iScience
·
2025
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IF 4.1
Shuya Wang,Xianlei Sun,Qingxuan Xin,Jianxiang Shi,Jin Li,Huilin Zhang,Mengjiao Xue,Fanxiang Yin,Zan Qiu,Xiaoqian Wang,Nannan Sun,Yingmei Li,Yaoyao Chen,Liyan Fu,Chaoqi Li,Shaohua Yan,Xian Zhao,Bolin Jue,Yanxia Gao,Baohong Yue,Bo Qin,Yong Jiang,Rongqun Guo
Wilson disease (WD) is caused by mutations of copper-transporting gene, ATP7B , leading to abnormal copper metabolism. A better characterization of WD is essential in understanding the effects of excess copper and how it disrupts immune regulation and hematopoietic development. Furthermore, exploration of the relationship between copper-mediated proliferation or cuproptosis and immune regulation is critical for developing new immune therapies. Therefore, we performed single-cell RNA sequencing (scRNA-seq) on peripheral blood mononuclear cells (PBMCs) to develop an atlas of immune landscape. Cells were clustered into several immune subsets, and cuproptosis-associated genes were assessed. Differential expression analysis was performed to identify WD-specific signatures by comparing transcriptome profiles of patients with WD with HDs. Excess copper impaired immune homeostasis and hematopoietic development. Then, we developed a map of immune landscape of patients with WD. Excess copper is involved in the metabolic reprogramming of immune cells, such as glycosis in CD14 + monocytes. We found that antigen processing-related pathway dysregulates in immune cells of patients with WD. Our study revealed that abnormal copper concentration influences the expression of HLA-I and HLA-II molecules. It is noteworthy that a high concentration of intracellular copper differs significantly from high concentration of extracellular copper. We have also identified a gene set of neurologic abnormality, which were dysregulated in PBMCs of patients with WD. We also observed abnormal expression of cuproptosis-associated genes in proliferating or malignant cells, providing new insights into the application of cuproptosis in cancer treatment.
研究领域:
医学
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免疫学
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分子生物学
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DOI
PubMed
高影响因子
ACS Applied Materials & Interfaces
·
2025
·
IF 8.2
Meiru Zhang,Hui Xu,Xiaozan Wu,Botao Chen,Xiyu Gong,Yongju He
Cuproptosis is a new copper-dependent form of regulated cell death and shows enormous promise in cancer therapy. However, its therapeutic performance is compromised by the strictly regulated copper metabolism and highly expressed intracellular glutathione (GSH). Herein, an intelligent nanoplatform (NSeMON-P@CuT/LipD) is rationally developed as a copper metabolic disrupter, GSH consumer, and Fenton-like reaction trigger for cancer cuproptosis/ferroptosis/apoptosis therapy. NSeMON-P@CuT/LipD is constructed from the preparation of diselenide-bridged mesoporous organosilica nanoparticles, and then pemetrexed (Pem) is loaded followed by surface deposition with a Cu2+-3,3′-dithiobis(propionohydrazide) (TPH) coordinated network and coating with a diclofenac (DC)-encapsulated liposome. In response to the specific tumor microenvironment, the obtained NSeMON-P@CuT/LipD can release DC, Cu2+, and Pem and simultaneously amplify cellular oxidative stress by consuming GSH and catalyzing endogenous H2O2 into hydroxyl radicals (•OH). Both liberated DC and augmented oxidative stress can inhibit glycolysis, reduce ATP level, and then block copper transporter ATP7B, resulting in metabolic disorders and the high retention of copper in cells for •OH generation. Moreover, the overloaded copper can promote dihydrolipoamide S-acetyltransferase oligomerization and Fe–S cluster protein loss, thus evoking cuproptosis. Collectively, the augmented oxidative stress activates prominent ferroptosis, which cooperates with cuproptosis and Pem-mediated apoptosis to significantly inhibit the tumor growth of 4T1 tumor-bearing mice. This study demonstrates feasible strategies to enhance tumor cuproptosis using a single nanoplatform and may also inspire the design of advanced cuproptosis-related therapies.
研究领域:
纳米医学
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肿瘤学
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细胞生物学
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产品关联
DOI
PubMed
高影响因子
Foods
·
2025
·Vol. 14
·期 4
·679
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IF 5.1
Delai Yang,Shujuan Xuan,Wang Zhang,Huan Wu,Yuge Jiang,An Zhou
Wilson’s disease (WD) is an inherited disorder characterized by abnormal copper metabolism with complex pathological features. Currently, the mechanism of copper overload-induced hepatic injury is unclear. Green tea is a natural chelator, and its main ingredients, green tea polyphenol (GTP) and L-theanine (L-TA) are good at binding to heavy metals like iron and copper. There have been no reports on green tea extracts (GTE) for the treatment of Wilson’s disease. This study investigated the hepatoprotective effect of GTE on WD model mice. Initially, we examined the impact of green tea extract on copper metabolism, excretion, and hepatoprotective effects in WD model toxic milk mice. Then, Ultra performance liquid chromatography (UPLC-DAD) was established to analyze GTP and L-TA in green tea extract. Further screening of eight active components and copper complex active components in green tea extract was carried out by ion analyzer. Finally, we verified the pharmacodynamic effects of these active ingredients at the animal level. The results showed that GTE improves liver function and attenuates liver injury in TX mice by promoting tissue copper excretion and inhibiting oxidative stress, which provides a theoretical basis for green tea’s potential to improve the clinical symptoms of WD.
研究领域:
医学
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分子生物学
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药理学
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产品关联
DOI
PubMed
高影响因子
COLLOIDS AND SURFACES B-BIOINTERFACES
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2025
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IF 5.6
Yun Gao,Renlu Han,Zhen Guo,Zekai Zhuang,Jie Fu,Yafei Hou,Jiancheng Yu,Keqi Tang
Cuproptosis is a currently discovered programmed cell death modality driven by copper (Cu) ions, which shows potential application prospects in overcoming apoptotic resistance in cancer therapy due to its unique mechanism. Nevertheless, the efficiency of cuproptosis is restricted by strict Cu metabolism regulation. Herein, elesclomol (ES) and glucose oxidase (GOx) co-loaded CuFe 2 O 4 (CF) nanoplatform (termed as CFEG) was elaborately engineered to boost cuproptosis through multi-pathway copper metabolisms regulation. After triggered by tumor-overexpressed glutathione (GSH), the released ES continuously chelated and targeted transport Cu ions through a shuttle mechanism to mitochondria where cuproptosis was initiated, which dramatically improved the influx efficiency of Cu. Additionally, GOx-mediated glucose oxidation reaction together with Cu and Fe ions stimulated Fenton reaction simultaneously amplified intracellular oxidative pressure by hydrogen peroxide (H 2 O 2 ) self-supply and subsequent hydroxyl radical (•OH) generation, which down-regulated Cu exporter ATP7A expression and inhibited Cu ions efflux, thereby exacerbating cuproptosis. Furthermore, the consumption of GSH simultaneously reduced the chelation of GSH with Cu and promote the •OH generation, further potentiating the occurrence of cuproptosis. Collectively, such the multi-pathway copper metabolisms regulation including improved Cu influx, inhibited Cu efflux and GSH depletion significantly boosted cuproptosis, which synergized with photothermal effect of CF to efficiently repressed the growth of tumor in mice without causing systemic toxicity. This work provides a multivariate mode for enhanced tumor cuproptosis therapy, and may also inspire the design of advanced cuproptosis-related nanomedicine system.
研究领域:
生物医学工程
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癌症治疗
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纳米医学
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产品关联
DOI
PubMed
高影响因子
MOLECULAR PHARMACEUTICS
·
2023
·
IF 4.9
Zhaomin Tang,Shuting Jiang,Wanlan Tang,Qian He,Huangzhao Wei,Chengyu Jin,Shuai Wang,Hui Zhang
Chemodynamic therapy (CDT) that involves the use of Fenton catalysts to convert endogenous hydrogen peroxide (H2O2) to hydroxyl radicals (·OH) constitutes a promising strategy for cancer therapy; however, insufficient endogenous H2O2 and glutathione (GSH) overexpression render its efficiency unsatisfactory. Herein, we present an intelligent nanocatalyst that comprises copper peroxide nanodots and DOX-loaded mesoporous silica nanoparticles (MSNs) (DOX@MSN@CuO2) and can self-supply exogenous H2O2 and respond to specific tumor microenvironments (TME). Following endocytosis into tumor cells, DOX@MSN@CuO2 initially decomposes into Cu2+ and exogenous H2O2 in the weakly acidic TME. Subsequently, Cu2+ reacts with high GSH concentrations, thereby inducing GSH depletion and reducing Cu2+ to Cu+ Next, the generated Cu+ undergoes Fenton-like reactions with exogenous H2O2 to accelerate toxic ·OH production, which exhibits a rapid reaction rate and is responsible for tumor cell apoptosis, thereby enhancing CDT. Furthermore, the successful delivery of DOX from the MSNs achieves chemotherapy and CDT integration. Thus, this excellent strategy can resolve the problem of insufficient CDT efficacy due to limited H2O2 and GSH overexpression. Integrating H2O2 self-supply and GSH deletion enhances CDT, and DOX-induced chemotherapy endows DOX@MSN@CuO2 with effective tumor growth-inhibiting properties alongside minimal side effects in vivo.
研究领域:
肿瘤学
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生物医学工程
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药理学
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产品关联
DOI
PubMed
高影响因子
Animal Nutrition
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2021
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IF 6.383
Yang Wen,Runxian Li,Xiangshu Piao,Gang Lin,Pingli He
Copper (Cu) is an essential trace element in the production of swine. This study was conducted to investigate the effect of 3 different sources of Cu on growth performance, Cu metabolism, and intestinal microorganisms of finishing pigs, so as to estimate the bioavailability of the 3 sources for pigs. A total of 42 male finishing pigs (88.74 ± 5.74 kg) were randomly allocated to 7 treatments. The factors were 3 sources (CuSO 4 , Cu-glycine, Cu-proteinate) and 2 levels (5 and 20 mg/kg) of Cu, plus one negative control treatment (0 mg/kg added Cu level) for the entire 28-d experiment. The average daily gain (ADG) and feed to gain ratio (F:G) both increased when Cu was added. The Cu level in liver, bile, kidney, serum, lung, urine and feces rose ( P < 0.001) with increasing dietary Cu level regardless of the source. Meanwhile, pigs receiving organic Cu (glycinate or proteinate) retained more Cu and excreted less Cu than those receiving inorganic Cu (CuSO 4 ), which showed that organic forms were more bioavailable. At the transcriptional level, changes in the level and source of dietary Cu resulted in modulation of transporters. In the jejunal mucosa, import transporter high affinity copper uptake protein 1 ( CTR1 ) and export transporter ATPase copper transporting alpha ( ATP7A ) in supplemental Cu treatments were down-regulated compared to the control. Also, peptide transporter 1 ( PepT1 ) and lanine-serine-cysteine transporter, type-2 ( ASCT2 ) were significantly ( P < 0.01) up-regulated in 20 mg/kg Cu-proteinate and Cu-glycinate treatments, respectively. Microbial diversity was lowest in the 20 mg/kg CuSO 4 treatment, and the ratio of Firmicutes to Bacteroidetes was higher in added Cu treatments, especially Cu-glycinate treatment. These results indicate that uptake of different Cu forms is facilitated by different transporters and transport mechanisms, and compared with inorganic Cu, organic Cu provides benefits to intestinal microflora and reduces Cu excretion.
研究领域:
动物营养学
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微生物学
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兽医学
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产品关联
DOI
PubMed
高影响因子
PHYTOMEDICINE
·
2022
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IF 6.656
Xun Sun,Xinyu Zhang,Hui Yan,Hongfei Wu,Shijian Cao,Wenchen Zhao,Ting Dong,An Zhou
Background Hepatolenticular degeneration (HLD) is an autosomal recessive disorder concerning copper metabolism . Copper overload is also accompanied by iron overload in HLD patients , which can lead to ferroptosis . Curcumin , the active component in turmeric, has the potential to inhibit ferroptosis. Purpose The current study proposed a systematic investigation of the protective effects of curcumin against HLD and the underlying mechanisms. Methods The protective effect of curcumin on toxic milk (TX) mice was studied. Liver tissue was observed via hematoxylin-eosin (H&E) staining and the ultrastructure of the liver tissue was observed through transmission electron microscopy . Copper levels in the tissues, serum, and metabolites were measured by atomic absorption spectrometry (AAS). In addition, serum and liver indicators were evaluated. In cellular experiments, the effect of curcumin on the viability of rat normal liver cells (BRL-3A) was determined via the 3-[4,5-dimethylthiazol-2-yl)]-2,5-diphenyltetrazolium bromide (MTT) assay. Cell and mitochondrial morphology were observed in curcumin-mediated HLD model cells. The intracellular copper ion fluorescence intensity was observed via fluorescence microscopy , and intracellular copper iron content was detected using AAS. Further, oxidative stress indicators were evaluated. Cellular reactive oxygen species (ROS) and cellular mitochondrial membrane potential were examined via flow cytometry. Furthermore, the expression levels of nuclear factor erythroid-2-related factor 2 (Nrf2), heme oxygenase-1 (HO-1), and glutathione peroxidase 4 (GPX4) were determined via western blotting (WB). Results The histopathology of the liver confirmed the hepatoprotective effects of curcumin. Curcumin improved copper metabolism in TX mice. Both serum liver enzyme markers and antioxidant enzyme levels indicated the protective effect of curcumin against HLD-related liver injury. The MTT assay results showed that curcumin was protective against excess copper-induced injury. Curcumin improved the morphology of HLD model cells and their mitochondrial morphology. The Cu 2+ fluorescent probe and the AAS results indicated that curcumin reduced Cu 2+ content in HLD hepatocytes. In addition, curcumin improved oxidative stress levels and prevented the decline of mitochondrial membrane potential in HLD model cells. The ferroptosis inducer Erastin reversed these effects of curcumin. WB revealed that curcumin promoted Nrf2, HO-1, and GPX4 protein expression in HLD model cells, and the Nrf2 inhibitor ML385 reversed the effects of curcumin. Conclusion Curcumin demonstrates a protective role by expelling copper and inhibiting ferroptosis, activating the Nrf2/HO-1/GPX4 signaling pathway in HLD.
研究领域:
药理学
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毒理学
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分子生物学
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细胞生物学
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神经病学
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产品关联
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
INTERNATIONAL JOURNAL OF PHARMACEUTICS
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2023
·
IF 5.8
Jingzhe Zhang,Maosen Han,Jing Zhang,Mohnad Abdalla,Peng Sun,Zhenmei Yang,Cai Zhang,Ying Liu,Chen Chen,Xinyi Jiang
Small cell lung cancer (SCLC) is one of the most devastating type of human lung cancer and has a high propensity to metastasize into the brain. Cuproptosis recently has been defined as a copper dependent cell death, offers a new lens to develop the novel copper-based nanostructure inducing cuproptosis for suppressing tumor growth and metastasis. Here, we report a syphilis mimetic TP0751-peptide decorated stem cell membrane-coated copper-based metal organic framework (Cu-MOF) nanodelivery system for SCLC brain metastasis. The Cu-MOF is employed as nanocarrier to support siRNA with high loading efficiency, and its pH sensitivity facilitates endosomal disruption upon cellular uptake. Furthermore, the cell membrane coating Cu-MOF presents a good biocompatibility, high BBB transcytosis, and specific uptake by tumor cells within the brain. In vitro and in vivo trials have shown that TP-M−Cu−MOF/siATP7a exhibited high silencing efficiency against target gene, specifically blocked copper trafficking, increased copper intake, triggered cuproptosis, and improved therapeutic efficacy in SCLC brain metastasis tumor-bearing mice. Overall, the biomimetic nanodelivery platform presented here further offers a promising way of orchestrating gene therapy to target copper-dependent signalling for reprogramming copper metabolism and cuproptosis-based synergistic therapy in mice bearing brain metastases.
研究领域:
肿瘤学
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纳米技术
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药理学
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分子生物学
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产品关联
DOI
PubMed
高影响因子
Advanced Science
·
2025
·
IF 14.1
Tingting Wang,Wengui Lu,Zhifei Cheng,Luyao Wang,Zhenzhen Jiang,Yike Yue,Pengyu Jiang,Zehua Xia,Lei He,Fengying Wang,Limin Wu,Qi Wang,Hui Han
Wilson's disease (WD), as a typical disease of excessive Cu 2+ deposition, is characterized by disorders of copper metabolism in the brain and thereby damaging the reproductive system. Conventional interventions using copper chelators can temporarily reduce intracellular copper (in-copper), but continuous re-entry of extracellular copper (ex-copper) into cells results in suboptimal therapy. Effective therapy requires multipronged copper metabolism management. Here, an orally administered, engineered Ganoderma-derived extracellular vesicle (CZGE) is developed for synergistic in/ex-copper regulation. Specifically, CZGE is designed by co-fusing Ganoderma-derived extracellular vesicle (GEVs) and targeted nanomicelles containing zinc-curcumin (Zn-Cur) complex (ZCNs). CZGE, with β -glucan-enriched GEVs and kisspeptin-10-modified ZCNs, can effectively penetrate intestinal and brain barriers after oral administration to target hypothalamic neurons.After internalization, Zn-Cur released from CZGE replaces excess Cu 2+ to form copper-curcumin (Cu-Cur) and release Zn 2+ via ion exchange. Cu-Cur reduces in-copper and neuroinflammation via the Nrf2/NLRP3 pathway, while Zn 2+ inhibits ex-copper influx by activating zinc transporter 1. In WD mice, CZGE alleviates hypothalamic copper deposition, activates ERK1/2 phosphorylation, and repairs reproductive dysfunction by modulating the hypothalamic-pituitary-testicular axis. It first reveals a targeted nanomedicine based on ion exchange that multipronged management in-copper and ex-copper, offering a promising therapeutic strategy for addressing WD with reproductive dysfunction.
研究领域:
纳米技术
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生物医学工程
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神经科学
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生殖医学
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代谢疾病
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药学
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生物无机化学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Biomaterials Science
·
2023
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IF 6.6
Muse Ji,Hongbing Liu,Hanxun Wang,Xinxin Liang,Mingli Wei,Dongmei Shi,Jingxin Gou,Tian Yin,Haibing He,Xing Tang,Yu Zhang
Chemodynamic therapy (CDT) is an emerging oncological treatment that can kill tumor cells by generating lethal hydroxyl radical (•OH) via Fenton or Fenton-like reaction inside tumors. However, the overexpression of glutathione (GSH) and low reaction efficiency in the tumor microenvironment (TME) limited the therapeutic efficacy of CDTs. Herein, CDT agents (Cu2+) and chemotherapeutic agent (Axitinib, AXB) were employed to fabricate a novel pH-activatable metal ion-drug coordinated nanoparticles (Cu-AXB NPs) for enhancing the treatment of tumors. The obtained nanoparticles exhibited ultrahigh drug loading capacity of 87.55% and had an average size of 180 nm. Moreover, the characteristics of excellent plasma stability and pH-responsive drug release contribute to the long circulation in the blood and targeted therapy at the weakly acidic tumor site. The released AXB could play a chemotherapeutic role in killing tumor cells and Cu2+ ion could be reduced to Cu+ by GSH, further generating toxic •OH with hydrogen peroxide (H2O2) for CDT through Fenton-like reaction. Cu-AXB NPs could also efficiently break copper metabolic balances and increase the intracellular Cu content, thus amplifying CDT. In vitro research results of cytotoxicity and apoptosis confirmed the optimal tumor cell killing efficacy of the Cu-AXB NPs, which was attributed to the synergistic effect of CDT with chemotherapy. What is more, Cu-AXB NPs exhibited good tumor targeting and potent tumor inhibition effect (77.53% inhibition), while exhibiting good biocompatibility in tumor bearing mice. In conclusion, this work provided a promising strategy for safe and efficient cancer therapy through the combination of CDT with chemotherapy.
研究领域:
癌症治疗
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纳米技术
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药学
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生物医学工程
✓ 已验证
产品关联
DOI
PubMed
高影响因子
危险品化学品经营许可证（带存储）