https://scholars.lib.ntu.edu.tw/handle/123456789/461773
標題: | Arsenic induces pancreatic β-cell apoptosis via the oxidative stress-regulated mitochondria-dependent and endoplasmic reticulum stress-triggered signaling pathways | 作者: | Lu T.-H. Su C.-C. Chen Y.-W. CHING-YAO YANG Wu C.-C. Hung D.-Z. Chen C.-H. Cheng P.-W. Liu S.-H. Huang C.-F. |
公開日期: | 2011 | 卷: | 201 | 期: | 1 | 起(迄)頁: | 15-26 | 來源出版物: | Toxicology Letters | 摘要: | Arsenic (As), a ubiquitous toxic metal, is an important environmental and industrial pollutant throughout the world. Inorganic As (iAs) is usually more harmful than organic ones and with a high risk of diabetes incidence by exposure. However, the toxicological effects of iAs on growth and function of pancreatic β-cells still remain unclear. Here, we found that iAs significantly decreased insulin secretion and cell viability, and increased ROS and MDA formation in pancreatic β-cell-derived RIN-m5F cells. iAs also induced the increases in sub-G1 hypodiploids, annexin V-Cy3 binding, and caspase-3 activity in RIN-m5F cells, indicating that iAs could induce β-cell apoptosis. Moreover, iAs induced MAPKs activation, mitochondria dysfunction, p53 up-regulation, Bcl-2 and Mdm-2 down-regulation, PARP, and caspase cascades, which displayed features of mitochondria-dependent apoptotic signals. In addition, exposure of RIN-m5F cells to iAs, could trigger ER stress as indicated by the enhancement in ER stress-related molecules induction (such as GRP78, GRP94, CHOP, and XBP1), procaspase-12 cleavage, and calpain activation. The iAs-induced apoptosis and its-related signalings could be effectively reversed by antioxidant N-acetylcysteine. We next observed that exposure of mice to iAs in drinking water for 6 consecutive weeks significantly decreased decreased the plasma insulin, elevated glucose intolerance and plasma lipid peroxidation, and induced islet cells apoptosis, which accompanied with arsenic accumulation in the whole blood and pancreas. N-acetylcysteine effectively antagonized the iAs-induced responses in mice. Taken together, these results suggest that iAs-induced oxidative stress causes pancreatic β-cells apoptosis via the mitochondria-dependent and ER stress-triggered signaling pathways. ? 2010 Elsevier Ireland Ltd. |
URI: | https://www.scopus.com/inward/record.uri?eid=2-s2.0-79651473588&doi=10.1016%2fj.toxlet.2010.11.019&partnerID=40&md5=4335c7709561726e28ff4be085fc2cb1 https://scholars.lib.ntu.edu.tw/handle/123456789/461773 |
ISSN: | 0378-4274 | DOI: | 10.1016/j.toxlet.2010.11.019 | SDG/關鍵字: | acetylcysteine; arsenic; calpain; caspase; caspase 3; insulin; lipocortin 5; mitogen activated protein kinase; nicotinamide adenine dinucleotide adenosine diphosphate ribosyltransferase; procaspase 12; procaspase 3; protein bcl 2; protein MDM2; protein p53; unclassified drug; animal experiment; apoptosis; article; cell protection; cell viability; controlled study; endoplasmic reticulum; enzyme activation; glucose intolerance; insulin blood level; insulin release; lipid peroxidation; male; mitochondrion; mouse; nonhuman; oxidative stress; pancreas islet beta cell; priority journal; protein cleavage; protein expression; upregulation; Acetylcysteine; Animals; Apoptosis; Arsenic; Cell Line, Tumor; Cell Survival; Endoplasmic Reticulum; Insulin; Insulin-Secreting Cells; Lipid Peroxidation; Male; Mice; Mice, Inbred ICR; Mitochondria; Mitogen-Activated Protein Kinases; Oxidative Stress; Phosphorylation; Poly(ADP-ribose) Polymerases; Rats; Reactive Oxygen Species; Signal Transduction; Tumor Suppressor Protein p53; Mus |
顯示於: | 醫學系 |
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