Pieter Spincemaille1, Duc-Hung Pham2, Gursimran Chandhok3, Jef Verbeek4, Andree Zibert3, Louis Libbrecht5, Hartmut Schmidt3, Camila V Esguerra2, Peter A M de Witte2, Bruno P A Cammue6, David Cassiman4, Karin Thevissen1. 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.
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-toxicityzebrafish 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 humanglioblastomaU87 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-toxicityzebrafish 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.
Authors: Patrizia Tavormina; Barbara De Coninck; Natalia Nikonorova; Ive De Smet; Bruno P A Cammue Journal: Plant Cell Date: 2015-08-14 Impact factor: 11.277
Authors: Xuan-Bac Nguyen; Stanislav Kislyuk; Duc-Hung Pham; Angela Kecskés; Jan Maes; Deirdre Cabooter; Pieter Annaert; Peter De Witte; Annelii Ny Journal: Int J Mol Sci Date: 2017-02-08 Impact factor: 5.923
Authors: Pieter Spincemaille; Gursimran Chandhok; Andree Zibert; Hartmut Schmidt; Jef Verbeek; Patrick Chaltin; Bruno P Cammue; David Cassiman; Karin Thevissen Journal: Microb Cell Date: 2014-10-24
Authors: Pieter Spincemaille; Hamed Alborzinia; Jeroen Dekervel; Petra Windmolders; Jos van Pelt; David Cassiman; Olivier Cheneval; David J Craik; Julia Schur; Ingo Ott; Stefan Wölfl; Bruno P A Cammue; Karin Thevissen Journal: Molecules Date: 2014-09-19 Impact factor: 4.411