Cited by 50Genomics, phytochemicals, and oxidative stressNuclear Receptors and SignalingParkinson's Disease Mechanisms and Treatments

Nrf2-Keap1 antioxidant defense and cell survival signaling are upregulated by 17β-estradiol in homocysteine-treated dopaminergic sh-Sy5y cells

Chen, Cheng-Sheng, Tseng, Yu-Ting, Hsu, Ya-Yun, Lo, Yi-Ching·2013·Neuroendocrinology

Abstract

BACKGROUND AND AIMS: A recent neuroimaging study discovered the neurotoxicity effects of homocysteine (Hcy), which is only seen in elderly women. Estrogens exert a variety of actions on brain function that influence cognitive function, mood, and neuroprotection. The Kelch-like ECH-associated protein 1 (Keap1)/nuclear factor erythroid 2-related factor 2 (Nrf2) antioxidant defense pathway has been well-known to afford neuroprotection. Here, we first demonstrate the roles of Nrf2-Keap1 in 17β-estradiol (E2) cytoprotection and Hcy toxicity and the protective mechanisms of E2 on Hcy cytotoxicity in human dopaminergic SH-SY5Y cells. METHODS: Cell viability was determined by trypan blue method. Protein expression was determined by Western blot analysis. Superoxide dismutase (SOD) activity was determined by ELISA. Reactive oxygen species (ROS) production was determined by flow cytometry. RESULTS: In Hcy-treated SH-SY5Y cells, E2 increased cell viability, attenuated ROS production, activated Akt signaling and inhibited glycogen synthase kinase-3β (GSK-3β), a kinase known to participate in neurodegeneration. Moreover, E2 treatment led to Nrf2 dissociation from Keap1, the main negative regulator of Nrf2 activity in the cytoplasm, and increased the protein level of Nrf2 in the nucleus, with a significant increase in HO-1 expression and SOD activity in Hcy-treated cells. E2-induced Nrf2 activation was attenuated by the PI3K inhibitor LY294002 and the estrogen receptor antagonist ICI 182,780. Further, E2 decreased Hcy-induced apoptotic death by upregulating the antiapoptotic protein Bcl-2, decreasing cytochrome c release from mitochondria, and attenuating apoptotic cascade activation (Bax, caspase-9, and caspase-3). CONCLUSION: E2 activates cell survival signaling and Nrf2-Keap1 antioxidant defense pathway and attenuates Hcy cytotoxicity.

Integrity signals

Registry

Crossref · 10.1159/000342692

Cites

39 of 39 references verified0 citation errors · 0 not checkable

Statistics

Recomputing p-values needs the paper’s full text.

Claims the paper makes

This paper’s full text isn’t openly available, so its claims and self-check weren’t run. The registry and citation checks still apply.

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • 17β-estradiol regulates multiple other aspects of mitochondrial function through ERs, including ROS generation, antioxidant defense, and Ca2+ handling.

    “Moreover, 17β-estradiol also appears to regulate multiple other aspects of mitochondrial function through ERs, including ROS generation, antioxidant defense, and Ca2+ handling (126–131).”

Cites

Flagged first, then by citations

Cited by

Sorted by citations

Authors
Chen, C.-S., Tseng, Y.-T., Hsu, Y.-Y., & Lo, Y.-C.
Affiliations
Kaohsiung Medical University Chung-Ho Memorial Hospital (TW)
Venue
Neuroendocrinology
Publisher
S. Karger AG
Published
2012-11-02
Volume
97
Issue
3
Pages
232-241
ISSN
  • 0028-3835 (ISSN-L)
  • 1423-0194
OpenAlex
W2033037571
Cited by
50
References
39
Citations by year
2025: 3 · 2024: 5 · 2023: 4 · 2022: 3 · 2021: 3 · 2020: 4 · 2019: 6 · 2018: 4 · 2017: 3 · 2016: 2 · 2015: 4 · 2014: 8 · 2013: 1
FWCI
1.67
Type
journal article
Language
en
Open access
closed
Locations
  • Neuroendocrinology (publishedVersion)
  • PubMed (publishedVersion)
Funders
Kaohsiung Medical University
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics, phytochemicals, and oxidative stress
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Nuclear Receptors and Signaling
  • Health Sciences › Medicine › Neurology › Parkinson's Disease Mechanisms and Treatments
Keywords
Nrf2/Keap1 pathway, estradiol, neuroprotection, antioxidant defense, cell survival signaling, Akt signaling, glycogen synthase kinase-3β, heme oxygenase-1, superoxide dismutase, reactive oxygen species, apoptosis, estrogen receptor, PI3K signaling, caspase activation, Bcl-2
MeSH terms
Glycogen Synthase Kinase 3 beta, Kelch-Like ECH-Associated Protein 1, Fulvestrant, Antioxidants, Cell Survival, Chromones, Estradiol, Estrogen Antagonists, Homocysteine, Humans, Morpholines, Superoxide Dismutase, Signal Transduction, Up-Regulation, Apoptosis, Reactive Oxygen Species, Proto-Oncogene Proteins c-bcl-2, Glycogen Synthase Kinase 3, Cytochromes c, Cell Line, Tumor, Protein Kinase Inhibitors, Intracellular Signaling Peptides and Proteins, NF-E2-Related Factor 2, Dopaminergic Neurons

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review