PMID- 29626480
OWN - NLM
STAT- MEDLINE
DCOM- 20181009
LR  - 20181009
IS  - 1090-2104 (Electronic)
IS  - 0006-291X (Linking)
VI  - 499
IP  - 4
DP  - 2018 May 23
TI  - TSPA as a novel ATF6alpha translocation inducer efficiently ameliorates insulin 
      sensitivity restoration and glucose homeostasis in db/db mice.
PG  - 948-953
LID - S0006-291X(18)30788-5 [pii]
LID - 10.1016/j.bbrc.2018.04.025 [doi]
AB  - Activating transcription factor 6alpha (ATF6alpha) as a transducer in unfolded protein 
      response (UPR), plays an important role in liver glucose metabolism and insulin 
      resistance. Thus, targeting ATF6alpha activation has been proposed to be a potential 
      strategy for anti-T2DM drug discovery. Here, we determined that small molecule 
      2-[5-[1-(4-chlorophenoxy)ethyl]-4-phenyl-4H-1,2,4-triazol-3-yl]sulfanyl-N-(1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazol-4-yl)acetamide 
      (TSPA) functioned as an ATF6alpha translocation inducer effectively promoting ATF6alpha 
      translocation into nucleus and ameliorating glucose homeostasis on db/db mice. 
      TSPA promoted ATF6alpha translocation into nucleus without incresing C/EBP-homologous 
      protein (CHOP) expression. TSPA restored the tunicamycin (TM)-stimulated insulin 
      receptor (IR) desensitization through ATF6alpha activation, inhibited gluconeogenesis 
      and efficiently improved glucose homeostasis on db/db mice. Furthermore, TSPA 
      protected insulin pathway involving p38/X-box binding protein 1s (Xbp1s)/ER 
      chaperones signaling pathway. Our current study has determined that ATF6alpha was a 
      promising therapeutic target and also highlighted the potential of TSPA in the 
      treatment of type 2 diabetes mellitus (T2DM).
CI  - Copyright (c) 2018 Elsevier Inc. All rights reserved.
FAU - Zhou, Tingting
AU  - Zhou T
AD  - Wuxi School of Medicine, Jiangnan University, 1800 Lihu Road, Wuxi 214122, China; 
      CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, 
      Chinese Academy of Sciences, Shanghai 201203, China.
FAU - Cheng, Yanhua
AU  - Cheng Y
AD  - School of Pharmacy, China Pharmaceutical University, Jiangsu, Nanjing 210009, 
      China.
FAU - Yan, Wenzhong
AU  - Yan W
AD  - Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China 
      University of Science and Technology, Shanghai 200237, China.
FAU - Shi, Xiaofan
AU  - Shi X
AD  - CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, 
      Chinese Academy of Sciences, Shanghai 201203, China.
FAU - Xu, Xin
AU  - Xu X
AD  - CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, 
      Chinese Academy of Sciences, Shanghai 201203, China.
FAU - Zhou, Jinpei
AU  - Zhou J
AD  - School of Pharmacy, China Pharmaceutical University, Jiangsu, Nanjing 210009, 
      China.
FAU - Li, Jian
AU  - Li J
AD  - Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China 
      University of Science and Technology, Shanghai 200237, China. Electronic address: 
      jianli@ecust.edu.cn.
FAU - Chen, Jing
AU  - Chen J
AD  - CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, 
      Chinese Academy of Sciences, Shanghai 201203, China. Electronic address: 
      jingchen@simm.ac.cn.
FAU - Shen, Xu
AU  - Shen X
AD  - CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, 
      Chinese Academy of Sciences, Shanghai 201203, China; State Key Laboratory 
      Cultivation Base for TCM Quality and Efficacy, School of Medicine and Life 
      Sciences, Nanjing University of Chinese Medicine, 138 Xianlin Road, Nanjing 
      210023, China.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20180409
PL  - United States
TA  - Biochem Biophys Res Commun
JT  - Biochemical and biophysical research communications
JID - 0372516
RN  - 0 (Acetamides)
RN  - 0 (Activating Transcription Factor 6)
RN  - 0 (Pyrazoles)
RN  - 0 (Triazoles)
RN  - 0 (X-Box Binding Protein 1)
RN  - 11089-65-9 (Tunicamycin)
RN  - 147336-12-7 (Transcription Factor CHOP)
RN  - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt)
RN  - EC 2.7.11.24 (p38 Mitogen-Activated Protein Kinases)
RN  - IY9XDZ35W2 (Glucose)
SB  - IM
MH  - Acetamides/*pharmacology
MH  - Activating Transcription Factor 6/*metabolism
MH  - Animals
MH  - Cell Line, Tumor
MH  - Cell Nucleus/drug effects/metabolism
MH  - Diabetes Mellitus, Experimental/*metabolism/*pathology
MH  - Endoplasmic Reticulum/drug effects/metabolism
MH  - Glucose/*metabolism
MH  - *Homeostasis
MH  - Humans
MH  - *Insulin Resistance
MH  - Male
MH  - Mice
MH  - Protein Transport/drug effects
MH  - Proto-Oncogene Proteins c-akt/metabolism
MH  - Pyrazoles/*pharmacology
MH  - Signal Transduction/drug effects
MH  - Transcription Factor CHOP/metabolism
MH  - Triazoles/*pharmacology
MH  - Tunicamycin/pharmacology
MH  - X-Box Binding Protein 1/metabolism
MH  - p38 Mitogen-Activated Protein Kinases/metabolism
OTO - NOTNLM
OT  - ATF6alpha
OT  - ER stress
OT  - Insulin resistance
OT  - T2DM
OT  - TSPA
EDAT- 2018/04/08 06:00
MHDA- 2018/10/10 06:00
CRDT- 2018/04/08 06:00
PHST- 2018/04/01 00:00 [received]
PHST- 2018/04/03 00:00 [accepted]
PHST- 2018/04/08 06:00 [pubmed]
PHST- 2018/10/10 06:00 [medline]
PHST- 2018/04/08 06:00 [entrez]
AID - S0006-291X(18)30788-5 [pii]
AID - 10.1016/j.bbrc.2018.04.025 [doi]
PST - ppublish
SO  - Biochem Biophys Res Commun. 2018 May 23;499(4):948-953. doi: 
      10.1016/j.bbrc.2018.04.025. Epub 2018 Apr 9.