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  4. Molybdenum induces pancreatic β-cell dysfunction and apoptosis via interdependent of JNK and AMPK activation-regulated mitochondria-dependent and ER stress-triggered pathways
 
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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

Journal
Toxicology and Applied Pharmacology
Journal Volume
294
Pages
54-64
Date Issued
2016
Author(s)
Yang T.-Y.
Yen C.-C.
Lee K.-I.
Su C.-C.
CHING-YAO YANG  
Wu C.-C.
Hsieh S.-S.
Ueng K.-C.
Huang C.-F.
DOI
10.1016/j.taap.2016.01.013
URI
https://www.scopus.com/inward/record.uri?eid=2-s2.0-84956762749&doi=10.1016%2fj.taap.2016.01.013&partnerID=40&md5=3d6d928f8fc45612e7a9ef21357dd289
https://scholars.lib.ntu.edu.tw/handle/123456789/461724
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. ? 2016 Elsevier Inc.
SDGs

[SDGs]SDG3

Other Subjects
2 (2 amino 3 methoxyphenyl)chromone; activating transcription factor 4; activating transcription factor 6; caspase 12; caspase 3; caspase 7; caspase 9; cytochrome c; glucose regulated protein 78; glycogen synthase kinase 3alpha; glycogen synthase kinase 3beta; growth arrest and DNA damage inducible protein 153; hydroxymethylglutaryl coenzyme A reductase kinase; initiation factor 2alpha; Janus kinase; mitogen activated protein kinase 1; mitogen activated protein kinase 3; molybdenum; nicotinamide adenine dinucleotide adenosine diphosphate ribosyltransferase; small interfering RNA; X box binding protein 1; Casp3 protein, mouse; caspase 3; hydroxymethylglutaryl coenzyme A reductase kinase; Janus kinase; molybdenum; animal cell; animal experiment; animal model; apoptosis; Article; cell viability; controlled study; cytotoxicity; endoplasmic reticulum stress; enzyme activation; enzyme phosphorylation; genetic transfection; glucose intolerance; insulin blood level; male; mitochondrial membrane potential; mitochondrion; molecular pathology; mouse; nonhuman; pancreas islet beta cell; pancreas islet disease; premedication; protein expression; regulatory mechanism; RINm5f cell line; signal transduction; toxicology; animal; apoptosis; cell survival; cytology; drug effects; endoplasmic reticulum stress; enzyme activation; enzymology; Institute for Cancer Research mouse; metabolism; mitochondrion; pancreas islet; pancreas islet beta cell; AMP-Activated Protein Kinases; Animals; Apoptosis; Caspase 3; Cell Survival; Endoplasmic Reticulum Stress; Enzyme Activation; Insulin-Secreting Cells; Islets of Langerhans; Janus Kinases; Membrane Potential, Mitochondrial; Mice; Mice, Inbred ICR; Mitochondria; Molybdenum; RNA, Small Interfering; Signal Transduction
Publisher
Academic Press Inc.
Type
journal article

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