PMID- 27884298
OWN - NLM
STAT- MEDLINE
DCOM- 20170522
LR  - 20211204
IS  - 1090-2104 (Electronic)
IS  - 0006-291X (Linking)
VI  - 481
IP  - 3-4
DP  - 2016 Dec 9
TI  - MHY1485 activates mTOR and protects osteoblasts from dexamethasone.
PG  - 212-218
LID - S0006-291X(16)31790-9 [pii]
LID - 10.1016/j.bbrc.2016.10.104 [doi]
AB  - Dexamethasone (Dex) exerts cytotoxic effects to cultured osteoblasts. The 
      potential effect of MHY1485, a small-molecular mammalian target of rapamycin 
      (mTOR) activator, against the process was studied here. In both osteoblastic 
      MC3T3-E1 cells and primary murine osteoblasts, treatment with MHY1485 
      significantly ameliorated Dex-induced cell death and apoptosis. mTOR inhibition, 
      through mTOR kinase inhibitor OSI-027 or mTOR shRNAs, abolished MHY1485-mediated 
      osteoblast cytoprotection against Dex. Intriguingly, activation of mTOR complex 
      (mTORC1), but not mTORC2, is required for MHY1485's anti-Dex activity. mTORC1 
      inhibitors (rapamycin and RAD001) or Raptor knockdown almost reversed 
      MHY1485-induced osteoblast cytoprotection. mTORC2 inhibition, via shRNA knockdown 
      of Rictor, failed to affect MHY1485's activity in MC3T3-E1 cells. Further studies 
      showed that MHY1485 treatment in MC3T3-E1 cells and primary murine osteoblasts 
      significantly inhibited Dex-induced mitochondrial death pathway activation, the 
      latter was tested by mitochondrial depolarization, cyclophilin D-ANT-1 
      association and cytochrome C cytosol release. Together, these results suggest 
      that MHY1485 activates mTORC1 signaling to protect osteoblasts from Dex.
CI  - Copyright A(c) 2016 Elsevier Inc. All rights reserved.
FAU - Zhao, Sai
AU  - Zhao S
AD  - Department of Paediatrics, Huai'an First People's Hospital, Nanjing Medical 
      University, Huai'an, China.
FAU - Chen, Caiyun
AU  - Chen C
AD  - Clinical Laboratory, Huai'an First People's Hospital, Nanjing Medical University, 
      Huai'an, China.
FAU - Wang, Shouguo
AU  - Wang S
AD  - Department of Orthopedics, Huai'an First People's Hospital, Nanjing Medical 
      University, Huai'an, China. Electronic address: shouguoha126@126.com.
FAU - Ji, Feng
AU  - Ji F
AD  - Department of Orthopedics, Huai'an First People's Hospital, Nanjing Medical 
      University, Huai'an, China.
FAU - Xie, Yue
AU  - Xie Y
AD  - Department of Orthopedics, Huai'an First People's Hospital, Nanjing Medical 
      University, Huai'an, China.
LA  - eng
PT  - Journal Article
PL  - United States
TA  - Biochem Biophys Res Commun
JT  - Biochemical and biophysical research communications
JID - 0372516
RN  - 0 (4,6-dimorpholino-N-(4-nitrophenyl)-1,3,5-triazin-2-amine)
RN  - 0 (Morpholines)
RN  - 0 (Multiprotein Complexes)
RN  - 0 (Triazines)
RN  - 7S5I7G3JQL (Dexamethasone)
RN  - EC 2.7.11.1 (Mechanistic Target of Rapamycin Complex 1)
RN  - EC 2.7.11.1 (Mechanistic Target of Rapamycin Complex 2)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
SB  - IM
MH  - Animals
MH  - Cell Death/drug effects
MH  - Cell Line
MH  - Cytoprotection/*drug effects
MH  - Dexamethasone/*toxicity
MH  - Mechanistic Target of Rapamycin Complex 1
MH  - Mechanistic Target of Rapamycin Complex 2
MH  - Mice
MH  - Mitochondria/drug effects/metabolism
MH  - Morpholines/*pharmacology
MH  - Multiprotein Complexes/metabolism
MH  - TOR Serine-Threonine Kinases/*metabolism
MH  - Triazines/*pharmacology
OTO - NOTNLM
OT  - Dexamethasone
OT  - MHY1485
OT  - Mitochondrial death pathway
OT  - Osteoblasts
OT  - mTOR
EDAT- 2016/11/26 06:00
MHDA- 2017/05/23 06:00
CRDT- 2016/11/26 06:00
PHST- 2016/10/10 00:00 [received]
PHST- 2016/10/25 00:00 [accepted]
PHST- 2016/11/26 06:00 [entrez]
PHST- 2016/11/26 06:00 [pubmed]
PHST- 2017/05/23 06:00 [medline]
AID - S0006-291X(16)31790-9 [pii]
AID - 10.1016/j.bbrc.2016.10.104 [doi]
PST - ppublish
SO  - Biochem Biophys Res Commun. 2016 Dec 9;481(3-4):212-218. doi: 
      10.1016/j.bbrc.2016.10.104.