https://scholars.lib.ntu.edu.tw/handle/123456789/376795
標題: | Cadmium Induces Apoptosis in Pancreatic β-Cells through a Mitochondria-Dependent Pathway: The Role of Oxidative Stress-Mediated c-Jun N-Terminal Kinase Activation | 作者: | SHING-HWA LIU | 公開日期: | 2013 | 卷: | 8 | 期: | 2 | 來源出版物: | PLoS ONE | 摘要: | Cadmium (Cd), one of well-known highly toxic environmental and industrial pollutants, causes a number of adverse health effects and diseases in humans. The growing epidemiological studies have suggested a possible link between Cd exposure and diabetes mellitus (DM). However, the toxicological effects and underlying mechanisms of Cd-induced pancreatic β-cell injury are still unknown. In this study, we found that Cd significantly decreased cell viability, and increased sub-G1 hypodiploid cells and annexin V-Cy3 binding in pancreatic β-cell-derived RIN-m5F cells. Cd also increased intracellular reactive oxygen species (ROS) generation and malondialdehyde (MDA) production and induced mitochondrial dysfunction (the loss of mitochondrial membrane potential (MMP) and the increase of cytosolic cytochrome c release), the decreased Bcl-2 expression, increased p53 expression, poly (ADP-ribose) polymerase (PARP) cleavage, and caspase cascades, which accompanied with intracellular Cd accumulation. Pretreatment with the antioxidant N-acetylcysteine (NAC) effectively reversed these Cd-induced events. Furthermore, exposure to Cd induced the phosphorylations of c-jun N-terminal kinases (JNK), extracellular signal-regulated kinases (ERK)1/2, and p38-mitogen-activated protein kinase (MAPK), which was prevented by NAC. Additionally, the specific JNK inhibitor SP600125 or JNK-specific small interference RNA (si-RNA) transfection suppressed Cd-induced β-cell apoptosis and related signals, but not ERK1/2 and p38-MAPK inhibitors (PD98059 and SB203580) did not. However, the JNK inhibitor or JNK-specific si-RNA did not suppress ROS generation in Cd-treated cells. These results indicate that Cd induces pancreatic β-cell death via an oxidative stress downstream-mediated JNK activation-triggered mitochondria-regulated apoptotic pathway. ? 2013 Chang et al. |
URI: | http://www.scopus.com/inward/record.url?eid=2-s2.0-84873557177&partnerID=MN8TOARS http://scholars.lib.ntu.edu.tw/handle/123456789/376795 |
DOI: | 10.1371/journal.pone.0054374 | SDG/關鍵字: | 2 (2 amino 3 methoxyphenyl)chromone; 4 (4 fluorophenyl) 2 (4 methylsulfinylphenyl) 5 (4 pyridyl)imidazole; acetylcysteine; anthra[1,9 cd]pyrazol 6(2h) one; cadmium; caspase; cell protein; cytochrome c; lipocortin 5; malonaldehyde; mitogen activated protein kinase 1; mitogen activated protein kinase p38; nicotinamide adenine dinucleotide adenosine diphosphate ribosyltransferase; protein bcl 2; protein Cy3; protein p53; reactive oxygen metabolite; small interfering RNA; stress activated protein kinase; unclassified drug; cadmium; caspase; cytochrome c; insulin; malonaldehyde; mitogen activated protein kinase; mitogen activated protein kinase p38; nicotinamide adenine dinucleotide adenosine diphosphate ribosyltransferase; protein bcl 2; protein p53; reactive oxygen metabolite; stress activated protein kinase; animal cell; apoptosis; article; cell mediated cytotoxicity; cell viability; controlled study; cytotoxicity test; diploidy; enzyme activation; enzyme phosphorylation; mitochondrial membrane potential; nonhuman; oxidative stress; pancreas islet beta cell; protein cleavage; protein expression; protein protein interaction; rat; signal transduction; animal; apoptosis; cell line; cell survival; cytology; drug effects; Institute for Cancer Research mouse; male; metabolism; mitochondrion; oxidative stress; pancreas islet beta cell; physiology; secretion (process); Animals; Apoptosis; Cadmium; Caspases; Cell Line; Cell Survival; Cytochromes c; Extracellular Signal-Regulated MAP Kinases; Insulin; Insulin-Secreting Cells; JNK Mitogen-Activated Protein Kinases; Male; Malondialdehyde; MAP Kinase Signaling System; Mice, Inbred ICR; Mitochondria; Oxidative Stress; p38 Mitogen-Activated Protein Kinases; Poly(ADP-ribose) Polymerases; Proto-Oncogene Proteins c-bcl-2; Rats; Reactive Oxygen Species; Tumor Suppressor Protein p53 |
顯示於: | 毒理學研究所 |
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