title: Melatonin modifies cellular stress in the liver of septic mice by reducing reactive oxygen species and increasing the unfolded protein response.
abstract: OBJECTIVE
  Melatonin's hepatoprotective actions have numerously been demonstrated in the past but the underlying molecular mechanisms are widely unknown. For a better understanding of melatonin's effects on hepatic stress response this study aimed to elucidate alterations in oxidative stress, unfolded protein response and acute phase response in septic mice.
  
  
  METHODS
  Male C3H/HeN mice underwent sham operation or cecal ligation and incision and remained anesthetized for 5h. Production of reactive oxygen species was determined by electron spin resonance spectroscopy. Protein and mRNA expression levels were determined by western blot analysis and quantitative real-time PCR, respectively.
  
  
  RESULTS
  Production of reactive oxygen species was strongly increased in the aorta and liver after 5h of polymicrobial sepsis which was entirely inhibited by treatment with melatonin. SOD-1 levels did not differ between the groups. Sepsis also induced the upregulation of VCAM-1 and ICAM-1 independent of melatonin treatment but probably regulated via ERK1/2 signaling. Melatonin triggered the transcriptional upregulation of PERK in septic animals which seems to be independent on ERK1/2 signaling and NR4A1 activation. Melatonin therapy also engendered an increased expression of CHOP, but apoptosis was not initiated. Furthermore, sepsis reduced the expression of the transcription factor CREBH which was entirely suppressed by melatonin.
  
  
  CONCLUSIONS
  This study gives new insight into the mechanisms by which melatonin might confer its hepatoprotective actions during polymicrobial sepsis. The results clearly show the melatonin-mediated amelioration of oxidative stress as well as alterations in the cellular stress mechanisms via the unfolded protein response and the acute phase response.
authors.affiliation: Department of Anaesthesiology, Intensive Care and Pain Therapy, Saarland University Medical Center, Kirrbergerstrasse 57, 66421 Homburg /Saar, Germany. Electronic address: astrid.kleber@uks.eu.
authors.forename: Astrid
authors.initials: A
authors.lastname: Kleber
authors.affiliation: Department of Anaesthesiology, Intensive Care and Pain Therapy, Saarland University Medical Center, Kirrbergerstrasse 57, 66421 Homburg /Saar, Germany. Electronic address: darius.kubulus@uks.eu.
authors.forename: Darius
authors.initials: D
authors.lastname: Kubulus
authors.affiliation: Department of Anaesthesiology, Intensive Care and Pain Therapy, Saarland University Medical Center, Kirrbergerstrasse 57, 66421 Homburg /Saar, Germany. Electronic address: danielroessler@yahoo.de.
authors.forename: Daniel
authors.initials: D
authors.lastname: Rössler
authors.affiliation: Department of Anaesthesiology, Intensive Care and Pain Therapy, Saarland University Medical Center, Kirrbergerstrasse 57, 66421 Homburg /Saar, Germany. Electronic address: beate.wolf@uks.eu.
authors.forename: Beate
authors.initials: B
authors.lastname: Wolf
authors.affiliation: Department of Anaesthesiology, Intensive Care and Pain Therapy, Saarland University Medical Center, Kirrbergerstrasse 57, 66421 Homburg /Saar, Germany. Electronic address: thomas.volk@uks.eu.
authors.forename: Thomas
authors.initials: T
authors.lastname: Volk
authors.affiliation: Department of Internal Medicine, Nephrology and Hypertension, Saarland University Medical Center, Kirrbergerstrasse 40, 66421 Homburg /Saar, Germany. Electronic address: timo.speer@uks.eu.
authors.forename: Thimoteus
authors.initials: T
authors.lastname: Speer
authors.affiliation: Department of Anaesthesiology, Intensive Care and Pain Therapy, Saarland University Medical Center, Kirrbergerstrasse 57, 66421 Homburg /Saar, Germany. Electronic address: tobias.fink@uks.eu.
authors.forename: Tobias
authors.initials: T
authors.lastname: Fink
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D015153:Blotting, Western; D004195:Disease Models, Animal; D004578:Electron Spin Resonance Spectroscopy; D008099:Liver / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008297:Male; D008550:Melatonin / Q000494:pharmacology*; D051379:Mice; D008809:Mice, Inbred C3H; D018384:Oxidative Stress / Q000187:drug effects*; D017382:Reactive Oxygen Species / Q000378:metabolism*; D060888:Real-Time Polymerase Chain Reaction; D018805:Sepsis / Q000378:metabolism / Q000473:pathology*; D056811:Unfolded Protein Response / Q000187:drug effects*
chemical_list: D000975:Antioxidants; D017382:Reactive Oxygen Species; D008550:Melatonin
keywords: Acute phase response; Melatonin; Reactive oxygen species; Sepsis; Unfolded protein response