PMID- 28420170
OWN - NLM
STAT- MEDLINE
DCOM- 20170629
LR  - 20211204
IS  - 1422-0067 (Electronic)
IS  - 1422-0067 (Linking)
VI  - 18
IP  - 4
DP  - 2017 Apr 17
TI  - Fisetin Protects PC12 Cells from Tunicamycin-Mediated Cell Death via Reactive 
      Oxygen Species Scavenging and Modulation of Nrf2-Driven Gene Expression, SIRT1 
      and MAPK Signaling in PC12 Cells.
LID - 10.3390/ijms18040852 [doi]
LID - 852
AB  - BACKGROUND: Fisetin (3,7,3',4'-tetrahydroxyflavone) is a dietary flavonol and 
      exhibits antioxidant, anti-inflammatory, and neuroprotective activities. However, 
      high concentration of fisetin is reported to produce reactive oxygen species 
      (ROS), induce endoplasmic reticulum (ER) stress and cause cytotoxicity in cancer 
      cells. The aim of this study is to investigate the cytoprotective effects of low 
      concentration of fisetin against tunicamycin (Tm)-mediated cytotoxicity in 
      neuronal-like catecholaminergic PC12 cells. METHODS: Cell viability was assayed 
      by MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) and 
      apoptotic and autophagic markers were analyzed by Western blot. Gene expression 
      of unfolded protein response (UPR) and Phase II enzymes was further investigated 
      using RT-Q-PCR or Western blotting. Intracellular ROS level was measured using 
      2',7'-dichlorodihydrofluorescein diacetate (H(2)DCFDA) by a fluorometer. The 
      effects of fisetin on mitogen activated protein kinases (MAPKs) and SIRT1 
      (Sirtuin 1) signaling pathways were examined using Western blotting and specific 
      inhibitors. RESULTS: Fisetin (<20 microM) restored cell viability and repressed 
      apoptosis, autophagy and ROS production in Tm-treated cells. Fisetin attenuated 
      Tm-mediated expression of ER stress genes, such as glucose-regulated proteins 78 
      (GRP78), C/EBP homologous protein (CHOP also known as GADD153) and Tribbles 
      homolog 3 (TRB3), but induced the expression of nuclear E2 related factor 
      (Nrf)2-targeted heme oxygenase (HO)-1, glutamate cysteine ligase (GCL) and 
      cystine/glutamate transporter (xCT/SLC7A11), in both the presence and absence of 
      Tm. Moreover, fisetin enhanced phosphorylation of ERK (extracellular 
      signal-regulated kinase), JNK (c-JUN NH(2)-terminal protein kinase), and p38 MAPK. 
      Addition of JNK and p38 MAPK inhibitor significantly antagonized its 
      cytoprotective activity and modulatory effects on UPR. Fisetin also restored 
      Tm-inhibited SIRT1 expression and addition of sirtinol (SIRT1 activation 
      inhibitor) significantly blocked fisetin-mediated cytoprotection. In conclusion, 
      this result shows that fisetin activates Nrf2, MAPK and SIRT1, which may elicit 
      adaptive cellular stress response pathways so as to protect cells from Tm-induced 
      cytotoxicity.
FAU - Yen, Jui-Hung
AU  - Yen JH
AD  - Department of Molecular Biology and Human Genetics, Tzu Chi University, Hualien 
      970, Taiwan. imyenjh@hotmail.com.
FAU - Wu, Pei-Shan
AU  - Wu PS
AD  - Department of Biotechnology, Chia Nan University of Pharmacy and Science, Tainan 
      717, Taiwan. dc7575@gmail.com.
FAU - Chen, Shu-Fen
AU  - Chen SF
AD  - Department of Health and Nutrition, Chia Nan University of Pharmacy and Science, 
      Tainan 717, Taiwan. ichensf@mail.cnu.edu.tw.
FAU - Wu, Ming-Jiuan
AU  - Wu MJ
AD  - Department of Biotechnology, Chia Nan University of Pharmacy and Science, Tainan 
      717, Taiwan. imwu@mail.cnu.edu.tw.
LA  - eng
PT  - Journal Article
DEP - 20170417
PL  - Switzerland
TA  - Int J Mol Sci
JT  - International journal of molecular sciences
JID - 101092791
RN  - 0 (Antioxidants)
RN  - 0 (Endoplasmic Reticulum Chaperone BiP)
RN  - 0 (Flavonoids)
RN  - 0 (Flavonols)
RN  - 0 (HSPA5 protein, human)
RN  - 0 (NF-E2-Related Factor 2)
RN  - 0 (Reactive Oxygen Species)
RN  - EC 3.5.1.- (Sirtuin 1)
RN  - OO2ABO9578 (fisetin)
SB  - IM
MH  - Animals
MH  - Antioxidants/*pharmacology
MH  - Apoptosis/drug effects
MH  - Autophagy/drug effects
MH  - Endoplasmic Reticulum Chaperone BiP
MH  - Endoplasmic Reticulum Stress/drug effects/genetics
MH  - Flavonoids/*pharmacology
MH  - Flavonols
MH  - Gene Expression Regulation/*drug effects
MH  - MAP Kinase Signaling System/drug effects
MH  - NF-E2-Related Factor 2/*metabolism
MH  - Oxidative Stress/genetics
MH  - PC12 Cells
MH  - Rats
MH  - Reactive Oxygen Species/*metabolism
MH  - Signal Transduction/*drug effects
MH  - Sirtuin 1/genetics/*metabolism
PMC - PMC5412436
OTO - NOTNLM
OT  - HO-1
OT  - SIRT1
OT  - fisetin
OT  - p38 MAPK
OT  - tunicamycin
COIS- The authors declare no conflict of interest.
EDAT- 2017/04/20 06:00
MHDA- 2017/07/01 06:00
PMCR- 2017/04/01
CRDT- 2017/04/20 06:00
PHST- 2017/03/05 00:00 [received]
PHST- 2017/03/26 00:00 [revised]
PHST- 2017/04/12 00:00 [accepted]
PHST- 2017/04/20 06:00 [entrez]
PHST- 2017/04/20 06:00 [pubmed]
PHST- 2017/07/01 06:00 [medline]
PHST- 2017/04/01 00:00 [pmc-release]
AID - ijms18040852 [pii]
AID - ijms-18-00852 [pii]
AID - 10.3390/ijms18040852 [doi]
PST - epublish
SO  - Int J Mol Sci. 2017 Apr 17;18(4):852. doi: 10.3390/ijms18040852.