondria contributes to hesperidin\u2010induced paraptosis in HepG2 cells. J. Cell. Physiol. 231: 1261\u20131268, 2016. \u00a9 2015 Wiley Periodicals, Inc.<\/jats:p><\/jats:sec>","DOI":"10.1002\/jcp.25222","type":"journal-article","created":{"date-parts":[[2015,10,22]],"date-time":"2015-10-22T22:58:43Z","timestamp":1445554723000},"page":"1261-1268","source":"Crossref","is-referenced-by-count":80,"title":["Mitochondrial Dysfunction and Ca<sup>2+<\/sup> Overload Contributes to Hesperidin Induced Paraptosis in Hepatoblastoma Cells, HepG2"],"prefix":"10.1002","volume":"231","author":[{"given":"Silvia","family":"Yumnam","sequence":"first","affiliation":[{"name":"Research Institute of Life Science College of Veterinary Medicine (BK21 plus project) Gyeongsang National University, Gazwa Jinju Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gyeong Eun","family":"Hong","sequence":"additional","affiliation":[{"name":"Research Institute of Life Science College of Veterinary Medicine (BK21 plus project) Gyeongsang National University, Gazwa Jinju Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Suchismita","family":"Raha","sequence":"additional","affiliation":[{"name":"Research Institute of Life Science College of Veterinary Medicine (BK21 plus project) Gyeongsang National University, Gazwa Jinju Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Venu Venkatarame Gowda","family":"Saralamma","sequence":"additional","affiliation":[{"name":"Research Institute of Life Science College of Veterinary Medicine (BK21 plus project) Gyeongsang National University, Gazwa Jinju Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ho Jeong","family":"Lee","sequence":"additional","affiliation":[{"name":"Research Institute of Life Science College of Veterinary Medicine (BK21 plus project) Gyeongsang National University, Gazwa Jinju Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Won\u2010Sup","family":"Lee","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine Institute of Health Sciences Gyeongsang National University Jinju Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eun\u2010Hee","family":"Kim","sequence":"additional","affiliation":[{"name":"Department of Nursing Science International University of Korea Jinju Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gon Sup","family":"Kim","sequence":"additional","affiliation":[{"name":"Research Institute of Life Science College of Veterinary Medicine (BK21 plus project) Gyeongsang National University, Gazwa Jinju Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2015,12,2]]},"reference":[{"key":"e_1_2_6_2_1","doi-asserted-by":"publisher","DOI":"10.5152\/tjg.2015.6544"},{"key":"e_1_2_6_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0344-0338(11)81151-9"},{"key":"e_1_2_6_4_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajpcell.00139.2004"},{"key":"e_1_2_6_5_1","doi-asserted-by":"publisher","DOI":"10.1053\/j.gastro.2006.01.006"},{"key":"e_1_2_6_6_1","doi-asserted-by":"publisher","DOI":"10.1021\/cr900019j"},{"key":"e_1_2_6_7_1","doi-asserted-by":"publisher","DOI":"10.1038\/sj.cdd.4400404"},{"key":"e_1_2_6_8_1","doi-asserted-by":"publisher","DOI":"10.1002\/ijc.25516"},{"key":"e_1_2_6_9_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ceca.2006.08.016"},{"key":"e_1_2_6_10_1","first-page":"157","article-title":"Mixed hepatoblastoma in child. 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