https://scholars.lib.ntu.edu.tw/handle/123456789/461750
Title: | Arsenic induces reactive oxygen species-caused neuronal cell apoptosis through JNK/ERK-mediated mitochondria-dependent and GRP 78/CHOP-regulated pathways | Authors: | Lu T.-H. Tseng T.-J. Su C.-C. Tang F.-C. Yen C.-C. Liu Y.-Y. CHING-YAO YANG Wu C.-C. Chen K.-L. Hung D.-Z. Chen Y.-W. |
Issue Date: | 2014 | Journal Volume: | 224 | Journal Issue: | 1 | Start page/Pages: | 130-140 | Source: | Toxicology Letters | Abstract: | Arsenic (As), a well-known high toxic metal, is an important environmental and industrial contaminant, and it induces oxidative stress, which causes many adverse health effects and diseases in humans, particularly in inorganic As (iAs) more harmful than organic As. Recently, epidemiological studies have suggested a possible relationship between iAs exposure and neurodegenerative disease development. However, the toxicological effects and underlying mechanisms of iAs-induced neuronal cell injuries are mostly unknown. The present study demonstrated that iAs significantly decreased cell viability and induced apoptosis in Neuro-2a cells. iAs also increased oxidative stress damage (production of malondialdehyde (MDA) and ROS, and reduction of Nrf2 and thioredoxin protein expression) and induced several features of mitochondria-dependent apoptotic signals, including: mitochondrial dysfunction, the activations of PARP and caspase cascades, and the increase in caspase-3 activity. Pretreatment with the antioxidant N-acetylcysteine (NAC) effectively reversed these iAs-induced responses. iAs also increased the phosphorylation of JNK and ERK1/2, but did not that p38-MAPK, in treated Neuro-2a cells. NAC and the specific JNK inhibitor (SP600125) and ERK1/2 inhibitor (PD98059) abrogated iAs-induced cell cytotoxicity, caspase-3/-7 activity, and JNK and ERK1/2 activation. Additionally, exposure of Neuro-2a cells to iAs triggered endoplasmic reticulum (ER) stress identified through several key molecules (GRP 78, CHOP, XBP-1, and caspase-12), which was prevented by NAC. Transfection with GRP 78- and CHOP-specific si-RNA dramatically suppressed GRP 78 and CHOP expression, respectively, and attenuated the activations of caspase-12, -7, and -3 in iAs-exposed cells. Therefore, these results indicate that iAs induces ROS causing neuronal cell death via both JNK/ERK-mediated mitochondria-dependent and GRP 78/CHOP-triggered apoptosis pathways. ? 2013 Elsevier Ireland Ltd. |
URI: | https://www.scopus.com/inward/record.uri?eid=2-s2.0-84887550914&doi=10.1016%2fj.toxlet.2013.10.013&partnerID=40&md5=23934fed1fa5a1dc08cc07a66eaf2700 https://scholars.lib.ntu.edu.tw/handle/123456789/461750 |
ISSN: | 0378-4274 | DOI: | 10.1016/j.toxlet.2013.10.013 | SDG/Keyword: | 2 (2 amino 3 methoxyphenyl)chromone; acetylcysteine; anthra[1,9 cd]pyrazol 6(2h) one; arsenic; caspase 12; caspase 3; caspase 7; glucose regulated protein 78; growth arrest and DNA damage inducible protein 153; malonaldehyde; mitogen activated protein kinase; mitogen activated protein kinase 1; mitogen activated protein kinase 3; mitogen activated protein kinase p38; nicotinamide adenine dinucleotide adenosine diphosphate ribosyltransferase; reactive oxygen metabolite; small interfering RNA; stress activated protein kinase; stress activated protein kinase 1; thioredoxin; transcription factor Nrf2; X box binding protein 1; animal cell; apoptosis; article; cell death; cell viability; endoplasmic reticulum stress; enzyme activation; enzyme activity; flow cytometry; genetic transfection; mitochondrial membrane potential; mitochondrion; nerve cell; neuroblastoma cell; nonhuman; oxidative stress; priority journal; protein expression; protein phosphorylation; signal transduction; Western blotting; Apoptosis; Arsenic; c-Jun N-terminal kinase; C/EBP homologue protein; CHOP; endoplasmic reticulum stress; Endoplasmic reticulum stress (ER stress); ER stress; ERK; extracellular signal-related kinase; glucose-regulated protein; GRP; JNK; MAPKs; mitochondrial membrane potential; mitogen-activated protein kinases; Mitogen-activated protein kinases (MAPKs); MMP; N-acetylcysteine; NAC; Neurotoxicity; Nrf2; nuclear-factor-E2-related factor 2; PARP; poly (ADP-ribose) polymerase; reactive oxygen species; Reactive oxygen species (ROS); ROS; si-RNA; small interference RNA; X-box binding protein-1; XBP-1; Animals; Apoptosis; Arsenic; Extracellular Signal-Regulated MAP Kinases; Heat-Shock Proteins; JNK Mitogen-Activated Protein Kinases; MAP Kinase Signaling System; Mice; Mitochondria; Neurons; Reactive Oxygen Species; Transcription Factor CHOP [SDGs]SDG3 |
Appears in Collections: | 醫學系 |
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