PMID- 29433360
OWN - NLM
STAT- MEDLINE
DCOM- 20180926
LR  - 20180926
IS  - 1532-2513 (Electronic)
IS  - 0892-3973 (Linking)
VI  - 40
IP  - 3
DP  - 2018 Jun
TI  - AMPK/Nrf2 signaling is involved in the anti-neuroinflammatory action of 
      Petatewalide B from Petasites japonicus against lipopolysaccharides in microglia.
PG  - 232-241
LID - 10.1080/08923973.2018.1434791 [doi]
AB  - OBJECTIVES: Abnormal microglia secrete neuroinflammatory factors that play a 
      pivotal role in neurodegenerative-disorder development. Thus, regulating abnormal 
      microglia-activation could be a promising therapeutic strategy. The purposes of 
      this study included investigating the effect of Petatewalide B on 
      lipopolysaccharide- (LPS-) stimulated microglia and exploring the role of the 
      AMPK/Nrf2- (adenosine monophosphate-activated protein kinase/nuclear factor 
      erythroid 2-related factor 2) signaling pathway in the anti-neuroinflammatory 
      function of Petatewalide B. METHODS: We divided the microglia into four groups: a 
      control group, a Petatewalide B-treated group, an LPS-treated group, and an LPS 
      and Petatewalide B-treated group. The four groups of microglia were experimented 
      with, using the NO, ELISA, and promoter assays, and western blotting was 
      conducted to determine LPS-stimulated neuroinflammatory responses. RESULTS: We 
      found that pretreatment with Petatewalide B strongly alleviates interleukin- 
      (IL-) 1beta, IL-6, and tumor-necrosis-factor-alpha (TNF-alpha) production, and suppresses 
      iNOS and nitric oxide (NO) overexpression in LPS-stimulated microglia. The 
      AMPK/Nrf2-signaling pathway is important for inducing anti-neuroinflammatory 
      responses. Mechanistic studies report that Petatewalide B increases nuclear-Nrf2 
      translocation, and heme oxygenase-1 (HO-1) and NAD(P)H: quinone oxidoreductase 1 
      (NQO1) expression in a dose-dependent manner. Furthermore, Petatewalide B 
      significantly up-regulates HO-1 and NQO1 by specifically improving 
      antioxidant-response-elements-transcription activity. We then investigated 
      whether Nrf2/HO-1/NQO1 contribute to the anti-neuroinflammatory properties of 
      Petatewalide B. Nrf2, HO-1, and NQO1 small-integrating-ribonucleic-acids (siRNAs) 
      significantly blocked Petatewalide B-attenuated iNOS-promoter-activity in 
      LPS-stimulated microglia. Furthermore, Petatewalide B also up-regulated 
      AMPK-phosphorylation in a dose-dependent manner. We next evaluated whether 
      blocking AMPK-phosphorylation using an inhibitor (compound C) would critically 
      affect anti-neuroinflammatory responses. We found that the AMPK-phosphorylation 
      is associated with nuclear-Nrf2 translocation and elevated HO-1 and NQO1 
      expression levels. Our data also showed that AMPK-inhibitor pretreatment 
      significantly reverses Petatewalide B-attenuated iNOS-promoter-activity in 
      LPS-stimulated microglia. CONCLUSIONS: Our findings provide the possible 
      mechanism of the anti-neuroinflammatory properties of Petatewalide B that result 
      from beneficial responses in the AMPK/Nrf2-signaling pathway.
FAU - Park, Sun Young
AU  - Park SY
AD  - a Bio-IT Fusion Technology Research Institute, Pusan National University , Busan 
      , Korea.
FAU - Choi, Min Hyun
AU  - Choi MH
AD  - b Department of Horticultural Bioscience , Pusan National University , Myrang , 
      Korea.
FAU - Li, Mei
AU  - Li M
AD  - b Department of Horticultural Bioscience , Pusan National University , Myrang , 
      Korea.
FAU - Li, Ke
AU  - Li K
AD  - b Department of Horticultural Bioscience , Pusan National University , Myrang , 
      Korea.
FAU - Park, Geuntae
AU  - Park G
AD  - c Department of Nanomaterials Engineering , Pusan National University , Busan , 
      Korea.
FAU - Choi, Young-Whan
AU  - Choi YW
AD  - b Department of Horticultural Bioscience , Pusan National University , Myrang , 
      Korea.
LA  - eng
PT  - Journal Article
DEP - 20180212
PL  - England
TA  - Immunopharmacol Immunotoxicol
JT  - Immunopharmacology and immunotoxicology
JID - 8800150
RN  - 0 (Anti-Inflammatory Agents)
RN  - 0 (Lipopolysaccharides)
RN  - 0 (NF-E2-Related Factor 2)
RN  - 0 (Nfe2l2 protein, mouse)
RN  - 0 (Sesquiterpenes)
RN  - EC 2.7.11.31 (AMP-Activated Protein Kinases)
SB  - IM
MH  - AMP-Activated Protein Kinases/*metabolism
MH  - Animals
MH  - Anti-Inflammatory Agents/chemistry/*pharmacology
MH  - Cell Line
MH  - Lipopolysaccharides/*toxicity
MH  - Mice
MH  - NF-E2-Related Factor 2/*metabolism
MH  - Petasites/*chemistry
MH  - Sesquiterpenes/chemistry/*pharmacology
MH  - Signal Transduction/*drug effects
OTO - NOTNLM
OT  - AMPK
OT  - Nrf2
OT  - Petatewalide B
OT  - anti-neuroinflammation
OT  - microglia
EDAT- 2018/02/13 06:00
MHDA- 2018/09/27 06:00
CRDT- 2018/02/14 06:00
PHST- 2018/02/13 06:00 [pubmed]
PHST- 2018/09/27 06:00 [medline]
PHST- 2018/02/14 06:00 [entrez]
AID - 10.1080/08923973.2018.1434791 [doi]
PST - ppublish
SO  - Immunopharmacol Immunotoxicol. 2018 Jun;40(3):232-241. doi: 
      10.1080/08923973.2018.1434791. Epub 2018 Feb 12.