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Cuproptosis-related genes signature and validation of differential expression and the potential targeting drugs in temporal lobe epilepsy
Introduction: Temporal lobe epilepsy (TLE) is the most common subtype of epilepsy in adults and is characterized by neuronal loss, gliosis, and sprouting mossy fibers in the hippocampus. But the mechanism underlying neuronal loss has not been fully elucidated. A new programmed cell death, cuproptosi...
Autores principales: | , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Frontiers Media S.A.
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10330702/ https://www.ncbi.nlm.nih.gov/pubmed/37435496 http://dx.doi.org/10.3389/fphar.2023.1033859 |
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author | Yang, Xiaolin Zhang, Xiaoqing Shen, Kaifeng Wang, Zhongke Liu, Guolong Huang, Kaixuan He, Zeng Li, Yang Hou, Zhi Lv, Shengqing Zhang, Chunqing Yang, Hui Liu, Shiyong Ke, Yanyan |
author_facet | Yang, Xiaolin Zhang, Xiaoqing Shen, Kaifeng Wang, Zhongke Liu, Guolong Huang, Kaixuan He, Zeng Li, Yang Hou, Zhi Lv, Shengqing Zhang, Chunqing Yang, Hui Liu, Shiyong Ke, Yanyan |
author_sort | Yang, Xiaolin |
collection | PubMed |
description | Introduction: Temporal lobe epilepsy (TLE) is the most common subtype of epilepsy in adults and is characterized by neuronal loss, gliosis, and sprouting mossy fibers in the hippocampus. But the mechanism underlying neuronal loss has not been fully elucidated. A new programmed cell death, cuproptosis, has recently been discovered; however, its role in TLE is not clear. Methods: We first investigated the copper ion concentration in the hippocampus tissue. Then, using the Sample dataset and E-MTAB-3123 dataset, we analyzed the features of 12 cuproptosis-related genes in TLEs and controls using the bioinformatics tools. Then, the expression of the key cuproptosis genes were confirmed using real-time PCR and immunohistochemical staining (IHC). Finally, the Enrichr database was used to screen the small molecules and drugs targeting key cuproptosis genes in TLE. Results: The Sample dataset displayed four differentially expressed cuproptosis-related genes (DECRGs; LIPT1, GLS, PDHA1, and CDKN2A) while the E-MTAB-3123 dataset revealed seven DECRGs (LIPT1, DLD, FDX1, GLS, PDHB, PDHA1, and DLAT). Remarkably, only LIPT1 was uniformly upregulated in both datasets. Additionally, these DECRGs are implicated in the TCA cycle and pyruvate metabolism—both crucial for cell cuproptosis—as well as various immune cell infiltrations, especially macrophages and T cells, in the TLE hippocampus. Interestingly, DECRGs were linked to most infiltrating immune cells during TLE’s acute phase, but this association considerably weakened in the latent phase. In the chronic phase, DECRGs were connected with several T-cell subclasses. Moreover, LIPT1, FDX1, DLD, and PDHB were related to TLE identification. PCR and IHC further confirmed LIPT1 and FDX1’s upregulation in TLE compared to controls. Finally, using the Enrichr database, we found that chlorzoxazone and piperlongumine inhibited cell cuproptosis by targeting LIPT1, FDX1, DLD, and PDHB. Conclusion: Our findings suggest that cuproptosis is directly related to TLE. The signature of cuproptosis-related genes presents new clues for exploring the roles of neuronal death in TLE. Furthermore, LIPT1 and FDX1 appear as potential targets of neuronal cuproptosis for controlling TLE’s seizures and progression. |
format | Online Article Text |
id | pubmed-10330702 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | Frontiers Media S.A. |
record_format | MEDLINE/PubMed |
spelling | pubmed-103307022023-07-11 Cuproptosis-related genes signature and validation of differential expression and the potential targeting drugs in temporal lobe epilepsy Yang, Xiaolin Zhang, Xiaoqing Shen, Kaifeng Wang, Zhongke Liu, Guolong Huang, Kaixuan He, Zeng Li, Yang Hou, Zhi Lv, Shengqing Zhang, Chunqing Yang, Hui Liu, Shiyong Ke, Yanyan Front Pharmacol Pharmacology Introduction: Temporal lobe epilepsy (TLE) is the most common subtype of epilepsy in adults and is characterized by neuronal loss, gliosis, and sprouting mossy fibers in the hippocampus. But the mechanism underlying neuronal loss has not been fully elucidated. A new programmed cell death, cuproptosis, has recently been discovered; however, its role in TLE is not clear. Methods: We first investigated the copper ion concentration in the hippocampus tissue. Then, using the Sample dataset and E-MTAB-3123 dataset, we analyzed the features of 12 cuproptosis-related genes in TLEs and controls using the bioinformatics tools. Then, the expression of the key cuproptosis genes were confirmed using real-time PCR and immunohistochemical staining (IHC). Finally, the Enrichr database was used to screen the small molecules and drugs targeting key cuproptosis genes in TLE. Results: The Sample dataset displayed four differentially expressed cuproptosis-related genes (DECRGs; LIPT1, GLS, PDHA1, and CDKN2A) while the E-MTAB-3123 dataset revealed seven DECRGs (LIPT1, DLD, FDX1, GLS, PDHB, PDHA1, and DLAT). Remarkably, only LIPT1 was uniformly upregulated in both datasets. Additionally, these DECRGs are implicated in the TCA cycle and pyruvate metabolism—both crucial for cell cuproptosis—as well as various immune cell infiltrations, especially macrophages and T cells, in the TLE hippocampus. Interestingly, DECRGs were linked to most infiltrating immune cells during TLE’s acute phase, but this association considerably weakened in the latent phase. In the chronic phase, DECRGs were connected with several T-cell subclasses. Moreover, LIPT1, FDX1, DLD, and PDHB were related to TLE identification. PCR and IHC further confirmed LIPT1 and FDX1’s upregulation in TLE compared to controls. Finally, using the Enrichr database, we found that chlorzoxazone and piperlongumine inhibited cell cuproptosis by targeting LIPT1, FDX1, DLD, and PDHB. Conclusion: Our findings suggest that cuproptosis is directly related to TLE. The signature of cuproptosis-related genes presents new clues for exploring the roles of neuronal death in TLE. Furthermore, LIPT1 and FDX1 appear as potential targets of neuronal cuproptosis for controlling TLE’s seizures and progression. Frontiers Media S.A. 2023-06-26 /pmc/articles/PMC10330702/ /pubmed/37435496 http://dx.doi.org/10.3389/fphar.2023.1033859 Text en Copyright © 2023 Yang, Zhang, Shen, Wang, Liu, Huang, He, Li, Hou, Lv, Zhang, Yang, Liu and Ke. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. |
spellingShingle | Pharmacology Yang, Xiaolin Zhang, Xiaoqing Shen, Kaifeng Wang, Zhongke Liu, Guolong Huang, Kaixuan He, Zeng Li, Yang Hou, Zhi Lv, Shengqing Zhang, Chunqing Yang, Hui Liu, Shiyong Ke, Yanyan Cuproptosis-related genes signature and validation of differential expression and the potential targeting drugs in temporal lobe epilepsy |
title | Cuproptosis-related genes signature and validation of differential expression and the potential targeting drugs in temporal lobe epilepsy |
title_full | Cuproptosis-related genes signature and validation of differential expression and the potential targeting drugs in temporal lobe epilepsy |
title_fullStr | Cuproptosis-related genes signature and validation of differential expression and the potential targeting drugs in temporal lobe epilepsy |
title_full_unstemmed | Cuproptosis-related genes signature and validation of differential expression and the potential targeting drugs in temporal lobe epilepsy |
title_short | Cuproptosis-related genes signature and validation of differential expression and the potential targeting drugs in temporal lobe epilepsy |
title_sort | cuproptosis-related genes signature and validation of differential expression and the potential targeting drugs in temporal lobe epilepsy |
topic | Pharmacology |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10330702/ https://www.ncbi.nlm.nih.gov/pubmed/37435496 http://dx.doi.org/10.3389/fphar.2023.1033859 |
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