PMID- 34310962
OWN - NLM
STAT- MEDLINE
DCOM- 20220204
LR  - 20220902
IS  - 1872-9711 (Electronic)
IS  - 0161-813X (Print)
IS  - 0161-813X (Linking)
VI  - 86
DP  - 2021 Sep
TI  - Manganese-induced reactive oxygen species activate IkappaB kinase to upregulate YY1 
      and impair glutamate transporter EAAT2 function in human astrocytes in vitro.
PG  - 94-103
LID - S0161-813X(21)00082-6 [pii]
LID - 10.1016/j.neuro.2021.07.004 [doi]
AB  - Dysregulation of the astrocytic glutamate transporter excitatory amino acid 
      transporter 2 (EAAT2) is associated with several neurological disorders, 
      including Parkinson's disease, Alzheimer's disease, and manganism, the latter 
      induced by chronic exposure to high levels of manganese (Mn). Mechanisms of 
      Mn-induced neurotoxicity include impairment of EAAT2 function secondary to the 
      activation of the transcription factor Yin Yang 1 (YY1) by nuclear factor 
      kappa-light-chain-enhancer of activated B cells (NF-kappaB). However, the upstream 
      mechanisms by which Mn-induced NF-kappaB activates YY1 remain to be elucidated. In 
      the present study, we used the H4 human astrocyte cell line to test if Mn 
      activates YY1 through the canonical NF-kappaB signaling pathway, leading to EAAT2 
      repression. The results demonstrate that Mn exposure induced phosphorylation of 
      the upstream kinase IkappaB kinase (IKK-beta), leading to NF-kappaB p65 translocation, 
      increased YY1 promoter activity, mRNA/protein levels, and consequently repressed 
      EAAT2. Results also demonstrated that Mn-induced oxidative stress and subsequent 
      TNF-alpha production were upstream of IKK-beta activation, as antioxidants attenuated 
      Mn-induced TNF-alpha production and IKK-beta activation. Moreover, TNF-alpha inhibition 
      attenuated the Mn-induced activation of IKK-beta and YY1. Taken together, Mn-induced 
      oxidative stress and TNF-alpha mediates activation of NF-kappaB signaling and YY1 
      upregulation, leading to repression of EAAT2. Thus, targeting reactive oxygen 
      species (ROS), TNF-alpha and IKK-beta may attenuate Mn-induced YY1 activation and 
      consequent EAAT2 repression.
CI  - Copyright (c) 2021 Elsevier B.V. All rights reserved.
FAU - Rizor, Asha
AU  - Rizor A
AD  - Department of Pharmaceutical Sciences, College of Pharmacy, Florida A&M 
      University, Tallahassee, FL, 32301, USA.
FAU - Pajarillo, Edward
AU  - Pajarillo E
AD  - Department of Pharmaceutical Sciences, College of Pharmacy, Florida A&M 
      University, Tallahassee, FL, 32301, USA.
FAU - Nyarko-Danquah, Ivan
AU  - Nyarko-Danquah I
AD  - Department of Pharmaceutical Sciences, College of Pharmacy, Florida A&M 
      University, Tallahassee, FL, 32301, USA.
FAU - Digman, Alexis
AU  - Digman A
AD  - Department of Pharmaceutical Sciences, College of Pharmacy, Florida A&M 
      University, Tallahassee, FL, 32301, USA.
FAU - Mooneyham, Leyah
AU  - Mooneyham L
AD  - Department of Pharmaceutical Sciences, College of Pharmacy, Florida A&M 
      University, Tallahassee, FL, 32301, USA.
FAU - Son, Deok-Soo
AU  - Son DS
AD  - Department of Biochemistry and Cancer Biology, Meharry Medical College, 
      Nashville, TN, USA.
FAU - Aschner, Michael
AU  - Aschner M
AD  - Department of Molecular Pharmacology, Albert Einstein College of Medicine Bronx, 
      New York, NY, 10461, USA; Sechenov First Moscow State Medical University, Moscow, 
      Russia.
FAU - Lee, Eunsook
AU  - Lee E
AD  - Department of Pharmaceutical Sciences, College of Pharmacy, Florida A&M 
      University, Tallahassee, FL, 32301, USA. Electronic address: 
      eunsook.lee@famu.edu.
LA  - eng
GR  - U54 MD007582/MD/NIMHD NIH HHS/United States
GR  - SC1 CA200519/CA/NCI NIH HHS/United States
GR  - R01 ES020852/ES/NIEHS NIH HHS/United States
GR  - R01 ES024756/ES/NIEHS NIH HHS/United States
GR  - R01 ES031282/ES/NIEHS NIH HHS/United States
GR  - R01 ES010563/ES/NIEHS NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
DEP - 20210724
PL  - Netherlands
TA  - Neurotoxicology
JT  - Neurotoxicology
JID - 7905589
RN  - 0 (Excitatory Amino Acid Transporter 2)
RN  - 0 (Reactive Oxygen Species)
RN  - 0 (SLC1A2 protein, human)
RN  - 0 (YY1 Transcription Factor)
RN  - 0 (YY1 protein, human)
RN  - 42Z2K6ZL8P (Manganese)
RN  - EC 2.7.11.10 (I-kappa B Kinase)
SB  - IM
MH  - Astrocytes/drug effects/*metabolism
MH  - Cells, Cultured
MH  - Excitatory Amino Acid Transporter 2/antagonists & inhibitors/*biosynthesis
MH  - Humans
MH  - I-kappa B Kinase/*metabolism
MH  - Manganese/*toxicity
MH  - Oxidative Stress/drug effects/physiology
MH  - Reactive Oxygen Species/*metabolism
MH  - Up-Regulation/drug effects/physiology
MH  - YY1 Transcription Factor/*biosynthesis
PMC - PMC8440474
MID - NIHMS1730851
OTO - NOTNLM
OT  - EAAT2
OT  - Manganese
OT  - NF-kappaB
OT  - Oxidative stress
OT  - TNF-alpha
OT  - YY1
COIS- Declaration of interests The authors declare that they have no known competing 
      financial interests or personal relationships that could have appeared to 
      influence the work reported in this paper.
EDAT- 2021/07/27 06:00
MHDA- 2022/02/05 06:00
PMCR- 2022/09/01
CRDT- 2021/07/26 20:10
PHST- 2021/06/07 00:00 [received]
PHST- 2021/07/14 00:00 [revised]
PHST- 2021/07/21 00:00 [accepted]
PHST- 2021/07/27 06:00 [pubmed]
PHST- 2022/02/05 06:00 [medline]
PHST- 2021/07/26 20:10 [entrez]
PHST- 2022/09/01 00:00 [pmc-release]
AID - S0161-813X(21)00082-6 [pii]
AID - 10.1016/j.neuro.2021.07.004 [doi]
PST - ppublish
SO  - Neurotoxicology. 2021 Sep;86:94-103. doi: 10.1016/j.neuro.2021.07.004. Epub 2021 
      Jul 24.