Until recently, necrotic cells death was considered an uncontrolled process. However, evidence was recently presented that necrosis is a regulated process associated with many clinical conditions. Humanin and its derivatives are peptides known for their anti-apoptotic activity against Alzheimer’s disease. Recently, the humanin-derivative AGA(C8R)-HNG17 (PAGASRLLLLTGEIDLP) was found to have protective effect against necrosis in traumatic brain injury model in mice. We have demonstrated now the protective effect of AGA(C8R)-HNG17 against necrosis in a dose dependent manner in HepG2 cells in vitro, where necrosis was induced in a glucose-free medium by chemohypoxia. Moreover, it was further demonstrated in a model of acetaminophen-induced liver injury in C57BL/6J male mice, in vivo. Intraperitoneal administration of the peptide at 10 and 30 mg/kg significantly prevented the increase in two plasma markers for necrosis, alanine aminotransferase (ALT, EC 188.8.131.52) and aspartate aminotransferase (AST, EC 184.108.40.206). Mitochondrial dysfunction is known to be the main cause of hepatic failure. Hence, the protection from liver injury by AGA(C8R)-HNG17, which we have recently found to target the mitochondria, may be mediated by mitochondrial regulation. Currently, there is no effective treatment for liver diseases, in which necrosis is involved. These findings may provide a new anti-necrotic strategy against APAP-induced liver injury and other liver diseases associated with necrosis using AGA(C8R)-HNG17 as a therapeutic agent.
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The authors thank Dr. Mark M Karpasas and Lina Saveliev from the Analytical Research Services Unit, Ben Gurion University of the Negev, for mass spectrometric analysis of the peptide, and Dr. Nurit Hadad for her help in the in vivo experiments. The financial support of the Kamin Program from the Chief Scientist of the Ministry of Economy of Israel (to AH Parola, I Nathan, and R Kasher), the James-Frank Center for Laser-Matter Interaction (to AH Parola), the Edmund Safra Foundation for Functional Bio-polymer, the New-York University Shanghai (NYUSH) research grant (to AH Parola), the Lyonel Israels’ Chair Fund (I Nathan), and the Pratt postdoctoral fellowships (to Meridor D. and Khalfin B.) are gratefully acknowledged.
Compliance with Ethical Standards
Conflict of interest
The authors declare that they have no conflict of interest.
All animal procedures and care techniques were approved by the Ben-Gurion University of the Negev Committee for the Ethical Care and Use of Animals in Research.
Research Involving Human and Animal Participants
This article does not contain any studies with human participants performed by any of the authors.
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