Uncoupling protein-2 up-regulation and enhanced cyanide toxicity are mediated by PPARalpha activation and oxidative stress.

Uncoupling protein-2 up-regulation and enhanced cyanide toxicity are mediated by PPARalpha activation and oxidative stress. Research Abstract Details 

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Uncoupling protein-2 up-regulation and enhanced cyanide toxicity are mediated by PPARalpha activation and oxidative stress. Abstract Text:

X Zhang,L Li,K Prabhakaran,L Zhang,H B Leavesley,J L Borowitz,G E Isom,

Uncoupling protein 2 (UCP-2) is an inner mitochondrial membrane proton carrier that modulates mitochondrial membrane potential (DeltaPsi(m)) and uncouples oxidative phosphorylation. We have shown that up-regulation of UCP-2 by Wy14,643, a selective peroxisome proliferator-activated receptor-alpha (PPARalpha) agonist, enhances cyanide cytotoxicity. The pathway by which Wy14,643 up-regulates UCP-2 was determined in a dopaminergic cell line (N27 cells). Since dopaminergic mesencephalic cells are a primary brain target of cyanide, the N27 immortalized mesencephalic cell was used in this study. Wy14,643 produced a concentration- and time-dependent up-regulation of UCP-2 that was linked to enhanced cyanide-induced cell death. MK886 (PPARalpha antagonist) or PPARalpha knock-down by RNA interference (RNAi) inhibited PPARalpha activity as shown by the peroxisome proliferator response element-luciferase reporter assay, but only partially decreased up-regulation of UCP-2. The role of oxidative stress as an alternative pathway to UCP-2 up-regulation was determined. Wy14,643 induced a rapid surge of ROS generation and loading cells with glutathione ethyl ester (GSH-EE) or pre-treatment with vitamin E attenuated up-regulation of UCP-2. On the other hand, RNAi knockdown of PPARalpha did not alter ROS generation, suggesting a PPARalpha-independent component to the response. Co-treatment with PPARalpha-RNAi and GSH-EE blocked both the up-regulation of UCP-2 by Wy14,643 and the cyanide-induced cell death. It was concluded that a PPARalpha-mediated pathway and an oxidative stress pathway independent of PPARalpha mediate the up-regulation of UCP-2 and subsequent increased vulnerability to cyanide-induced cytotoxicity.

Uncoupling protein-2 up-regulation and enhanced cyanide toxicity are mediated by PPARalpha activation and oxidative stress. Publishing Authors By Initials

X Zhang,L Li,K Prabhakaran,L Zhang,HB Leavesley,JL Borowitz,GE Isom,

For similar heterocyclic compounds: heterocyclic compounds, 2-ring: benzopyrans: vitamin e research abstracts see: heterocyclic compounds: heterocyclic compounds, 2-ring: benzopyrans: vitamin e research

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Uncoupling protein-2 up-regulation and enhanced cyanide toxicity are mediated by PPARalpha activation and oxidative stress. Journal Published:

PUBLICATION TYPE: Research Support, N.I.H., Extr

Journal: Toxicology and applied pharmacology

VOLUME: 223

Page Numbers: 10-9

Journal Abbreviation: Toxicol. Appl. Pharmacol.

ISSN: 0041-008X

DAY: 18

MONTH: 05

YEAR: 2007

Uncoupling protein-2 up-regulation and enhanced cyanide toxicity are mediated by PPARalpha activation and oxidative stress. Information

Number of References:

LANGUAGE: eng

NlmUniqueID: 416575

Uncoupling protein-2 up-regulation and enhanced cyanide toxicity are mediated by PPARalpha activation and oxidative stress. Keywords Mesh Terms:

KEYWORDS: Vitamin E

MESH TERMS: pharmacology

Chemical & Substance for Abstract: Uncoupling protein-2 up-regulation and enhanced cyanide toxicity are mediated by PPARalpha activation and oxidative stress. Information

Substance Name: Glutathione

Registry Number: 70-18-8

Grant and Affiliation Information for Uncoupling protein-2 up-regulation and enhanced cyanide toxicity are mediated by PPARalpha activation and oxidative stress.

AFFILIATION: Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University, West Lafayette, IN 47907-1333, USA.

Country: United States

AGENCY: United States NIEHS

GRANT: ES04140

ACRONYM: ES

MEDLINETA: Toxicol Appl Pharmacol

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