SCIENCE OF THE TOTAL ENVIRONMENT
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2024
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IF 8.2
Ziwei Chen,Jia Liu,Manjia Zheng,Minhua Mo,Xiaowen Hu,Chang Liu,Janak Lal Pathak,Lijing Wang,Liangjiao Chen
Yttrium oxide nanoparticles (Y 2 O 3 NPs), extensively utilized rare earth nanoparticles, exhibited a diverse range of applications across various fields, which leading to increased human exposure. Moreover, potential neurotoxic risks have been associated with their use, yet the underlying mechanism remains unclear. The present study aimed to investigate the effects of Y 2 O 3 NPs on cognitive function in rats with a particular focus on elucidating the pivotal role played by astrocytes in this process. The results demonstrated that Y 2 O 3 NPs induced cognitive and memory impairment in rats, copper (Cu) accumulation and cuproptosis of astrocytes as contributing factors. Furthermore, we elucidated that Y 2 O 3 NPs induced astrocytes cuproptosis by inhibiting TRIM24/DTNBP1/ATP7A signaling pathway-mediated cellular Cu efflux. We provide, for the first time, the important involvement of astrocytes in Y 2 O 3 NPs-induced neurotoxicity, elucidating that cuproptosis as the primary mode of cell death. These results offer valuable insights for the future safe application of rare earth nanoparticles in field of neurology.
研究领域:
神经科学
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毒理学
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纳米技术
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细胞生物学
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DOI
PubMed
高影响因子
CANCER RESEARCH
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2025
·Vol. 85
·期 20
·3999-4017
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IF 16.6
Zhao Jian,Zhang Weijie,Zeng Yuanyuan,Lu Di,Ma Chenkang,Zhang Mengzhu,Cai Xin,Huang Zhifan,Yang Hongli,Li Jianjun,Zhu Jianjie,Huang Jian-An,Liu Zeyi
Despite progress in tumor-targeted therapy, oncogenic KRAS remains a major challenge in treating lung adenocarcinoma. In clinical practice, KRAS G12C inhibitors have limited response rates and are associated with acquired drug resistance. Cuproptosis is a recently identified form of copper (Cu)-mediated cell death, and previous studies have revealed that Cu metabolism plays an important role in the development of KRAS-driven tumors. In this study, we revealed the therapeutic value of the Cu ionophore elesclomol (ES) for treating KRAS G12 -mutant–driven lung adenocarcinoma. KRAS G12 -mutant lung adenocarcinoma cells relied on the Cu exporter ATP7A to maintain Cu homeostasis. ES induced cellular Cu accumulation and cuproptosis by upregulating the expression of the E3 ligase OSTM1, which interacted with the IRGY motif of ATP7A to promote ubiquitination and degradation. KRAS G12D transgenic mice and lung cancer organoids derived from the mice were used to validate the therapeutic effects of ES and Cu in vivo and in vitro . These findings indicate that KRAS G12 -driven lung adenocarcinoma relies on ATP7A-mediated Cu metabolic homeostasis, which can be perturbed with ES as an effective treatment strategy. Significance: The copper ionophore elesclomol is effective for treating KRAS-driven lung cancer by activating the OSTM1-ATP7A regulatory axis to perturb copper metabolism homeostasis.
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PubMed
高影响因子
International Journal of Nanomedicine
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2025
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IF 6.5
Manjia Zheng,Ziwei Chen,Jiling Xie,Qiyuan Yang,Minhua Mo,Liangjiao Chen
Background: The cerebral cortex is the foundation of cognitive function, and an imbalance in copper homeostasis in the cerebral cortex may cause cognitive and memory dysfunction. Metal exposure may disrupt copper (Cu) homeostasis in cells, leading to cognitive impairment. Yttrium oxide nanoparticles (Y2O3 NPs) are widely used in the biomedical field and have potential neurotoxicity. However, the influence of Y2O3 NPs on cognitive memory function in the brain is currently unclear.Methods: The effects of Y2O3 NPs on cognitive and memory function were evaluated by rat behavioural experiments after intraperitoneal injection in a rat model. Subsequently, histological analysis was conducted on the cerebral cortex, and the Cu content and expression levels of cuproptosis-related proteins were detected both in vitro and in vivo. Finally, the copper output protein Cu transporting alpha polypeptide (ATP7A) was screened and detected at the mRNA and protein levels. Plasmid transfection experiments further confirmed that Y2O3 NPs mediate disordered Cu output through ATP7A.Results: Y2O3 NP exposure induced cognitive and memory dysfunction in rats. This effect was related to the disruption of copper homeostasis in neuronal cells caused by Y2O3 NPs, which induced cuproptosis. Further research revealed that Y2O3 NPs downregulate ATP7A expression, thus disrupting copper output and inducing cuproptosis.Conclusion: Y2O3 NPs induce cognitive and memory dysfunction by mediating the disruption of copper output in neuronal cells, revealing the toxicity of Y2O3 NPs to neurons. These findings contribute to their safe application in the biomedical field.
研究领域:
神经科学
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毒理学
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分子生物学
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DOI
PubMed
高影响因子
Nature Communications
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2024
·Vol. 15
·期 1
·1-17
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IF 14.7
Guan Meng,Cheng Kai,Xie Xiao-Ting,Li Yong,Ma Meng-Wen,Zhang Bin,Chen Si,Chen Wei,Liu Bo,Fan Jin-Xuan,Zhao Yuan-Di
Cuproptosis is an emerging mode of programmed cell death for tumor suppression but sometimes gets resisted by tumor cells resist under specific mechanisms. Inhibiting copper transporter ATPase (ATP7A) was found to disrupt copper ion homeostasis, thereby enhancing the effect of cuproptosis and eventually inhibiting tumor invasion and metastasis. In this study, we develop a multifunctional nanoplatfrom based on Cu 9 S 8 (CAPSH), designed to enhance cuproptosis in tumor cells by specifically targeting ATP7A interference, while combining thermodynamic therapy with immune effects. The release of copper ions from CAPSH and the copper homeostasis interference by siRNA cooperatively increases the concentration of copper ions in tumor cells, which induces effectively cuproptosis and activates immune responses for suppressing development and metastasis of tumor. This nanoplatform simultaneously regulates cuproptosis from both principles of onset and development, facilitating the application of cuproptosis in tumor therapy.
研究领域:
肿瘤学
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分子生物学
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纳米技术
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免疫学
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产品关联
DOI
PubMed
高影响因子
JOURNAL OF MEDICINAL CHEMISTRY
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2024
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IF 6.8
Ying-Da Zang,Hai-Jie Wu,Xin-Yi Chen,Zhi-Ling Ma,Chuang-Jun Li,Jie Ma,Xiao-Guang Chen,Li Sheng,Sen Zhang,Dong-Ming Zhang
Cisplatin is a widely used drug for the clinical treatment of tumors. However, nephrotoxicity limits its widespread use. A series of compounds including eight analogs (G3-G10) and 40 simplifiers (G11-G50) were synthesized based on the total synthesis of Psiguamer A and B, which were novel meroterpenoids with unusual skeletons from the leaves of Psidium guajava. Among these compounds, (d)-G8 showed the strongest protective effect on cisplatin-induced acute kidney injury (AKI) in vitro and vivo, and slightly enhanced the antitumor efficacy of cisplatin. A mechanistic study showed that (d)-G8 promoted the efflux of cisplatin via upregulating the copper transporting efflux proteins ATP7A and ATP7B. It enhanced autophagy through the activation of the adenosine monophosphate–activated protein kinase (AMPK) signaling pathway. (d)-G8 showed no acute toxicity or apparent pathological damage in the healthy mice at a single dose of 1 g/kg. This study provides a promising lead against cisplatin-induced AKI.
研究领域:
药理学
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药物化学
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毒理学
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分子生物学
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DOI
PubMed
高影响因子
Acta Pharmaceutica Sinica B
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2024
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IF 14.7
Xiaoyu Wu,Zijun Bai,Hui Wang,Hanqing Wang,Dahai Hou,Yunzhu Xu,Guanqun Wo,Haibo Cheng,Dongdong Sun,Weiwei Tao
Copper-based nanomaterials demonstrate promising potential in cancer therapy. Cu + efficiently triggers a Fenton-like reaction and further consumes the high level of glutathione, initiating chemical dynamic therapy (CDT) and ferroptosis. Cuproptosis, a newly identified cell death modality that represents a great prospect in cancer therapy, is activated. However, active homeostatic systems rigorously keep copper levels within cells exceptionally low, which hinders the application of cooper nanomaterials-based therapy. Herein, a novel strategy of CRISPR-Cas9 RNP nanocarrier to deliver cuprous ions and suppress the expression of copper transporter protein ATP7A for maintaining a high level of copper in cytoplasmic fluid is developed. The Cu 2 O and organosilica shell would degrade under the high level of glutathione and weak acidic environment, further releasing RNP and Cu + . The liberated Cu + triggered a Fenton-like reaction for CDT and partially transformed to Cu 2+ , consuming intracellular GSH and initiating cuproptosis and ferroptosis efficiently. Meanwhile, the release of RNP effectively reduced the expression of copper transporter ATP7A, subsequently increasing the accumulation of cooper and enhancing the efficacy of CDT, cuproptosis, and ferroptosis. Such tumor microenvironment responsive multimodal nanoplatform opens an ingenious avenue for colorectal cancer therapy based on gene editing enhanced synergistic cuproptosis/CDT/ferroptosis.
研究领域:
生物技术
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纳米技术
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肿瘤学
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基因编辑
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DOI
PubMed
高影响因子
Redox Biology
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2023
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IF 11.4
Dingbang Huang,Lixuan Chen,Qiuyi Ji,Yang Xiang,Qin Zhou,Kaiju Chen,Xiaoshun Zhang,Fei Zou,Xingmei Zhang,Zaihua Zhao,Tao Wang,Gang Zheng,Xiaojing Meng
Alzheimer's disease (AD) is a common neurodegenerative disease that is associated with multiple environmental risk factors, including heavy metals. Lead (Pb) is a heavy metal contaminant, which is closely related to the incidence of AD. However, the research on the role of microglia in Pb-induced AD-like pathology is limited. To determine the mechanism by which Pb exposure aggravates AD progression and the role of microglial activation, we exposed APP/PS1 mice and Aβ 1-42 -treated BV-2 cells to Pb. Our results suggested that chronic Pb exposure exacerbated learning and memory impairments in APP/PS1 mice. Pb exposure increased the activation of microglia in the hippocampus of APP/PS1 mice, which was associated with increased deposition of Aβ 1-42 , and induced hippocampal neuron damage. Pb exposure upregulated copper transporter 1 (CTR1) and downregulated copper P-type ATPase transporter (ATP7A) in the hippocampus of APP/PS1 mice and Aβ 1-42 -treated BV-2 cells. Moreover, Pb enhanced mitochondrial translocation of the mitochondrial copper transporter COX17, leading to an increase in mitochondrial copper concentration and mitochondrial damage. This could be reversed by copper-chelating agents or by inhibiting the mitochondrial translocation of COX17. The increased mitochondrial copper concentration caused by increased mitochondrial translocation of COX17 after Pb exposure may be related to the enhanced mitochondrial import pathway of AIF/CHCHD4. These results indicate that Pb induces the activation of microglia by increasing the concentration of copper in the mitochondria of microglia, and microglia release inflammatory factors to promote neuroinflammation, thus aggravating the pathology of AD. The present study provides new ideas for the prevention of Pb-induced AD.
研究领域:
神经科学
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毒理学
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神经退行性疾病
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DOI
PubMed
高影响因子
ENVIRONMENTAL POLLUTION
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2024
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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
JOURNAL OF NANOBIOTECHNOLOGY
·
2025
·Vol. 23
·期 1
·1-20
·
IF 12.6
Gu Lina,Sun Ying,Bai Tingjie,Shao Sijie,Tang Shumin,Xue Panpan,Cai Wanlin,Qin Xian,Zeng Xuemei,Yan Shuangqian
Elevated copper levels induce tumor cuproptosis and ferroptosis, leading to immunogenic cell death and subsequent antitumor immune responses. However, dysregulated copper metabolism in tumor cells maintains homeostatic copper balance, while hypoxic microenvironments hinder therapeutic efficacy. In this study, we present a nanozyme system, termed Cu ss OMEp, comprising a copper-based nanovector (Cu ss NV) that is PEGylated and loaded with omeprazole, a copper transporter inhibitor, to enhance tumor synergistic immunotherapy by promoting cuproptosis and ferroptosis. Cu ss NV is assembled from dithiodiglycolic acid and copper ions, exhibiting peroxidase, glutathione oxidase, and catalase-like activities, along with responsive degradability. This nanozyme alleviates tumor hypoxia by producing oxygen, induces ferroptosis through the generation of lethal hydroxyl radicals, and depletes glutathione. Additionally, omeprazole increases cellular copper concentration and oxidative stress by inhibiting the intracellular copper-transporting ATPase 1 (ATP7A), enhancing lipoylated protein oligomerization and cuproptosis. In a breast tumor mouse model, Cu ss OMEp elicits robust antitumor immune responses, including dendritic cell maturation and T cell proliferation. When combined with PD-1 antibodies (αPD-1), Cu ss OMEp significantly inhibits tumor metastasis in bilateral and lung metastatic models. This work presents a functional nanozyme system as a promising strategy for synergistic tumor immunotherapy leveraging ferroptosis and cuproptosis Graphical abstract
研究领域:
生物医学工程
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肿瘤学
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免疫学
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产品关联
DOI
PubMed
高影响因子
ADVANCED FUNCTIONAL MATERIALS
·
2023
·
IF 19
Fan Zhao,Liying Liang,Heng Wang,Chen Wang,Dan Su,Yao Ying,Wangchang Li,Juan Li,Jingwu Zheng,Liang Qiao,Xiaozhou Mou,Shenglei Che,Jing Yu
Copper overload is a novel way to achieve copper-ion-interference therapy by disrupting copper homeostasis and treating diseases through multiple cell death pathways. However, it is difficult to reach copper overload since excess intracellular copper ions will be pumped out. Herein, copper overload is achieved by both raising cellular uptake and reducing the efflux of copper ions using hydrogen sulfide (H 2 S)-responsive copper hydroxyphosphate nanoparticles (Cu 2 (PO 4 )(OH) NPs). After immersion in an H 2 S-enriched colon cancer microenvironment, Cu 2 (PO 4 )(OH) NPs can transform into copper sulfide NPs with reduced size for higher cell entering, resulting in improved Fenton activity as well as copper ion dissociation. Reactive oxygen species generated by the Fenton reaction not only activate inflammasomes and Caspase-1 proteins, cause the cleavage of gasdermin D to induce pyroptosis, but also affect mitochondrial function and down-regulate copper exporter ATP7A to further reduce the copper excretion. The combination of higher endocytosis and lower exportation leads to maximized copper overload. Together with the efficient copper ions release, mitochondrial tricarboxylic acid cycle can be disrupted and iron-sulfur cluster proteins are downregulated, ultimately triggering cuproptosis. As both pyroptosis and cuproptosis are efficient ways to induce cell death, this study provides a novel way to realize effective tumor-targeted therapy based on H 2 S-activated copper overload with simple Cu 2 (PO 4 )(OH) NPs.
研究领域:
肿瘤学
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纳米技术
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细胞生物学
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治疗学
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产品关联
DOI
高影响因子
Small
·
2024
·
IF 13
Jiao Chang,Weimin Yin,Hui Zhi,Shiyu Chen,Jiuyuan Sun,Yuge Zhao,Li Huang,Liangyi Xue,Xiaoyou Zhang,Tingting Zhang,Haiqing Dong,Yongyong Li
Cuproptosis is an emerging programmed cell death, displaying great potential in cancer treatment. However, intracellular copper content to induce cuproptosis is unmet, which mainly ascribes to the intracellular pumping out equilibrium mechanism by copper exporter ATP7A and ATP7B. Therefore, it is necessary to break such export balance mechanisms for desired cuproptosis. Mediated by diethyldithiocarbamate (DTC) coordination, herein a strategy to efficiently assemble copper ions into polydopamine nanostructure (PDA-DTC/Cu) for reprogramming copper metabolism of tumor is developed. The deposited Cu 2+ can effectively trigger the aggregation of lipoylated proteins to induce cuproptosis of tumor cells. Beyond elevating intracellular copper accumulation, PDA-DTC/Cu enables to break the balance of copper metabolism by disrupting mitochondrial function and restricting the adenosine triphosphate (ATP) energy supply, thus catalytically inhibiting the expressions of ATP7A and ATP7B of tumor cells to enhance cuproptosis. Meanwhile, the killed tumor cells can induce immunogenic cell death (ICD) to stimulate the immune response. Besides, PDA-DTC/Cu NPs can promote the repolarization of tumor-associated macrophages (TAMs ) to relieve the tumor immunosuppressive microenvironment (TIME). Collectively, PDA-DTC/Cu presented a promising “one stone two birds” strategy to realize copper accumulation and inhibit copper export simultaneously to enhance cuproptosis for 4T1 murine breast cancer immunotherapy.
研究领域:
癌症生物学
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纳米技术
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免疫治疗
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细胞生物学
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材料科学
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DOI
PubMed
高影响因子
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