Cargando…

Ebselen, Iron Uptake Inhibitor, Alleviates Iron Overload-Induced Senescence-Like Neuronal Cells SH-SY5Y via Suppressing the mTORC1 Signaling Pathway

Increasing evidence highlights that excessive iron accumulation in the brain plays a vital role in neuronal senescence and is implicated in the pathogenesis of age-related neurodegenerative diseases, including Alzheimer's disease (AD) and Parkinson's disease (PD). Therefore, the chemical c...

Descripción completa

Detalles Bibliográficos
Autores principales: Mukem, Sirirak, Sayoh, Ibrahim, Maungchanburi, Saowanee, Thongbuakaew, Tipsuda
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Hindawi 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10509000/
https://www.ncbi.nlm.nih.gov/pubmed/37731679
http://dx.doi.org/10.1155/2023/6641347
_version_ 1785107645900783616
author Mukem, Sirirak
Sayoh, Ibrahim
Maungchanburi, Saowanee
Thongbuakaew, Tipsuda
author_facet Mukem, Sirirak
Sayoh, Ibrahim
Maungchanburi, Saowanee
Thongbuakaew, Tipsuda
author_sort Mukem, Sirirak
collection PubMed
description Increasing evidence highlights that excessive iron accumulation in the brain plays a vital role in neuronal senescence and is implicated in the pathogenesis of age-related neurodegenerative diseases, including Alzheimer's disease (AD) and Parkinson's disease (PD). Therefore, the chemical compounds that eliminate an iron overload may provide better protection against oxidative stress conditions that cause the accumulation of senescent cells during brain aging. Ebselen has been identified as a strongly useful compound in the research on redox biology mechanisms. We hypothesized that ebselen could alleviate an iron overload-induced oxidative stress and consequently reverses the senescence-like phenotypes in the neuronal cells. In the present study, SH-SY5Y cells were treated with ferric ammonium citrate (FAC) before ebselen, and the evaluation of the cellular iron homeostasis, the indicators of oxidative stress, and the onset of senescence phenotypes and mechanisms were carried out accordingly. Our findings showed that ebselen ameliorated the FAC-mediated iron overload by decreasing the expression of divalent metal transporter 1 (DMT1) and ferritin light chain (FT-L) proteins. In contrast, it increased the expression of ferroportin 1 (FPN1) protein and its correlation led to a decrease in the expression of the cytosolic labile iron pool (LIP). Furthermore, ebselen significantly reduced reactive oxygen species (ROS) and rescued the mitochondrial membrane potential (ΔΨm). Notably, ebselen restored the biomarkers of cellular senescence by reducing the number of senescence-associated β-galactosidase (SA-β-gal) positive cells and senescence-associated secretory phenotypes (SASP). This also suppressed the expression of p53 protein targeting DNA damage response (DDR)/p21 cyclin-dependent kinase (CDK) inhibitor through a mTORC1 signaling pathway. Potentially, ebselen could be a therapeutic agent for treating brain aging and AD by mitigating iron accumulation and restoring senescence in SH-SY5Y cells.
format Online
Article
Text
id pubmed-10509000
institution National Center for Biotechnology Information
language English
publishDate 2023
publisher Hindawi
record_format MEDLINE/PubMed
spelling pubmed-105090002023-09-20 Ebselen, Iron Uptake Inhibitor, Alleviates Iron Overload-Induced Senescence-Like Neuronal Cells SH-SY5Y via Suppressing the mTORC1 Signaling Pathway Mukem, Sirirak Sayoh, Ibrahim Maungchanburi, Saowanee Thongbuakaew, Tipsuda Adv Pharmacol Pharm Sci Research Article Increasing evidence highlights that excessive iron accumulation in the brain plays a vital role in neuronal senescence and is implicated in the pathogenesis of age-related neurodegenerative diseases, including Alzheimer's disease (AD) and Parkinson's disease (PD). Therefore, the chemical compounds that eliminate an iron overload may provide better protection against oxidative stress conditions that cause the accumulation of senescent cells during brain aging. Ebselen has been identified as a strongly useful compound in the research on redox biology mechanisms. We hypothesized that ebselen could alleviate an iron overload-induced oxidative stress and consequently reverses the senescence-like phenotypes in the neuronal cells. In the present study, SH-SY5Y cells were treated with ferric ammonium citrate (FAC) before ebselen, and the evaluation of the cellular iron homeostasis, the indicators of oxidative stress, and the onset of senescence phenotypes and mechanisms were carried out accordingly. Our findings showed that ebselen ameliorated the FAC-mediated iron overload by decreasing the expression of divalent metal transporter 1 (DMT1) and ferritin light chain (FT-L) proteins. In contrast, it increased the expression of ferroportin 1 (FPN1) protein and its correlation led to a decrease in the expression of the cytosolic labile iron pool (LIP). Furthermore, ebselen significantly reduced reactive oxygen species (ROS) and rescued the mitochondrial membrane potential (ΔΨm). Notably, ebselen restored the biomarkers of cellular senescence by reducing the number of senescence-associated β-galactosidase (SA-β-gal) positive cells and senescence-associated secretory phenotypes (SASP). This also suppressed the expression of p53 protein targeting DNA damage response (DDR)/p21 cyclin-dependent kinase (CDK) inhibitor through a mTORC1 signaling pathway. Potentially, ebselen could be a therapeutic agent for treating brain aging and AD by mitigating iron accumulation and restoring senescence in SH-SY5Y cells. Hindawi 2023-09-12 /pmc/articles/PMC10509000/ /pubmed/37731679 http://dx.doi.org/10.1155/2023/6641347 Text en Copyright © 2023 Sirirak Mukem et al. https://creativecommons.org/licenses/by/4.0/This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
spellingShingle Research Article
Mukem, Sirirak
Sayoh, Ibrahim
Maungchanburi, Saowanee
Thongbuakaew, Tipsuda
Ebselen, Iron Uptake Inhibitor, Alleviates Iron Overload-Induced Senescence-Like Neuronal Cells SH-SY5Y via Suppressing the mTORC1 Signaling Pathway
title Ebselen, Iron Uptake Inhibitor, Alleviates Iron Overload-Induced Senescence-Like Neuronal Cells SH-SY5Y via Suppressing the mTORC1 Signaling Pathway
title_full Ebselen, Iron Uptake Inhibitor, Alleviates Iron Overload-Induced Senescence-Like Neuronal Cells SH-SY5Y via Suppressing the mTORC1 Signaling Pathway
title_fullStr Ebselen, Iron Uptake Inhibitor, Alleviates Iron Overload-Induced Senescence-Like Neuronal Cells SH-SY5Y via Suppressing the mTORC1 Signaling Pathway
title_full_unstemmed Ebselen, Iron Uptake Inhibitor, Alleviates Iron Overload-Induced Senescence-Like Neuronal Cells SH-SY5Y via Suppressing the mTORC1 Signaling Pathway
title_short Ebselen, Iron Uptake Inhibitor, Alleviates Iron Overload-Induced Senescence-Like Neuronal Cells SH-SY5Y via Suppressing the mTORC1 Signaling Pathway
title_sort ebselen, iron uptake inhibitor, alleviates iron overload-induced senescence-like neuronal cells sh-sy5y via suppressing the mtorc1 signaling pathway
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10509000/
https://www.ncbi.nlm.nih.gov/pubmed/37731679
http://dx.doi.org/10.1155/2023/6641347
work_keys_str_mv AT mukemsirirak ebselenironuptakeinhibitoralleviatesironoverloadinducedsenescencelikeneuronalcellsshsy5yviasuppressingthemtorc1signalingpathway
AT sayohibrahim ebselenironuptakeinhibitoralleviatesironoverloadinducedsenescencelikeneuronalcellsshsy5yviasuppressingthemtorc1signalingpathway
AT maungchanburisaowanee ebselenironuptakeinhibitoralleviatesironoverloadinducedsenescencelikeneuronalcellsshsy5yviasuppressingthemtorc1signalingpathway
AT thongbuakaewtipsuda ebselenironuptakeinhibitoralleviatesironoverloadinducedsenescencelikeneuronalcellsshsy5yviasuppressingthemtorc1signalingpathway