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Molybdenum induces pancreatic β-cell dysfunction and apoptosis via interdependent of JNK and AMPK activation-regulated mitochondria-dependent and ER stress-triggered pathways.
- Source :
-
Toxicology and applied pharmacology [Toxicol Appl Pharmacol] 2016 Mar 01; Vol. 294, pp. 54-64. Date of Electronic Publication: 2016 Jan 21. - Publication Year :
- 2016
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Abstract
- Molybdenum (Mo), a well-known toxic environmental and industrial pollutant, causes adverse health effects and diseases in humans and has received attention as a potential risk factor for DM. However, the roles of Mo in the mechanisms of the toxicological effects in pancreatic β-cells are mostly unclear. In this study, the results revealed dysfunction of insulin secretion and apoptosis in the pancreatic β-cell-derived RIN-m5F cells and the isolated mouse islets in response to Mo. These effects were accompanied by a mitochondria-dependent apoptotic signals including a decreased in the MMP, an increase in cytochrome c release, and the activation of caspase cascades and PARP. In addition, ER stress was triggered as indicated by several key molecules of the UPR. Furthermore, exposure to Mo induced the activation of ERK1/2, JNK, AMPKα, and GSK3-α/β. Pretreatment with specific pharmacological inhibitors (in RIN-m5F cells and isolated mouse islets) of JNK (SP600125) and AMPK (Compound C) or transfection with si-RNAs (in RIN-m5F cells) specific to JNK and AMPKα effectively prevented the Mo-induced apoptosis and related signals, but inhibitors of ERK1/2 and GSK3-α/β (PD98059 and LiCl, respectively) did not reverse the Mo-induced effects. Additionally, both the inhibitors and specific si-RNAs could suppress the Mo-induced phosphorylation of JNK and AMPKα each other. Taken together, these results suggest that Mo exerts its cytotoxicity on pancreatic β-cells by inducing dysfunction and apoptosis via interdependent JNK and AMPK activation downstream-regulated mitochondrial-dependent and ER stress-triggered apoptosis pathways.<br /> (Copyright © 2016 Elsevier Inc. All rights reserved.)
- Subjects :
- Animals
Caspase 3 metabolism
Cell Survival drug effects
Islets of Langerhans cytology
Islets of Langerhans metabolism
Membrane Potential, Mitochondrial drug effects
Mice
Mice, Inbred ICR
RNA, Small Interfering
Signal Transduction drug effects
AMP-Activated Protein Kinases drug effects
Apoptosis drug effects
Endoplasmic Reticulum Stress drug effects
Enzyme Activation drug effects
Insulin-Secreting Cells drug effects
Janus Kinases drug effects
Mitochondria drug effects
Mitochondria enzymology
Molybdenum pharmacology
Subjects
Details
- Language :
- English
- ISSN :
- 1096-0333
- Volume :
- 294
- Database :
- MEDLINE
- Journal :
- Toxicology and applied pharmacology
- Publication Type :
- Academic Journal
- Accession number :
- 26806093
- Full Text :
- https://doi.org/10.1016/j.taap.2016.01.013