INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
·
2023
·Vol. 24
·期 2
·1667
·
IF 5.6
Shengqi Huo,Qian Wang,Wei Shi,Lulu Peng,Yue Jiang,Mengying Zhu,Junyi Guo,Dewei Peng,Moran Wang,Lintong Men,Bingyu Huang,Jiagao Lv,Li Lin
Cuproptosis resulting from copper (Cu) overload has not yet been investigated in diabetic cardiomyopathy (DCM). Advanced glycosylation end products (AGEs) induced by persistent hyperglycemia play an essential role in cardiotoxicity. To clarify whether cuproptosis was involved in AGEs-induced cardiotoxicity, we analyzed the toxicity of AGEs and copper in AC16 cardiomyocytes and in STZ-induced or db/db-diabetic mouse models. The results showed that copper ionophore elesclomol induced cuproptosis in cardiomyocytes. It was only rescued by copper chelator tetrathiomolybdate rather than by other cell death inhibitors. Intriguingly, AGEs triggered cardiomyocyte death and aggravated it when incubated with CuCl2or elesclomol–CuCl2. Moreover, AGEs increased intracellular copper accumulation and exhibited features of cuproptosis, including loss of Fe–S cluster proteins (FDX1, LIAS, NDUFS8 and ACO2) and decreased lipoylation of DLAT and DLST. These effects were accompanied by decreased mitochondrial oxidative respiration, including downregulated mitochondrial respiratory chain complex, decreased ATP production and suppressed mitochondrial complex I and III activity. Additionally, AGEs promoted the upregulation of copper importer SLC31A1. We predicted that ATF3 and/or SPI1 might be transcriptional factors of SLC31A1 by online databases and validated that by ATF3/SPI1 overexpression. In diabetic mice, copper and AGEs increases in the blood and heart were observed and accompanied by cardiac dysfunction. The protein and mRNA profile changes in diabetic hearts were consistent with cuproptosis. Our findings showed, for the first time, that excessive AGEs and copper in diabetes upregulated ATF3/SPI1/SLC31A1 signaling, thereby disturbing copper homeostasis and promoting cuproptosis. Collectively, the novel mechanism might be an alternative potential therapeutic target for DCM.Keywords:cuproptosis;advanced glycosylation end products;diabetic cardiomyopathy;SLC31A1
研究领域:
心脏病学
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糖尿病
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分子生物学
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细胞信号传导
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病理生理学
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产品关联
DOI
PubMed
高影响因子
EXPERIMENTAL NEUROLOGY
·
2026
·
IF 4.8
Shiyao Feng,Boyu Sun,Longlong Tian,Mingkang Li,Guozhu Sun
Traumatic brain injury (TBI) is one of the most prevalent neurological disorders and a major cause of death and disability worldwide. Cuproptosis is a recently identified form of cell death. Nuclear factor erythroid 2-related factor 2 (Nrf2), a key transcription factor that has been widely investigated in TBI, may contribute to the regulation of cuproptosis. In this study, we investigated the role of cuproptosis in TBI and the regulatory mechanisms of Nrf2. We found that cuproptosis was induced following TBI in both patients and mouse models. In TBI mice, cuproptosis peaked at 3 days post-injury and predominantly occurred in neurons. Nrf2 deficiency aggravates neuronal cuproptosis after TBI, primarily through IRF7-mediated upregulation of SLC31A1. The Nrf2 activator dimethyl fumarate (DMF) suppresses neuronal injury and improves neurological function in TBI mice by inhibiting cuproptosis. Our results establish that cuproptosis is an important mechanism in TBI and that activation of Nrf2 mitigates TBI-induced cuproptosis by regulating the IRF7–SLC31A1 axis.
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产品关联
DOI
PubMed
高影响因子
CYTOTECHNOLOGY
·
2021
·Vol. 73
·期 3
·483-496
·
IF 2.058
Lu Hengxiao,Wang Hao,Sun Peidao,Wang Jiang,Li Shuhai,Xu Tongzhen
We investigated the role of miR-522-3p in thymoma-associated myasthenia gravis (TAMG), and the mechanism of action in T cells. The miR-522-3p expression in normal serum, non-thymoma MG patient serum and TAMG patient serum and tissues was detected by quantitative real-time PCR (qRT-PCR), respectively. We assessed miR-522-3p expression in Jurkat cells and human CD4 + T cells after activation by anti-CD3 and anti-CD28 using qRT-PCR. The viability, proliferation, cycle distribution and the levels of CD25, CD69, interleukin-2 (IL-2) and IL-10 in transfected Jurkat cells were detected by Cell counting kit-8, 5-ethynyl-2′-deoxyuridine (EdU), flow cytometry, qRT-PCR, respectively. Targeting relationships of miR-522-3p and SLC31A1 were predicted and validated by bioinformatics analysis and dual-luciferase reporter. The viability, proliferation, cycle distribution and the levels of SLC31A1, CD25, CD69, IL-2 and IL-10 in transfected Jurkat cells were detected by above methods and western blot. The miR-522-3p expression was declined in TAMG and activated T cells. MiR-522-3p inhibitor promoted cell viability, EdU positive cells, cycle progression, and the level of CD25, CD69, IL-2 and IL-10 in Jurkat cells, while the effect of miR-522-3p mimic was the opposite. SLC31A1 was targeted by miR-522-3p, and miR-522-3p inhibited SLC31A1 expression. Overexpressed SLC31A1 reversed the inhibitory effects of miR-522-3p mimic on cell viability, EdU positive cell, cycle progression, and the levels of IL-2 and IL-10 in transfected Jurkat cells. MiR-522-3p expression was down-regulated in TAMG, and miR-522-3p inhibited proliferation and activation by regulating SLC31A1 expression in T cells.
研究领域:
分子生物学
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免疫学
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医学遗传学
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DOI
PubMed
高影响因子
ENVIRONMENTAL POLLUTION
·
2024
·
IF 7.6
Ziyan Wang,Wei Zhang,Danyang Huang,Huiwen Kang,Jingyu Wang,Ziyan Liu,Guangyu Jiang,Ai Gao
Decabromodiphenyl ether (BDE-209) has been universally detected in environmental media and animals, but its damage to ovarian function and mechanism is still unclear, and melatonin has been shown to improve mammalian ovarian function. This study aimed to investigate the toxic effects of BDE-209 on the ovary and tried to improve ovarian function with melatonin. Herein, BDE-209 was administered orally to female SD rats for 60 days. Enzyme-linked immunosorbent assay, HE staining, transcriptome analysis, qPCR and immunohistochemical staining were used to explore and verify the potential mechanism. We found that BDE-209 exposure had effects on the ovary, as shown by abnormal changes in the estrous cycle, hormone levels and ovarian reserve function in rats, while increasing the proportion of collagen fibres in ovarian tissue. In terms of mechanism, cuproptosis, a form of cell death, was identified to play a crucial role in BDE-209-induced ovarian dysfunction, with the phenotype manifested as copper salt accumulation in ovary, downregulation of glutathione pathway metabolism and copper transfer molecule ( ATP7A/B ), and upregulation of FDX1 , lipoic acid pathway ( LIAS, LIPT1 ), pyruvate dehydrogenase complex components (DLAT, PDHB, PDHA1 ), and copper transfer molecule ( SLC31A1 ). Furthermore, possible interventions were explored. Notably, a supplement with melatonin has a repair effect on the damage to ovarian function by reversing the gene expression of cuproptosis-involved molecules. Overall, this study revealed that cuproptosis is involved in BDE-209-induced ovarian damage and the beneficial effect of melatonin on ovarian copper damage, providing evidence for the prevention and control of female reproductive damage induced by BDE-209.
研究领域:
毒理学
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生殖生物学
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药理学
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分子生物学
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DOI
PubMed
高影响因子
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