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NF-κB/p53-activated inflammatory response involves in diquat-induced mitochondrial dysfunction and apoptosis.
Environ Toxicol. 2018 Oct; 33(10):1005-1018.ET

Abstract

Inflammation generated by environmental toxicants including pesticides could be one of the factors underlying neuronal cell damage in neurodegenerative diseases. In this study, we investigated the mechanisms by which inflammatory responses contribute to apoptosis in PC12 cells treated with diquat. We found that diquat induced apoptosis, as demonstrated by the activation of caspases and nuclear condensation, inhibition of mitochondrial complex I activity, and decreased ATP level in PC12 cells. Diquat also reduced the dopamine level, indicating that cell death induced by diquat is due to cytotoxicity of dopaminergic neuronal components in these cells. Exposure of PC12 cells to diquat led to the production of reactive oxygen species (ROS), and the antioxidant N-acetyl-cystein attenuated the cytotoxicity of caspase-3 pathways. These results demonstrate that diquat-induced apoptosis is involved in mitochondrial dysfunction through production of ROS. Furthermore, diquat increased expression of cyclooxygenase-2 (COX-2) and tumor necrosis factor-α (TNF-α) via inflammatory stimulation. Diquat induced nuclear accumulation of NF-κB and p53 proteins. Importantly, an inhibitor of NF-κB nuclear translocation blocked the increase of p53. Both NF-κB and p53 inhibitors also blocked the diquat-induced inflammatory response. Pretreatment of cells with meloxicam, a COX-2 inhibitor, also blocked apoptosis and mitochondrial dysfunction. These results represent a unique molecular characterization of diquat-induced cytotoxicity in PC12 cells. Our results demonstrate that diquat induces cell damage in part through inflammatory responses via NF-κB-mediated p53 signaling. This suggests the potential to generate mitochondrial damage via inflammatory responses and inflammatory stimulation-related neurodegenerative disease.

Authors+Show Affiliations

Department of Pharmacology, College of Medicine, Hanyang University, Seoul, Republic of Korea. Graduate School of Biomedical Science and Engineering, Hanyang University, Seoul, Republic of Korea.Department of Pharmacology, College of Medicine, Hanyang University, Seoul, Republic of Korea. Graduate School of Biomedical Science and Engineering, Hanyang University, Seoul, Republic of Korea.Department of Pharmacology, College of Medicine, Hanyang University, Seoul, Republic of Korea. Graduate School of Biomedical Science and Engineering, Hanyang University, Seoul, Republic of Korea. Hanyang Biomedical Research Institute, Seoul, Republic of Korea.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

29484840

Citation

Choi, Su Eun, et al. "NF-κB/p53-activated Inflammatory Response Involves in Diquat-induced Mitochondrial Dysfunction and Apoptosis." Environmental Toxicology, vol. 33, no. 10, 2018, pp. 1005-1018.
Choi SE, Park YS, Koh HC. NF-κB/p53-activated inflammatory response involves in diquat-induced mitochondrial dysfunction and apoptosis. Environ Toxicol. 2018;33(10):1005-1018.
Choi, S. E., Park, Y. S., & Koh, H. C. (2018). NF-κB/p53-activated inflammatory response involves in diquat-induced mitochondrial dysfunction and apoptosis. Environmental Toxicology, 33(10), 1005-1018. https://doi.org/10.1002/tox.22552
Choi SE, Park YS, Koh HC. NF-κB/p53-activated Inflammatory Response Involves in Diquat-induced Mitochondrial Dysfunction and Apoptosis. Environ Toxicol. 2018;33(10):1005-1018. PubMed PMID: 29484840.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - NF-κB/p53-activated inflammatory response involves in diquat-induced mitochondrial dysfunction and apoptosis. AU - Choi,Su Eun, AU - Park,Yun Sun, AU - Koh,Hyun Chul, Y1 - 2018/02/27/ PY - 2017/09/18/received PY - 2018/02/08/revised PY - 2018/02/11/accepted PY - 2018/2/28/pubmed PY - 2018/10/13/medline PY - 2018/2/28/entrez KW - NF-κB signaling KW - diquat KW - inflammatory response KW - mitochondrial dysfunction KW - p53 signaling SP - 1005 EP - 1018 JF - Environmental toxicology JO - Environ Toxicol VL - 33 IS - 10 N2 - Inflammation generated by environmental toxicants including pesticides could be one of the factors underlying neuronal cell damage in neurodegenerative diseases. In this study, we investigated the mechanisms by which inflammatory responses contribute to apoptosis in PC12 cells treated with diquat. We found that diquat induced apoptosis, as demonstrated by the activation of caspases and nuclear condensation, inhibition of mitochondrial complex I activity, and decreased ATP level in PC12 cells. Diquat also reduced the dopamine level, indicating that cell death induced by diquat is due to cytotoxicity of dopaminergic neuronal components in these cells. Exposure of PC12 cells to diquat led to the production of reactive oxygen species (ROS), and the antioxidant N-acetyl-cystein attenuated the cytotoxicity of caspase-3 pathways. These results demonstrate that diquat-induced apoptosis is involved in mitochondrial dysfunction through production of ROS. Furthermore, diquat increased expression of cyclooxygenase-2 (COX-2) and tumor necrosis factor-α (TNF-α) via inflammatory stimulation. Diquat induced nuclear accumulation of NF-κB and p53 proteins. Importantly, an inhibitor of NF-κB nuclear translocation blocked the increase of p53. Both NF-κB and p53 inhibitors also blocked the diquat-induced inflammatory response. Pretreatment of cells with meloxicam, a COX-2 inhibitor, also blocked apoptosis and mitochondrial dysfunction. These results represent a unique molecular characterization of diquat-induced cytotoxicity in PC12 cells. Our results demonstrate that diquat induces cell damage in part through inflammatory responses via NF-κB-mediated p53 signaling. This suggests the potential to generate mitochondrial damage via inflammatory responses and inflammatory stimulation-related neurodegenerative disease. SN - 1522-7278 UR - https://www.unboundmedicine.com/medline/citation/29484840/NF_κB/p53_activated_inflammatory_response_involves_in_diquat_induced_mitochondrial_dysfunction_and_apoptosis_ L2 - https://doi.org/10.1002/tox.22552 DB - PRIME DP - Unbound Medicine ER -