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Arsenic induces reactive oxygen species-caused neuronal cell apoptosis through JNK/ERK-mediated mitochondria-dependent and GRP 78/CHOP-regulated pathways.
Toxicol Lett. 2014 Jan 03; 224(1):130-40.TL

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.

Authors+Show Affiliations

Department of Physiology, and Graduate Institute of Basic Medical Science, College of Medicine, China Medical University, Taichung 404, Taiwan.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

24157283

Citation

Lu, Tien-Hui, et al. "Arsenic Induces Reactive Oxygen Species-caused Neuronal Cell Apoptosis Through JNK/ERK-mediated Mitochondria-dependent and GRP 78/CHOP-regulated Pathways." Toxicology Letters, vol. 224, no. 1, 2014, pp. 130-40.
Lu TH, Tseng TJ, Su CC, et al. Arsenic induces reactive oxygen species-caused neuronal cell apoptosis through JNK/ERK-mediated mitochondria-dependent and GRP 78/CHOP-regulated pathways. Toxicol Lett. 2014;224(1):130-40.
Lu, T. H., Tseng, T. J., Su, C. C., Tang, F. C., Yen, C. C., Liu, Y. Y., Yang, C. Y., Wu, C. C., Chen, K. L., Hung, D. Z., & Chen, Y. W. (2014). Arsenic induces reactive oxygen species-caused neuronal cell apoptosis through JNK/ERK-mediated mitochondria-dependent and GRP 78/CHOP-regulated pathways. Toxicology Letters, 224(1), 130-40. https://doi.org/10.1016/j.toxlet.2013.10.013
Lu TH, et al. Arsenic Induces Reactive Oxygen Species-caused Neuronal Cell Apoptosis Through JNK/ERK-mediated Mitochondria-dependent and GRP 78/CHOP-regulated Pathways. Toxicol Lett. 2014 Jan 3;224(1):130-40. PubMed PMID: 24157283.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Arsenic induces reactive oxygen species-caused neuronal cell apoptosis through JNK/ERK-mediated mitochondria-dependent and GRP 78/CHOP-regulated pathways. AU - Lu,Tien-Hui, AU - Tseng,To-Jung, AU - Su,Chin-Chuan, AU - Tang,Feng-Cheng, AU - Yen,Cheng-Chieh, AU - Liu,Yu-Yun, AU - Yang,Ching-Yao, AU - Wu,Chin-Ching, AU - Chen,Kuo-Liang, AU - Hung,Dong-Zong, AU - Chen,Ya-Wen, Y1 - 2013/10/21/ PY - 2013/04/27/received PY - 2013/10/09/revised PY - 2013/10/11/accepted PY - 2013/10/26/entrez PY - 2013/10/26/pubmed PY - 2014/2/7/medline KW - Apoptosis KW - Arsenic KW - C/EBP homologue protein KW - CHOP KW - ER stress KW - ERK KW - Endoplasmic reticulum stress (ER stress) KW - GRP KW - JNK KW - MAPKs KW - MMP KW - Mitogen-activated protein kinases (MAPKs) KW - N-acetylcysteine KW - NAC KW - Neurotoxicity KW - Nrf2 KW - PARP KW - ROS KW - Reactive oxygen species (ROS) KW - X-box binding protein-1 KW - XBP-1 KW - c-Jun N-terminal kinase KW - endoplasmic reticulum stress KW - extracellular signal-related kinase KW - glucose-regulated protein KW - mitochondrial membrane potential KW - mitogen-activated protein kinases KW - nuclear-factor-E2-related factor 2 KW - poly (ADP-ribose) polymerase KW - reactive oxygen species KW - si-RNA KW - small interference RNA SP - 130 EP - 40 JF - Toxicology letters JO - Toxicol Lett VL - 224 IS - 1 N2 - 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. SN - 1879-3169 UR - https://www.unboundmedicine.com/medline/citation/24157283/Arsenic_induces_reactive_oxygen_species_caused_neuronal_cell_apoptosis_through_JNK/ERK_mediated_mitochondria_dependent_and_GRP_78/CHOP_regulated_pathways_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0378-4274(13)01356-8 DB - PRIME DP - Unbound Medicine ER -