Abstract |
Previous studies have suggested that elevated blood homocysteic acid (HCA) levels increased the risk of Alzheimer's disease (AD), but the underlying mechanisms are unclear. Herein, we studied the neuronal toxicity of HCA and the underlying mechanisms in HT-22 cells. Results showed that HCA induced cell death in concentration- and time-dependent manners, but did not activate Caspase-3. Additionally, HCA increased ROS production, depleted GSH, inactivated the Nrf2/HO-1 pathway, decreased mitochondrial membrane potential and increased the ratio of Bax/Bcl-2, two apoptosis-related proteins. Furthermore, HCA significantly increased the levels of p-JNK and p-c-Jun and its toxicity dramatically attenuated by SP600125, a specific JNK pathway inhibitor. Taken together, our results provide evidence that HCA induced cytotoxicity in HT-22 cells through down-regulating of Nrf2/HO-1 pathway and activating JNK/c-Jun pathway, supporting that HCA might be a therapeutic target for AD.
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Authors | Min Tan, Ying Ouyang, Minghua Jin, Meihui Chen, Peiqing Liu, Xiaojuan Chao, Ziwei Chen, Xiaohong Chen, Charles Ramassamy, Youheng Gao, Rongbiao Pi |
Journal | Toxicology letters
(Toxicol Lett)
Vol. 223
Issue 1
Pg. 1-8
(Oct 23 2013)
ISSN: 1879-3169 [Electronic] Netherlands |
PMID | 23994730
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Copyright | Copyright © 2013 Elsevier Ireland Ltd. All rights reserved. |
Chemical References |
- Anthracenes
- Membrane Proteins
- NF-E2-Related Factor 2
- Nfe2l2 protein, mouse
- Protein Kinase Inhibitors
- Proto-Oncogene Proteins c-bcl-2
- Reactive Oxygen Species
- Homocysteine
- homocysteic acid
- pyrazolanthrone
- Heme Oxygenase-1
- Hmox1 protein, mouse
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Topics |
- Animals
- Anthracenes
(pharmacology)
- Apoptosis
(drug effects)
- Cell Line
- Cell Survival
(drug effects)
- Dose-Response Relationship, Drug
- Down-Regulation
(drug effects)
- Heme Oxygenase-1
(metabolism)
- Homocysteine
(analogs & derivatives, toxicity)
- MAP Kinase Signaling System
(drug effects)
- Membrane Proteins
(metabolism)
- Mice
- Mitochondria
(drug effects)
- NF-E2-Related Factor 2
(metabolism)
- Neurons
(drug effects, enzymology, metabolism)
- Neurotoxicity Syndromes
(enzymology, etiology, metabolism)
- Oxidative Stress
(drug effects)
- Protein Kinase Inhibitors
(pharmacology)
- Proto-Oncogene Proteins c-bcl-2
(metabolism)
- Reactive Oxygen Species
(metabolism)
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