Journal
PEPTIDES
Volume 134, Issue -, Pages -Publisher
ELSEVIER SCIENCE INC
DOI: 10.1016/j.peptides.2020.170399
Keywords
Apoptosis; AKTc(D-Ser14)HN; Doxorubicin; Erk1/2; HUJInin; Humanin; Mitochondria; Myoprotection; Necrosis; Neuroprotection; Peptides; Synthetic analog
Funding
- Hebrew University of Jerusalem' Yissum Intramural Research Funds
- David R. Bloom Center for Pharmacy at the Hebrew University of Jerusalem, Israel
- Dr. Adolf and Klara Brettler Center for Research in Molecular Pharmacology and Therapeutics at the Hebrew University of Jerusalem, Israel
- Grass Center for Drug Design and Synthesis of Novel Therapeutics at the Hebrew University of Jerusalem, Israel
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Humanin (HN) is a 24-amino acid mitochondrial-derived peptide, best known for its ability to protect neurons from damage caused by ischemic stroke and neurodegenerative insults and cardiomyocytes from myocardial infarction or doxorubicin (Dox)-induced cardiotoxicity. This study examines the neuroprotective and myoprotective effects of HN novel synthetic analogs HUJInin and c(D-Ser14-HN), prepared by solid-phase peptide synthesis. The cellular models employed were oxygen-glucose-deprivation (OGD) followed by reoxygenation (R)-induced neurotoxicity in PC12 and SH-SY5Y neuronal cell cultures and Dox-induced cardiotoxicity in H9c2 and C2C12 myoblast cell cultures, respectively. Necrotic and apoptotic cell death was measured by LDH release and caspase-3 activity. Erk 1/2 and AKT phosphorylations were examined by western blotting. Mitochondrial calcium and mitochondrial membrane potential were measured using the fluorescent dye tetramethylrhodaminemethyl ester. It was found that HUJInin and c(D-Ser14-HN) conferred significant dose-dependent neuroprotection, a phenomenon related to attenuation of OGD insult-induced Erk 1/2 phosphorylation, stimulation of AKT phosphorylation and improvement of mitochondrial functions. These peptides also conferred myoprotective effect towards Dox-induced apo-necrotic cell death insults. HUJInin and c(D-Ser14-HN) synthetic analogs may provide new lead compounds for the development of a potential candidate drug for stroke treatment and/or Doxinduced cardiotoxicity therapy in cancer patients.
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