An Enzyme‐Engineered Nonporous Copper(I) Coordination Polymer Nanoplatform for Cuproptosis‐Based Synergistic Cancer Therapy

Advanced Materials, Journal Year: 2022, Volume and Issue: 34(43)

Published: Sept. 2, 2022

Abstract Cuproptosis, a newly identified form of regulated cell death that is copper‐dependent, offers great opportunities for exploring the use copper‐based nanomaterials inducing cuproptosis cancer treatment. Here, glucose oxidase (GOx)‐engineered nonporous copper(I) 1,2,4‐triazolate ([Cu(tz)]) coordination polymer (CP) nanoplatform, denoted as GOx@[Cu(tz)], starvation‐augmented and photodynamic synergistic therapy developed. Importantly, catalytic activity GOx shielded in scaffold but can be “turned on” efficient depletion only upon glutathione (GSH) stimulation cells, thereby proceeding starvation therapy. The GSH sensitizes cells to GOx@[Cu(tz)]‐mediated cuproptosis, producing aggregation lipoylated mitochondrial proteins, target copper‐induced toxicity. increased intracellular hydrogen peroxide (H 2 O ) levels, due oxidation glucose, activates type I (PDT) efficacy GOx@[Cu(tz)]. vivo experimental results indicate GOx@[Cu(tz)] produces negligible systemic toxicity inhibits tumor growth by 92.4% athymic mice bearing 5637 bladder tumors. This thought first report cupreous nanomaterial capable cuproptosis‐based cancer, which should invigorate studies pursuing rational design efficacious strategies based on cuproptosis.

Language: Английский

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A Novel Cuproptosis-Related Prognostic Gene Signature and Validation of Differential Expression in Clear Cell Renal Cell Carcinoma

Genes, Journal Year: 2022, Volume and Issue: 13(5), P. 851 - 851

Published: May 10, 2022

Clear cell renal carcinoma (ccRCC) is the most prevalent subtype of carcinoma, which characterized by metabolic reprogramming. Cuproptosis, a novel form death, highly linked to mitochondrial metabolism and mediated protein lipoylation. However, clinical impacts cuproptosis-related genes (CRGs) in ccRCC largely remain unclear. In current study, we systematically evaluated genetic alterations ccRCC. Our results revealed that CDKN2A, DLAT, DLD, FDX1, GLS, PDHA1 PDHB exhibited differential expression between normal tissues (|log2(fold change)| > 2/3 p < 0.05). Utilizing an iterative sure independence screening (SIS) method, separately constructed prognostic signature CRGs for predicting overall survival (OS) progression-free (PFS) patients. The score yielded area under curve (AUC) 0.658 0.682 prediction 5-year OS PFS, respectively. Kaplan−Meier analysis OS, higher risk gene was significantly correlated with worse (HR = 2.72 (2.01−3.68), log-rank 1.76 × 10−7). Patients had shorter PFS 2.83 (2.08−3.85), 3.66 Two independent validation datasets (GSE40435 (N 101), GSE53757 72)) were collected meta-analysis, suggesting CDKN2A (log2(fold change) 1.46, 95%CI: 1.75−2.35) showed while DLAT −0.54, −0.93−−0.15) FDX1 −1.01, −1.61−−0.42) lowly expressed. also associated immune infiltration levels programmed death 1 (PD-1) (CDKN2A: r 0.24, 2.14 10−8; FDX1: −0.17, 1.37 10−4). conclusion, could serve as potential predictor patients may offer insights into cancer treatment.

Language: Английский

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Toxicity of Heavy Metals and Recent Advances in Their Removal: A Review

Toxics, Journal Year: 2023, Volume and Issue: 11(7), P. 580 - 580

Published: July 3, 2023

Natural and anthropogenic sources of metals in the ecosystem are perpetually increasing; consequently, heavy metal (HM) accumulation has become a major environmental concern. Human exposure to HMs increased dramatically due industrial activities 20th century. Mercury, arsenic lead, chrome, cadmium have been most prevalent that caused human toxicity. Poisonings can be acute or chronic following via water, air, food. The bioaccumulation these results variety toxic effects on various tissues organs. Comparing mechanisms action reveals induce toxicity similar pathways, including production reactive oxygen species, inactivation enzymes, oxidative stress. conventional techniques employed for elimination deemed inadequate when HM concentration is less than 100 mg/L. In addition, methods exhibit certain limitations, secondary pollutants, high demand energy chemicals, reduced cost-effectiveness. As result, employment microbial bioremediation purpose detoxification emerged as viable solution, given microorganisms, fungi bacteria, superior biosorption bio-accumulation capabilities. This review deals with uptake associated HMs, will increase our knowledge their body organs, leading better management poisoning. aims enhance comprehension offer judicious selection remediation technology HMs. Microbial-based solutions sustainable could potentially crucial cost-effective reducing

Language: Английский

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Cuproptosis Induced by ROS Responsive Nanoparticles with Elesclomol and Copper Combined with αPD‐L1 for Enhanced Cancer Immunotherapy

Advanced Materials, Journal Year: 2023, Volume and Issue: 35(22)

Published: March 14, 2023

Cuproptosis is a new cell death that depends on copper (Cu) ionophores to transport Cu into cancer cells, which induces death. However, existing are small molecules with short blood half-life making it hard enough cells. Herein, reactive oxygen species (ROS)-sensitive polymer (PHPM) designed, used co-encapsulate elesclomol (ES) and form nanoparticles (NP@ESCu). After entering ES Cu, triggered by excessive intracellular ROS, readily released. work in concerted way not only kill cells cuproptosis, but also induce immune responses. In vitro, the ability of NP@ESCu efficiently cuproptosis investigated. addition, change transcriptomes treated explored RNA-Seq. vivo, found mice model subcutaneous bladder cancer, reprograming tumor microenvironment. Additionally, further combined anti-programmed protein ligand-1 antibody (αPD-L1). This study provides first report combining nanomedicine can αPD-L1 for enhanced therapy, thereby providing novel strategy future therapy.

Language: Английский

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Comprehensive Analysis of Cuproptosis-Related Genes in Immune Infiltration and Prognosis in Melanoma

Frontiers in Pharmacology, Journal Year: 2022, Volume and Issue: 13

Published: June 28, 2022

Skin cutaneous melanoma (SKCM, hereafter referred to as melanoma) is the most lethal skin cancer with increasing incidence. Regulated cell death plays an important role in tumorigenesis and serves target for almost all treatment strategies. Cuproptosis recently identified copper-dependent regulated form that relies on mitochondria respiration. However, its remains unknown. The correlation of cuproptosis-related genes tumor prognosis far be understood, either. In present study, we explored between by accessing analyzing a public database found 11 out 12 were upregulated tissues three (LIPT1, PDHA1, SLC31A1) have predictive value prognosis. subgroup patients higher gene expression showed longer overall survival than those lower expression. We chose LIPT1 further exploration. was increased biopsies independent favorable prognostic indicator patients. Moreover, positively correlated PD-L1 negatively associated Treg infiltration. after receiving immunotherapy, indicating LIPT1. Finally, pan-cancer analysis indicated differentially expressed diverse cancers compared normal multiple immune checkpoints, especially PD-L1. It could serve some types. conclusion, our study demonstrated genes, LIPT1, melanoma, revealed infiltration thus providing new clues assessment immunotherapy melanoma.

Language: Английский

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A novel Cuproptosis-related LncRNA signature to predict prognosis in hepatocellular carcinoma

Scientific Reports, Journal Year: 2022, Volume and Issue: 12(1)

Published: July 5, 2022

Abstract Increased intracellular toxicity due to an imbalance in copper homeostasis caused by ion accumulation could regulate the rate of cancer cell growth and proliferation. The goal this study was create a novel Cuproptosis-related lncRNA signature that may be utilized predict survival immunotherapy HCC patients. Cuproptosis-associated lncRNAs differentially expressed between tumor tissue normal were discovered first. By LASSO-Cox analysis, overlapping then build signature, which might used patient prognosis responsiveness immune checkpoint blockade (ICB) therapy. Differences infiltration subpopulations high low-risk score subgroups also analyzed. Moreover, nomogram based on clinical features developed demonstrated have good predictive potential. Finally, qRT-PCR performed HerpG2 MHCC-97H lines explore whether these indeed involved process Cuproptosis. In summary, we created prognostic profile linked Cuproptosis forecast response immunotherapy, provide new potential non-apoptotic therapeutic perspective for

Language: Английский

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A Hollow Amorphous Bimetal Organic Framework for Synergistic Cuproptosis/Ferroptosis/Apoptosis Anticancer Therapy via Disrupting Intracellular Redox Homeostasis and Copper/Iron Metabolisms

Advanced Functional Materials, Journal Year: 2022, Volume and Issue: 32(40)

Published: July 30, 2022

Abstract Cuproptosis is a very newly recognized regulated cell death modality that distinct from known mechanisms and shows enormous prospect in cancer treatment. However, its efficacy copper‐dependent restricted by strictly copper metabolism. Herein, novel copper/iron hybrid hollow amorphous metal organic framework (HaMOF) developed as an oxidative stress amplifier metabolic disrupter for synergistic cuproptosis/ferroptosis/apoptosis anticancer therapy. The HaMOF fabricated Cu 2+ , 3,3′‐dithiobis(propionohydrazide) Fe 3+ via unsaturated coordination‐etching integration strategy, then doxorubicin loaded followed surface decoration with hyaluronan. obtained DOX@Fe/CuTH exhibits tumor microenvironment‐triggered catalytic therapeutic property, wherein it can amplify cellular simultaneously boosting H 2 O production depleting glutathione. Moreover, cause mitochondrial dysfunction downregulate the expressions of transporter ATP7A iron FPN 1, thereby leading to disorders high retentions cytoplasm •OH generation. overloaded lipoylated protein dihydrolipoamide S‐acetyltransferase aggregation lead cuproptosis. Collectively, both augmented induce potent ferroptosis, which synergizes cuproptosis DOX‐mediated apoptosis efficiently suppress growth. This bimetallic nanoplatform provides new paradigm boost cuproptosis‐related therapies.

Language: Английский

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Lactylation of METTL16 promotes cuproptosis via m6A-modification on FDX1 mRNA in gastric cancer

Nature Communications, Journal Year: 2023, Volume and Issue: 14(1)

Published: Oct. 20, 2023

Abstract Cuproptosis, caused by excessively high copper concentrations, is urgently exploited as a potential cancer therapeutic. However, the mechanisms underlying initiation, propagation, and ultimate execution of cuproptosis in tumors remain unknown. Here, we show that content significantly elevated gastric (GC), especially malignant tumors. Screening reveals METTL16, an atypical methyltransferase, critical mediator through m 6 A modification on FDX1 mRNA. Furthermore, stress promotes METTL16 lactylation at site K229 followed cuproptosis. The process inhibited SIRT2. Elevated improves therapeutic efficacy ionophore– elesclomol. Combining elesclomol with AGK2, SIRT2-specific inhibitor, induce vitro vivo. These results reveal significance non-histone protein Given lactate concentrations GC, induction becomes promising strategy for GC.

Language: Английский

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Photothermally Triggered Copper Payload Release for Cuproptosis‐Promoted Cancer Synergistic Therapy

Angewandte Chemie International Edition, Journal Year: 2022, Volume and Issue: 62(12)

Published: Dec. 31, 2022

Abstract Cuproptosis is a new form of programmed cell death and exhibits enormous potential in cancer treatment. However, reducing the undesirable Cu ion release normal tissue maximizing copper‐induced therapeutic effect sites are two main challenges. In this study, we constructed photothermally triggered nanoplatform (Au@MSN‐Cu/PEG/DSF) to realize on‐demand delivery for synergistic therapy. The released disulfiram (DSF) chelated with 2+ situ generate highly cytotoxic bis(diethyldithiocarbamate)copper (CuET), causing apoptosis, formed + species promoted toxic mitochondrial protein aggregation, leading cuproptosis. Synergistic photothermal therapy, Au@MSN‐Cu/PEG/DSF could effectively kill tumor cells inhibit growth (inhibition rate up 80.1 %). These results provide promising perspective treatment based on cuproptosis, may also inspire design advanced nano‐therapeutic platforms.

Language: Английский

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The Role of Copper Homeostasis in Brain Disease

International Journal of Molecular Sciences, Journal Year: 2022, Volume and Issue: 23(22), P. 13850 - 13850

Published: Nov. 10, 2022

In the human body, copper is an important trace element and a cofactor for several enzymes involved in energy production, iron metabolism, neuropeptide activation, connective tissue synthesis, neurotransmitter synthesis. Copper also necessary cellular processes, such as regulation of intracellular signal transduction, catecholamine balance, myelination neurons, efficient synaptic transmission central nervous system. naturally present some foods available dietary supplement. Only small amounts are typically stored body large amount excreted through bile urine. Given critical role breadth local concentrations distribution transporter proteins brain to maintain steady state internal environment. The dysfunction metabolism or regulatory pathways results imbalance homeostasis brain, which can lead myriad acute chronic pathological effects on neurological function. It suggests unique mechanism linking neuronal activation within This article explores relationship between impaired neuropathophysiological progress diseases.

Language: Английский

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