4.4 Article

Novel humanin analogs confer neuroprotection and myoprotection to neuronal and myoblast cell cultures exposed to ischemia-like and doxorubicin-induced cell death insults

期刊

PEPTIDES
卷 134, 期 -, 页码 -

出版社

ELSEVIER SCIENCE INC
DOI: 10.1016/j.peptides.2020.170399

关键词

Apoptosis; AKTc(D-Ser14)HN; Doxorubicin; Erk1/2; HUJInin; Humanin; Mitochondria; Myoprotection; Necrosis; Neuroprotection; Peptides; Synthetic analog

资金

  1. Hebrew University of Jerusalem' Yissum Intramural Research Funds
  2. David R. Bloom Center for Pharmacy at the Hebrew University of Jerusalem, Israel
  3. Dr. Adolf and Klara Brettler Center for Research in Molecular Pharmacology and Therapeutics at the Hebrew University of Jerusalem, Israel
  4. 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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