PMID- 30951808
OWN - NLM
STAT- MEDLINE
DCOM- 20190506
LR  - 20190506
IS  - 1879-3169 (Electronic)
IS  - 0378-4274 (Linking)
VI  - 309
DP  - 2019 Jul
TI  - PKA- and Ca(2+)-dependent p38 MAPK/CREB activation protects against 
      manganese-mediated neuronal apoptosis.
PG  - 10-19
LID - S0378-4274(19)30086-4 [pii]
LID - 10.1016/j.toxlet.2019.04.004 [doi]
AB  - Although manganese (Mn) is an essential trace element, its excessive consumption 
      may lead to neuronal death and neurodegenerative disorders. Human cells launch 
      adaptive responses to attenuate Mn-induced neurotoxicity. However, the regulation 
      of the responsive proteins and their function during Mn-stimulated neurotoxicity 
      remain largely unknown. We report the role of cyclic adenosine monophosphate 
      (cAMP) response element-binding protein (CREB) in Mn-induced neuronal apoptosis. 
      Mn increased CREB phosphorylation and cellular apoptosis in both PC12 cells and 
      mouse brain tissue. Furthermore, downregulation of CREB with shRNA plasmid 
      transfection significantly worsened the PC12 cell apoptosis by decreasing mRNA 
      and protein expression of brain-derived neurotrophic factor (BDNF). Moreover, Mn 
      enhanced protein kinase A (PKA) activation and activation of the p38 MAPK and JNK 
      pathways. Inhibition of p38 MAPK rather than JNK effectively reduced the CREB 
      phosphorylation. Subsequent analysis showed that a PKA inhibitor blocked p38 MAPK 
      and CREB phosphorylation. Moreover, the intracellular Ca2+ chelator BAPTA-AM 
      decreased the phosphorylation of p38 MAPK and CREB but failed to reduce PKA 
      activation. In summary, p38 MAPK/CREB activation via PKA activation and increased 
      cellular Ca(2+) helped to alleviate Mn-induced neuronal apoptosis via BDNF 
      regulation. These findings improve our understanding of Mn-induced neurotoxicity 
      and the molecular targets to antagonise it.
CI  - Copyright (c) 2019 Elsevier B.V. All rights reserved.
FAU - Zhu, Ganlin
AU  - Zhu G
AD  - Department of Occupational Medicine and Environmental Toxicology, School of 
      Public Health, Nantong University, Nantong 226019, China.
FAU - Liu, Yiming
AU  - Liu Y
AD  - Department of Occupational Medicine and Environmental Toxicology, School of 
      Public Health, Nantong University, Nantong 226019, China.
FAU - Zhi, Ye
AU  - Zhi Y
AD  - Department of Occupational Medicine and Environmental Toxicology, School of 
      Public Health, Nantong University, Nantong 226019, China.
FAU - Jin, Yang
AU  - Jin Y
AD  - Department of Occupational Medicine and Environmental Toxicology, School of 
      Public Health, Nantong University, Nantong 226019, China.
FAU - Li, Jinlong
AU  - Li J
AD  - School of Pharmacy, Nangtong University, Nantong 226001, China. Electronic 
      address: jinlongli@ntu.edu.cn.
FAU - Shi, Weiwei
AU  - Shi W
AD  - Nantong Hospital of Traditional Chinese Medicine, Nantong 226001, China.
FAU - Liu, Yuting
AU  - Liu Y
AD  - Department of Occupational Medicine and Environmental Toxicology, School of 
      Public Health, Nantong University, Nantong 226019, China.
FAU - Han, Yu
AU  - Han Y
AD  - Department of Occupational Medicine and Environmental Toxicology, School of 
      Public Health, Nantong University, Nantong 226019, China.
FAU - Yu, Shali
AU  - Yu S
AD  - Department of Occupational Medicine and Environmental Toxicology, School of 
      Public Health, Nantong University, Nantong 226019, China.
FAU - Jiang, Junkang
AU  - Jiang J
AD  - Department of Occupational Medicine and Environmental Toxicology, School of 
      Public Health, Nantong University, Nantong 226019, China. Electronic address: 
      jiang_junkang@163.com.
FAU - Zhao, Xinyuan
AU  - Zhao X
AD  - Department of Occupational Medicine and Environmental Toxicology, School of 
      Public Health, Nantong University, Nantong 226019, China. Electronic address: 
      zhaoxinyuan@ntu.edu.cn.
LA  - eng
PT  - Journal Article
DEP - 20190402
PL  - Netherlands
TA  - Toxicol Lett
JT  - Toxicology letters
JID - 7709027
RN  - 0 (Brain-Derived Neurotrophic Factor)
RN  - 0 (Cyclic AMP Response Element-Binding Protein)
RN  - 42Z2K6ZL8P (Manganese)
RN  - EC 2.7.11.11 (Cyclic AMP-Dependent Protein Kinases)
RN  - EC 2.7.11.24 (p38 Mitogen-Activated Protein Kinases)
RN  - SY7Q814VUP (Calcium)
SB  - IM
MH  - Animals
MH  - Apoptosis/*drug effects
MH  - Brain-Derived Neurotrophic Factor/physiology
MH  - Calcium/*physiology
MH  - Cyclic AMP Response Element-Binding Protein/*physiology
MH  - Cyclic AMP-Dependent Protein Kinases/*physiology
MH  - MAP Kinase Signaling System/physiology
MH  - Male
MH  - Manganese/*toxicity
MH  - Mice
MH  - Mice, Inbred ICR
MH  - Neurons/*drug effects
MH  - PC12 Cells
MH  - Phosphorylation
MH  - Rats
MH  - p38 Mitogen-Activated Protein Kinases/*physiology
OTO - NOTNLM
OT  - CREB activation
OT  - Cellular Ca(2+)
OT  - Manganese
OT  - Neuronal apoptosis
OT  - PKA
EDAT- 2019/04/06 06:00
MHDA- 2019/05/07 06:00
CRDT- 2019/04/06 06:00
PHST- 2019/01/29 00:00 [received]
PHST- 2019/03/24 00:00 [revised]
PHST- 2019/04/01 00:00 [accepted]
PHST- 2019/04/06 06:00 [pubmed]
PHST- 2019/05/07 06:00 [medline]
PHST- 2019/04/06 06:00 [entrez]
AID - S0378-4274(19)30086-4 [pii]
AID - 10.1016/j.toxlet.2019.04.004 [doi]
PST - ppublish
SO  - Toxicol Lett. 2019 Jul;309:10-19. doi: 10.1016/j.toxlet.2019.04.004. Epub 2019 
      Apr 2.