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 184.108.40.206) and aspartate aminotransferase (AST, EC 220.127.116.11). 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.
This is a preview of subscription content, log in to check access.
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.
Almeda-Valdes P, Altamirano-Barrera A, Uribe M, Mendez-Sanchez N (2016) Metabolic features of alcoholic liver disease. Rev Recent Clin Trials 11:220–226CrossRefPubMedGoogle Scholar
Cohen-Yeshurun A, Trembovler V, Alexandrovich A, Ryberg E, Greasley PJ et al (2011) N-arachidonoyl-L-serine is neuroprotective after traumatic brain injury by reducing apoptosis. J Cereb Blood Flow Metab 31:1768–1777CrossRefPubMedPubMedCentralGoogle Scholar
Cover C, Mansouri A, Knight TR, Bajt ML, Lemasters JJ et al (2005) Peroxynitrite-induced mitochondrial and endonuclease-mediated nuclear DNA damage in acetaminophen hepatotoxicity. J Pharmacol Exp Ther 315:879–887CrossRefPubMedGoogle Scholar
Du K, Williams CD, McGill MR, Xie Y, Farhood A et al (2013) The gap junction inhibitor 2-aminoethoxy-diphenyl-borate protects against acetaminophen hepatotoxicity by inhibiting cytochrome P450 enzymes and c-jun N-terminal kinase activation. Toxicol Appl Pharmacol 273:484–491CrossRefPubMedGoogle Scholar
Feldman Z, Gurevitch B, Artru AA, Oppenheim A, Shohami E et al (1996) Effect of magnesium given 1 hour after head trauma on brain edema and neurological outcome. J Neurosurg 85:131–137CrossRefPubMedGoogle Scholar
Giboney PT (2005) Mildly elevated liver transaminase levels in the asymptomatic patient. Am Fam Phys 71:1105–1110Google Scholar
Guicciardi ME, Malhi H, Mott JL, Gores GJ (2013) Apoptosis and necrosis in the liver. Compr Physiol 3:977–1010PubMedGoogle Scholar
Gujral JS, Knight TR, Farhood A, Bajt ML, Jaeschke H (2002) Mode of cell death after acetaminophen overdose in mice: apoptosis or oncotic necrosis? Toxicol Sci 67:322–328CrossRefPubMedGoogle Scholar
Guo B, Zhai D, Cabezas E, Welsh K, Nouraini S et al (2003) Humanin peptide suppresses apoptosis by interfering with Bax activation. Nature 423:456–461CrossRefPubMedGoogle Scholar
Harada M, Habata Y, Hosoya M, Nishi K, Fuji R et al (2004) N-Formylated humanin activates both formyl peptide receptor-like 1 and 2. Biochem Biophys Res Commun 324:255–261CrossRefPubMedGoogle Scholar
Hashimoto Y, Ito Y, Niikura T, Shao Z, Hata M et al (2001a) Mechanisms of neuroprotection by a novel rescue factor Humanin from Swedish mutant amyloid precursor protein. Biochem Biophys Res Commun 283:460–468CrossRefPubMedGoogle Scholar
Hashimoto Y, Niikura T, Ito Y, Sudo H, Hata M et al (2001b) Detailed characterization of neuroprotection by a rescue factor humanin against various Alzheimer’s disease-relevant insults. J Neurosci 21:9235–9245CrossRefPubMedGoogle Scholar
Hashimoto Y, Niikura T, Tajima H, Yasukawa T, Sudo H et al (2001c) A rescue factor abolishing neuronal cell death by a wide spectrum of familial Alzheimer’s disease genes and Abeta. Proc Natl Acad Sci USA 98:6336–6341CrossRefPubMedPubMedCentralGoogle Scholar
Hashimoto Y, Kurita M, Aiso S, Nishimoto I, Matsuoka M (2009) Humanin inhibits neuronal cell death by interacting with a cytokine receptor complex or complexes involving CNTF receptor alpha/WSX-1/gp-130. Mol Biol Cell 20:2864–2873CrossRefPubMedPubMedCentralGoogle Scholar
Howell BA, Siler SQ, Shoda LKM, Yang Y, Woodhead JL, Watkins PB (2014) A mechanistic model of drug-induced liver injury aids the interpretation of elevated liver transaminase levels in a phase I clinical trial. CPT 3:1–8Google Scholar
Jaeschke H, McGill MR, Ramachandran A (2012) Oxidant stress, mitochondria, and cell death mechanisms in drug-induced liver injury: Lessons learned from acetaminophen hepatotoxicity. Drug Metab Rev 44:88–106CrossRefPubMedPubMedCentralGoogle Scholar
Jaeschke H, Williams CD, McGill MR, Xie Y, Ramachandran A (2013) Models of drug-induced liver injury for evaluation of phytotherapeutics and other natural products. Food Chem Toxicol 55:279–289CrossRefPubMedPubMedCentralGoogle Scholar
Jin H, Liu T, Wang W-X, Xu J-H, Yang P-B et al (2010) Protective effects of [Gly14]-humanin on β-amyloid-induced PC12 cell death by preventing mitochondrial dysfunction. Neurochem Int 56:417–423CrossRefPubMedGoogle Scholar
Jollow DJ, Mitchell JR, Potter WZ, Davis DC, Gillette JR, Brodie BB (1973) Acetaminophen-induced hepatic necrosis. II. Role of covalent binding in vivo. J Pharmacol Exp Ther 187:195–202PubMedGoogle Scholar
Korzeniewski C, Callewaert DM (1983) An enzyme-release assay for natural cytotoxicity. J Immunol Methods 64:313–320CrossRefPubMedGoogle Scholar
Latchoumycandane C, Goh CW, Ong MMK, Boelsterli UA (2007) Mitochondrial protection by the JNK inhibitor leflunomide rescues mice from acetaminophen-induced liver injury. Hepatology (Hoboken) 45:412–421CrossRefGoogle Scholar
Lawson JA, Fisher MA, Simmons CA, Farhood A, Jaeschke H (1999) Inhibition of fas receptor (CD95)-induced hepatic caspase activation and apoptosis by acetaminophen in mice. Toxicol Appl Pharmacol 156:179–186CrossRefPubMedGoogle Scholar
Tomishima Y, Ishitsuka Y, Matsunaga N, Nagatome M, Furusho H et al (2013) Ozagrel hydrochloride, a selective thromboxane A2 synthase inhibitor, alleviates liver injury induced by acetaminophen overdose in mice. BMC Gastroenterol 13:21CrossRefPubMedPubMedCentralGoogle Scholar
Williams CD, Bajt ML, Sharpe MR, McGill MR, Farhood A, Jaeschke H (2014) Neutrophil activation during acetaminophen hepatotoxicity and repair in mice and humans. Toxicol Appl Pharmacol 275:122–133CrossRefPubMedPubMedCentralGoogle Scholar
Yang R, Zou X, Koskinen M-L, Tenhunen J (2012) Ethyl pyruvate reduces liver injury at early phase but impairs regeneration at late phase in acetaminophen overdose. Crit Care 16:R9CrossRefPubMedPubMedCentralGoogle Scholar
Yin H, Cheng L, Holt M, Hail N Jr, MacLaren R, Ju C (2010) Lactoferrin protects against acetaminophen-induced liver injury in mice. Hepatology (Hoboken) 51:1007–1016Google Scholar
Ying G, Iribarren P, Zhou Y, Gong W, Zhang N et al (2004) Humanin, a newly identified neuroprotective factor, uses the G protein-coupled formylpeptide receptor-like-1 as a functional receptor. J Immunol 172:7078–7085CrossRefPubMedGoogle Scholar
Zhai D, Luciano F, Zhu X, Guo B, Satterthwait AC et al (2005) Humanin binds and nullifies Bid activity by blocking its activation of Bax and Bak. J Biol Chem 280:15815–15824CrossRefPubMedGoogle Scholar
Zhang L, Gavin T, Geohagen BC, Liu Q, Downey KJ, LoPachin RM (2013) Protective properties of 2-acetylcyclopentanone in a mouse model of acetaminophen hepatotoxicity. J Pharmacol Exp Ther 346:259–269CrossRefPubMedPubMedCentralGoogle Scholar
Zhou H, Chen L, Gao X, Luo B, Chen J (2012) Moderate traumatic brain injury triggers rapid necrotic death of immature neurons in the hippocampus. J Neuropathol Exp Neurol 71:348–359CrossRefPubMedPubMedCentralGoogle Scholar