PMID- 22686283 OWN - NLM STAT- MEDLINE DCOM- 20130322 LR - 20211203 IS - 1600-079X (Electronic) IS - 0742-3098 (Linking) VI - 53 IP - 4 DP - 2012 Nov TI - Melatonin prevents hemorrhagic shock-induced liver injury in rats through an Akt-dependent HO-1 pathway. PG - 410-6 LID - 10.1111/j.1600-079X.2012.01011.x [doi] AB - Although melatonin treatment following trauma-hemorrhage or ischemic reperfusion prevents organs from dysfunction and injury, the precise mechanism remains unknown. This study tested whether melatonin prevents liver injury following trauma-hemorrhage involved the protein kinase B (Akt)-dependent heme oxygenase (HO)-1 pathway. After a 5-cm midline laparotomy, male rats underwent hemorrhagic shock (mean blood pressure approximately 40 mmHg for 90 min) followed by fluid resuscitation. At the onset of resuscitation, rats were treated with vehicle, melatonin (2 mg/kg), or melatonin plus phosphoinositide 3-kinase (PI3K) inhibitor wortmannin (1 mg/kg). At 2 hr after trauma-hemorrhage, the liver tissue myeloperoxidase activity, malondialdehyde, adenosine triphosphate, serum alanine aminotransferase, and aspartate aminotransferase levels were significantly increased compared with sham-operated control. Trauma-hemorrhage resulted in a significant decrease in the Akt activation in comparison with the shams (relative density, 0.526 +/- 0.031 versus 1.012 +/- 0.066). Administration of melatonin following trauma-hemorrhage normalized liver Akt phosphorylation (0.993 +/- 0.061), further increased mammalian target of rapamycin (mTOR) activation (5.263 +/- 0.338 versus 2.556 +/- 0.225) and HO-1 expression (5.285 +/- 0.325 versus 2.546 +/- 0.262), and reduced cleaved caspase-3 levels (2.155 +/- 0.297 versus 5.166 +/- 0.309). Coadministration of wortmannin abolished the melatonin-mediated attenuation of the shock-induced liver injury markers. Our results collectively suggest that melatonin prevents hemorrhagic shock-induced liver injury in rats through an Akt-dependent HO-1 pathway. CI - (c) 2012 John Wiley & Sons A/S. FAU - Hsu, Jun-Te AU - Hsu JT AD - Department of Surgery, Chang Gung Memorial Hospital at Linkou, Chang Gung University College of Medicine, Taoyuan, Taiwan. hsujt2813@adm.cgmh.org.tw FAU - Kuo, Chia-Jung AU - Kuo CJ FAU - Chen, Tsung-Hsing AU - Chen TH FAU - Wang, Frank AU - Wang F FAU - Lin, Chun-Jun AU - Lin CJ FAU - Yeh, Ta-Sen AU - Yeh TS FAU - Hwang, Tsann-Long AU - Hwang TL FAU - Jan, Yi-Yin AU - Jan YY LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20120611 PL - England TA - J Pineal Res JT - Journal of pineal research JID - 8504412 RN - 0 (Androstadienes) RN - 0 (Cytokines) RN - 0 (Inflammation Mediators) RN - 0 (Phosphoinositide-3 Kinase Inhibitors) RN - 0 (Protein Kinase Inhibitors) RN - 4Y8F71G49Q (Malondialdehyde) RN - 8L70Q75FXE (Adenosine Triphosphate) RN - EC 1.11.1.7 (Peroxidase) RN - EC 1.14.14.18 (Heme Oxygenase (Decyclizing)) RN - EC 1.14.14.18 (Hmox1 protein, rat) RN - EC 2.6.1.1 (Aspartate Aminotransferases) RN - EC 2.6.1.2 (Alanine Transaminase) RN - EC 2.7.1.1 (mTOR protein, rat) RN - EC 2.7.1.137 (Phosphatidylinositol 3-Kinase) RN - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt) RN - EC 2.7.11.1 (TOR Serine-Threonine Kinases) RN - EC 3.4.22.- (Casp3 protein, rat) RN - EC 3.4.22.- (Caspase 3) RN - JL5DK93RCL (Melatonin) RN - XVA4O219QW (Wortmannin) SB - IM MH - Adenosine Triphosphate/metabolism MH - Alanine Transaminase/blood MH - Androstadienes/pharmacology MH - Animals MH - Aspartate Aminotransferases/blood MH - Caspase 3/metabolism MH - Cytokines/metabolism MH - Cytoprotection MH - Disease Models, Animal MH - Enzyme Activation MH - Heme Oxygenase (Decyclizing)/*metabolism MH - Inflammation Mediators/metabolism MH - Liver/*drug effects/enzymology/immunology/pathology MH - Liver Diseases/enzymology/etiology/immunology/pathology/*prevention & control MH - Male MH - Malondialdehyde/metabolism MH - Melatonin/*pharmacology MH - Peroxidase/metabolism MH - Phosphatidylinositol 3-Kinase/metabolism MH - Phosphoinositide-3 Kinase Inhibitors MH - Phosphorylation MH - Protein Kinase Inhibitors/pharmacology MH - Proto-Oncogene Proteins c-akt/*metabolism MH - Rats MH - Rats, Sprague-Dawley MH - Shock, Hemorrhagic/complications/*drug therapy/enzymology/immunology MH - Signal Transduction/*drug effects MH - TOR Serine-Threonine Kinases/metabolism MH - Wortmannin EDAT- 2012/06/13 06:00 MHDA- 2013/03/23 06:00 CRDT- 2012/06/13 06:00 PHST- 2012/06/13 06:00 [entrez] PHST- 2012/06/13 06:00 [pubmed] PHST- 2013/03/23 06:00 [medline] AID - 10.1111/j.1600-079X.2012.01011.x [doi] PST - ppublish SO - J Pineal Res. 2012 Nov;53(4):410-6. doi: 10.1111/j.1600-079X.2012.01011.x. Epub 2012 Jun 11.