PMID- 32377295
OWN - NLM
STAT- MEDLINE
DCOM- 20210204
LR  - 20210204
IS  - 1942-0994 (Electronic)
IS  - 1942-0900 (Print)
IS  - 1942-0994 (Linking)
VI  - 2020
DP  - 2020
TI  - New Synthetic 3-Benzoyl-5-Hydroxy-2H-Chromen-2-One (LM-031) Inhibits 
      Polyglutamine Aggregation and Promotes Neurite Outgrowth through Enhancement of 
      CREB, NRF2, and Reduction of AMPKalpha in SCA17 Cell Models.
PG  - 3129497
LID - 10.1155/2020/3129497 [doi]
LID - 3129497
AB  - Spinocerebellar ataxia type 17 (SCA17) is caused by a CAG/CAA expansion mutation 
      encoding an expanded polyglutamine (polyQ) tract in TATA-box binding protein 
      (TBP), a general transcription initiation factor. Suppression of cAMP-responsive 
      element binding protein- (CREB-) dependent transcription, impaired nuclear factor 
      erythroid 2-related factor 2 (NRF2) signaling, and interaction of AMP-activated 
      protein kinase (AMPK) with increased oxidative stress have been implicated to be 
      involved in pathogenic mechanisms of polyQ-mediated diseases. In this study, we 
      demonstrated decreased pCREB and NRF2 and activated AMPK contributing to 
      neurotoxicity in SCA17 SH-SY5Y cells. We also showed that licochalcone A and the 
      related in-house derivative compound 3-benzoyl-5-hydroxy-2H-chromen-2-one 
      (LM-031) exhibited antiaggregation, antioxidative, antiapoptosis, and 
      neuroprotective effects in TBP/Q(79)-GFP-expressing cell models. LM-031 and 
      licochalcone A exerted neuroprotective effects by upregulating pCREB and its 
      downstream genes, BCL2 and GADD45B, and enhancing NRF2. Furthermore, LM-031, but 
      not licochalcone A, reduced activated AMPKalpha. Knockdown of CREB and NRF2 and 
      treatment of AICAR (5-aminoimidazole-4-carboxamide 1-beta-D-ribofuranoside), an AMPK 
      activator, attenuated the aggregation-inhibiting and neurite outgrowth promoting 
      effects of LM-031 on TBP/Q(79) SH-SY5Y cells. The study results suggest the 
      LM-031 as potential therapeutics for SCA17 and probable other polyQ diseases.
CI  - Copyright (c) 2020 Chiung-Mei Chen et al.
FAU - Chen, Chiung-Mei
AU  - Chen CM
AUID- ORCID: 0000-0002-0769-0353
AD  - Department of Neurology, Chang-Gung Memorial Hospital, Chang Gung University 
      College of Medicine, Taoyuan 33302, Taiwan.
FAU - Chen, Wan-Ling
AU  - Chen WL
AD  - Department of Neurology, Chang-Gung Memorial Hospital, Chang Gung University 
      College of Medicine, Taoyuan 33302, Taiwan.
FAU - Yang, Shu-Ting
AU  - Yang ST
AD  - Department of Life Science, National Taiwan Normal University, Taipei 11677, 
      Taiwan.
FAU - Lin, Te-Hsien
AU  - Lin TH
AUID- ORCID: 0000-0002-1107-772X
AD  - Department of Life Science, National Taiwan Normal University, Taipei 11677, 
      Taiwan.
FAU - Yang, Shu-Mei
AU  - Yang SM
AD  - Department of Chemistry, National Taiwan Normal University, Taipei 11677, Taiwan.
FAU - Lin, Wenwei
AU  - Lin W
AD  - Department of Chemistry, National Taiwan Normal University, Taipei 11677, Taiwan.
FAU - Chao, Chih-Ying
AU  - Chao CY
AD  - Department of Neurology, Chang-Gung Memorial Hospital, Chang Gung University 
      College of Medicine, Taoyuan 33302, Taiwan.
FAU - Wu, Yih-Ru
AU  - Wu YR
AUID- ORCID: 0000-0003-1191-2542
AD  - Department of Neurology, Chang-Gung Memorial Hospital, Chang Gung University 
      College of Medicine, Taoyuan 33302, Taiwan.
FAU - Chang, Kuo-Hsuan
AU  - Chang KH
AUID- ORCID: 0000-0003-4972-9823
AD  - Department of Neurology, Chang-Gung Memorial Hospital, Chang Gung University 
      College of Medicine, Taoyuan 33302, Taiwan.
FAU - Lee-Chen, Guey-Jen
AU  - Lee-Chen GJ
AUID- ORCID: 0000-0003-4818-9917
AD  - Department of Life Science, National Taiwan Normal University, Taipei 11677, 
      Taiwan.
LA  - eng
PT  - Journal Article
DEP - 20200422
PL  - United States
TA  - Oxid Med Cell Longev
JT  - Oxidative medicine and cellular longevity
JID - 101479826
RN  - 0 (CREB1 protein, human)
RN  - 0 (Chalcones)
RN  - 0 (Chromones)
RN  - 0 (Cyclic AMP Response Element-Binding Protein)
RN  - 0 (NF-E2-Related Factor 2)
RN  - 0 (NFE2L2 protein, human)
RN  - 0 (Peptides)
RN  - 0 (Ribonucleotides)
RN  - 0 (TATA-Box Binding Protein)
RN  - 0 (TBP protein, human)
RN  - 26700-71-0 (polyglutamine)
RN  - 360-97-4 (Aminoimidazole Carboxamide)
RN  - EC 2.7.11.31 (AMP-Activated Protein Kinases)
RN  - F0X88YW0YK (AICA ribonucleotide)
RN  - JTV5467968 (licochalcone A)
RN  - Spinocerebellar Ataxia 17
SB  - IM
MH  - AMP-Activated Protein Kinases/*metabolism
MH  - Aminoimidazole Carboxamide/analogs & derivatives/pharmacology
MH  - Chalcones/pharmacology
MH  - Chromones/*pharmacology
MH  - Cyclic AMP Response Element-Binding Protein/*metabolism
MH  - Humans
MH  - NF-E2-Related Factor 2/*metabolism
MH  - Neuronal Outgrowth/*drug effects
MH  - Peptides/*antagonists & inhibitors/metabolism
MH  - Ribonucleotides/pharmacology
MH  - Spinocerebellar Ataxias/*drug therapy/*metabolism/pathology
MH  - TATA-Box Binding Protein/metabolism
PMC - PMC7195640
COIS- The authors declare that there is no conflict of interest.
EDAT- 2020/05/08 06:00
MHDA- 2021/02/05 06:00
PMCR- 2020/04/22
CRDT- 2020/05/08 06:00
PHST- 2020/02/22 00:00 [received]
PHST- 2020/03/25 00:00 [revised]
PHST- 2020/04/02 00:00 [accepted]
PHST- 2020/05/08 06:00 [entrez]
PHST- 2020/05/08 06:00 [pubmed]
PHST- 2021/02/05 06:00 [medline]
PHST- 2020/04/22 00:00 [pmc-release]
AID - 10.1155/2020/3129497 [doi]
PST - epublish
SO  - Oxid Med Cell Longev. 2020 Apr 22;2020:3129497. doi: 10.1155/2020/3129497. 
      eCollection 2020.