title: Melatonin prevents hepatic injury-induced decrease in Akt downstream targets phosphorylations.
abstract: Melatonin is a potent scavenger of reactive oxygen species and a strong antioxidant. Melatonin exerts protective effects against damage by the enhancing the Akt signal pathway, thus regulating apoptotic cell death. Akt phosphorylates pro-apoptotic proteins such as Bad and FoxO1 and inhibits the pro-apoptotic functions of these proteins. This study investigated the protective effects of melatonin through Akt and its downstream targets, Bad and FoxO1, in hepatic ischemia-reperfusion (I/R) damage. Adult mice were subjected to 1 h of hepatic ischemia and 3 h of reperfusion. Hepatic ischemia was induced by occlusions of the hepatic artery, portal vein, and bile duct. Melatonin (10 mg/kg, i.p.) or vehicle was administrated 15 min prior to ischemia and just before reperfusion. Serum aspartate aminotransferase and alanine aminotransferase levels were higher in I/R group than in sham-operated group. Melatonin attenuated increases in these levels. Moreover, melatonin attenuates injury-induced increases in positive TUNEL staining in hepatic tissues. Hepatic I/R injury induced reductions in the Akt up-stream target, PDK1 phosphorylation. The levels of phospho-Akt, phospho-Bad, and phospho-FoxO1 were decreased in vehicle-treated animals. However, melatonin prevented hepatic I/R injury-induced decreases in these proteins levels. Moreover, the interaction levels between phospho-Bad and 14-3-3 and between phospho-FoxO1 and 14-3-3 are reduced in vehicle-treated animals, and melatonin attenuated decreases in the binding levels of these proteins. 14-3-3 exerts an anti-apoptotic function by sequestration of Bad and FoxO1. These findings suggest that melatonin exerts protective effects in case of hepatic I/R damage by maintaining the binding of phospho-Bad and 14-3-3 and the binding of phospho-FoxO1 and 14-3-3, thus preventing activation of apoptotic cell death.
authors.affiliation: Department of Anatomy, College of Veterinary Medicine, Gyeongsang National University, Jinju, South Korea. pokoh@gnu.ac.kr
authors.forename: Phil-Ok
authors.initials: PO
authors.lastname: Koh
mesh_terms: D048948:14-3-3 Proteins / Q000378:metabolism; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors / Q000378:metabolism; D008099:Liver / Q000378:metabolism* / Q000473:pathology; D008107:Liver Diseases / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D008297:Male; D008550:Melatonin / Q000494:pharmacology*; D051379:Mice; D008813:Mice, Inbred ICR; D010766:Phosphorylation / Q000187:drug effects; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D015427:Reperfusion Injury / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D051025:bcl-Associated Death Protein / Q000378:metabolism
chemical_list: D048948:14-3-3 Proteins; D000975:Antioxidants; C494820:Bad protein, mouse; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; C467200:Foxo1 protein, mouse; C000631433:Pdk1 protein, mouse; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D051025:bcl-Associated Death Protein; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D008550:Melatonin