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Toxicol Appl Pharmacol. 2014 Oct 15;280(2):345-51. doi: 10.1016/j.taap.2014.08.005. Epub 2014 Aug 16.

The plant decapeptide OSIP108 prevents copper-induced toxicity in various models for Wilson disease.

Author information

1
Centre of Microbial and Plant Genetics (CMPG), KU Leuven, Kasteelpark Arenberg 20, 3001 Heverlee, Belgium.
2
Laboratory for Molecular Biodiscovery, KU Leuven, Campus Gasthuisberg, Herestraat 49, O&N2, 3000 Leuven, Belgium.
3
Clinic for Transplantation Medicine, Münster University Hospital, Albert-Schweitzer-Campus 1, Building A14, D-48149 Münster, Germany.
4
Department of Hepatology and Metabolic Center, University Hospital Gasthuisberg, Herestraat 49, 3000 Leuven, Belgium.
5
Department of Hepatology and Metabolic Center, University Hospital Gasthuisberg, Herestraat 49, 3000 Leuven, Belgium; Department of Pathology, University Hospital Ghent, De Pintelaan 185, 9000 Ghent, Belgium.
6
Centre of Microbial and Plant Genetics (CMPG), KU Leuven, Kasteelpark Arenberg 20, 3001 Heverlee, Belgium; Department of Plant Systems Biology, VIB, Technologiepark 927, 9052 Ghent, Belgium. Electronic address: bruno.cammue@biw.kuleuven.be.

Abstract

BACKGROUND:

Wilson disease (WD) is caused by accumulation of excess copper (Cu) due to a mutation in the gene encoding the liver Cu transporter ATP7B, and is characterized by acute liver failure or cirrhosis and neuronal cell death. We investigated the effect of OSIP108, a plant derived decapeptide that prevents Cu-induced apoptosis in yeast and human cells, on Cu-induced toxicity in various mammalian in vitro models relevant for WD and in a Cu-toxicity zebrafish larvae model applicable to WD.

METHODS:

The effect of OSIP108 was evaluated on viability of various cell lines in the presence of excess Cu, on liver morphology of a Cu-treated zebrafish larvae strain that expresses a fluorescent reporter in hepatocytes, and on oxidative stress levels in wild type AB zebrafish larvae.

RESULTS:

OSIP108 increased not only viability of Cu-treated CHO cells transgenically expressing ATP7B and the common WD-causing mutant ATP7B(H1069Q), but also viability of Cu-treated human glioblastoma U87 cells. Aberrancies in liver morphology of Cu-treated zebrafish larvae were observed, which were further confirmed as Cu-induced hepatotoxicity by liver histology. Injections of OSIP108 into Cu-treated zebrafish larvae significantly increased the amount of larvae with normal liver morphology and decreased Cu-induced production of reactive oxygen species.

CONCLUSIONS:

OSIP108 prevents Cu-induced toxicity in in vitro models and in a Cu-toxicity zebrafish larvae model applicable to WD.

GENERAL SIGNIFICANCE:

All the above data indicate the potential of OSIP108 as a drug lead for further development as a novel WD treatment.

KEYWORDS:

Copper; Hepatotoxicity; OSIP108; Wilson disease; Zebrafish

PMID:
25134866
DOI:
10.1016/j.taap.2014.08.005
[Indexed for MEDLINE]

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