PMID- 25958928
OWN - NLM
STAT- MEDLINE
DCOM- 20160506
LR  - 20211203
IS  - 1600-079X (Electronic)
IS  - 0742-3098 (Linking)
VI  - 59
IP  - 2
DP  - 2015 Sep
TI  - Melatonin inhibits autophagy and endoplasmic reticulum stress in mice with carbon 
      tetrachloride-induced fibrosis.
PG  - 151-62
LID - 10.1111/jpi.12247 [doi]
AB  - This study aimed to investigate whether inhibition of autophagy and endoplasmic 
      reticulum (ER stress) associates with the antifibrogenic effect of melatonin in 
      mice treated with carbon tetrachloride (CCl4 ). Mice received CCl4 5 muL/g body wt 
      i.p. twice a week for 4 wk or 6 wk. Melatonin was given at 5 or 10 mg/kg/day i.p, 
      beginning 2 wk after the start of CCl4 administration. Treatment with CCl4 
      resulted in fibrosis evidenced by the staining of alpha-smooth muscle actin 
      (alpha-SMA)-positive cells. CCl4 induced an autophagic response measured as the 
      presence of autophagic vesicles, protein 1 light chain 3 (LC3) staining, 
      conversion of LC3-I to autophagosome-associated LC3-II, changes in expression of 
      beclin-1, UV radiation resistance-associated gene (UVRAG), ubiquitin-like 
      autophagy-related (Atg5), Atg12, Atg16L1, sequestosome 1 (p62/SQSTM1), and 
      lysosome-associated membrane protein (LAMP)-2, and increased phosphorylation of 
      the mammalian target of rapamycin (mTOR). There was an increase in the expression 
      of the ER stress chaperones CCAAT/enhancer-binding protein homologous protein 
      (CHOP), immunoglobulin-heavy-chain-binding protein (BiP/GRP78), and 94-kDa 
      glucose-regulated protein (GRP94), and in the mRNA levels of pancreatic ER kinase 
      (PERK), activating transcription factor 6 (ATF6), ATF4, inositol-requiring enzyme 
      1 (IRE1), and spliced X-box-binding protein-1 (XBP1). Phospho-IRE1, ATF6, and 
      phospho-PERK protein concentration also increased significantly. 
      Immunohistochemical staining of alpha-SMA indicated an abrogation of hepatic stellate 
      cells activation by melatonin. Furthermore, treatment with the indole resulted in 
      significant inhibition of the autophagic flux and the unfolded protein response. 
      Findings from this study give new insight into molecular pathways accounting for 
      the protective effect of melatonin in fibrogenesis.
CI  - (c) 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.
FAU - San-Miguel, Beatriz
AU  - San-Miguel B
AD  - Institute of Biomedicine (IBIOMED), University of Leon, Leon, Spain.
FAU - Crespo, Irene
AU  - Crespo I
AD  - Institute of Biomedicine (IBIOMED), University of Leon, Leon, Spain.
AD  - Centro de Investigacion Biomedica en Red de Enfermedades Hepaticas y Digestivas 
      (CIBERehd), Leon, Spain.
FAU - Sanchez, Diana I
AU  - Sanchez DI
AD  - Institute of Biomedicine (IBIOMED), University of Leon, Leon, Spain.
FAU - Gonzalez-Fernandez, Barbara
AU  - Gonzalez-Fernandez B
AD  - Institute of Biomedicine (IBIOMED), University of Leon, Leon, Spain.
FAU - Ortiz de Urbina, Juan J
AU  - Ortiz de Urbina JJ
AD  - Institute of Biomedicine (IBIOMED), University of Leon, Leon, Spain.
FAU - Tunon, Maria J
AU  - Tunon MJ
AD  - Institute of Biomedicine (IBIOMED), University of Leon, Leon, Spain.
AD  - Centro de Investigacion Biomedica en Red de Enfermedades Hepaticas y Digestivas 
      (CIBERehd), Leon, Spain.
FAU - Gonzalez-Gallego, Javier
AU  - Gonzalez-Gallego J
AD  - Institute of Biomedicine (IBIOMED), University of Leon, Leon, Spain.
AD  - Centro de Investigacion Biomedica en Red de Enfermedades Hepaticas y Digestivas 
      (CIBERehd), Leon, Spain.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20150526
PL  - England
TA  - J Pineal Res
JT  - Journal of pineal research
JID - 8504412
RN  - 0 (Endoplasmic Reticulum Chaperone BiP)
RN  - 0 (Hspa5 protein, mouse)
RN  - JL5DK93RCL (Melatonin)
SB  - IM
MH  - Animals
MH  - Autophagy/*drug effects
MH  - Carbon Tetrachloride Poisoning/metabolism/pathology/*prevention & control
MH  - Endoplasmic Reticulum Chaperone BiP
MH  - Endoplasmic Reticulum Stress/*drug effects
MH  - Gene Expression Regulation/*drug effects
MH  - Liver/*metabolism/pathology
MH  - Liver Cirrhosis/chemically induced/metabolism/pathology/*prevention & control
MH  - Male
MH  - Melatonin
MH  - Mice
OTO - NOTNLM
OT  - ER stress
OT  - autophagy
OT  - carbon tetrachloride
OT  - fibrosis
OT  - liver
OT  - melatonin
EDAT- 2015/05/12 06:00
MHDA- 2016/05/07 06:00
CRDT- 2015/05/12 06:00
PHST- 2015/03/05 00:00 [received]
PHST- 2015/05/05 00:00 [accepted]
PHST- 2015/05/12 06:00 [entrez]
PHST- 2015/05/12 06:00 [pubmed]
PHST- 2016/05/07 06:00 [medline]
AID - 10.1111/jpi.12247 [doi]
PST - ppublish
SO  - J Pineal Res. 2015 Sep;59(2):151-62. doi: 10.1111/jpi.12247. Epub 2015 May 26.