ACS Nano
·
2023
·
IF 17.1
Wanrui Shi,Wenjie Feng,Siyuan Li,Yanqi Cui,Shuwei Liu,Huan Jiang,Yi Liu,Hao Zhang
Nanovaccine-based immunotherapy has been considered as a major pillar to stimulate the host immune system to recognize and eradicate tumor cells as well as establish a long-term immune memory to prevent tumor relapse and metastasis. However, the weak specificity and low cross-presentation of antigens, as well as the immunosuppressive microenvironments of tumor tissues, are still the major obstacles on exerting the therapeutic performance of tumor nanovaccines sufficiently. Herein, we design and construct cytosine guanine dinucleotide (CpG) oligodeoxynucleotide (ODN)-loaded aluminum hydroxyphosphate nanoparticles covered by Fe-Shikonin metal-phenolic networks (MPNs) (Alum-CpG@Fe-Shikonin NPs) as personalized in situ nanovaccines for antitumor immunity. Upon internalization by tumor cells, the shell of Fe-Shikonin MPNs will disassemble into Fe2+ and Shikonin to elicit the immunogenic cell death of tumor cells through ferroptosis and necroptosis. Then, dying tumor cell-released autologous tumor cell lysates will be absorbed by Alum NPs and codelivered with CpG ODN to professional antigen-presenting cells temporally and spatially to activate multistep cascade antitumor immune responses, including dendritic cell maturation, antigen cross-presentation, natural killer cell and cytotoxic T lymphocyte infiltrations, and tumor-associated macrophage repolarization. Benefiting from the synergistic effects of Alum NPs, CpG ODN, and Fe-Shikonin MPNs, our Alum-CpG@Fe-Shikonin NPs exhibit drastic cytotoxicity and accurate selectivity on eradicating primary tumor, strong abscopal effect on inhibiting distant tumor, and a long-term immune memory effect on preventing tumor metastasis and recurrence. Because our report provides a feasible strategy to in situ make full use of autologous tumor cell lysates, which present an entire spectrum of the patient’s personal epitopes without complicated ex vivo processes, such as extraction, purification, and sequencing, it may promote the development of personalized nanovaccines for antitumor immunity.
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Acta Biomaterialia
·
2023
·
IF 9.7
Jiawu Yu,Yuchen Zhang,Liqi Li,Yang Xiang,Xuemei Yao,Youbo Zhao,Kaiyong Cai,Menghuan Li,Zhongjun Li,Zhong Luo
Radiotherapy is a mainstream modality for breast cancer treatment that employs ionizing radiation (IR) to damage tumor cell DNA and elevate ROS stress, which demonstrates multiple clinically-favorable advantages including localized treatment and low invasiveness. However, breast cancer cells may activate the p53-mediated cell cycle regulation in response to radiotherapy to repair IR-induced cellular damage and facilitate post-treatment survival. F-Box and WD Repeat Domain Containing 7 (FBXW7) is a promoter of p53 degradation and critical nexus of cell proliferation and survival events. Herein, we engineered a cooperative radio-ferroptosis-stimulatory nanomedicine through coordination-driven self-assembly between ferroptosis-inducing Fe 2+ ions and FBXW7-inhibiting DNAzymes and further modification of tumor-targeting dopamine-modified hyaluronic acid (HA). The nanoassembly could be selectively internalized by breast cancer cells and disintegrated in lysosomes to release the therapeutic payload. DNAzyme readily abolishes FBXW7 expression and stabilizes phosphorylated p53 to cause irreversible G2 phase arrest for amplifying post-IR tumor cell apoptosis. Meanwhile, the p53 stabilization also inhibits the SLC7A11-cystine-GSH axis, which combines with the IR-upregulated ROS levels to amplify Fe 2+ -mediated ferroptotic damage. The DNAzyme-Fe-HA nanoassembly could thus systematically boost the tumor cell damaging effects of IR, presenting a simple and effective approach to augment the response of breast cancer to radiotherapy. Statement of Significance To overcome the intrinsic radioresistance in breast cancer, we prepared co-assembly of Fe 2+ and FBXW7-targeted DNAzymes and modified surface with dopamine conjugated hyaluronic acid (HA), which enabled tumor-specific FBXW7-targeted gene therapy and ferroptosis therapy in IR-treated breast cancers. The nanoassembly could be activated in acidic condition to release the therapeutic contents. Specifically, the DNAzymes could selectively degrade FBXW7 mRNA in breast cancer cells to simultaneously induce accumulation of p53 and retardation of NHEJ repair , eventually inducing irreversible cell cycle arrest to promote apoptosis. The p53 stabilization would also inhibit the SLC7A11/GSH/GPX4 axis to enhance Fe 2+ mediated ferroptosis. These merits could act in a cooperative manner to induce pronounced tumor inhibitory effect, offering new approaches for tumor radiosensitization in the clinics.
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FEBS Journal
·
2021
·Vol. 289
·期 7
·1968-1983
·
IF 5.542
Ting-Ting Wei,Meng-Yuan Zhang,Xin-Hua Zheng,Tian-Hua Xie,Wenjuan Wang,Jian Zou,Yan Li,Hong-Ying Li,Jiping Cai,Xiaolu Wang,Jianxin Tan,Xusheng Yang,Yong Yao,Lingpeng Zhu
Retinal pigment epithelium (RPE) cell damage is implicated in the pathogenesis of age-related macular degeneration (AMD). An increase of interferon-γ (IFN-γ) levels was observed in patients with AMD, but whether inflammatory factors are causally related to AMD progression is unclear. Here, we demonstrate a direct causal relationship between IFN-γ and RPE cell death. IFN-γ induced human retinal pigment epithelial cell (ARPE-19) death accompanied by increases in Fe 2+ , reactive oxygen species, lipid peroxidation, and glutathione (GSH) depletion, which are main characteristics of ferroptosis. Mechanistically, IFN-γ upregulates the level of intracellular Fe 2+ through inhibiting Fe 2+ efflux protein SLC40A1 and induces GSH depletion by blocking cystine/glutamate antiporter, System xc-. At the same time, treatment with IFN-γ decreases the level of glutathione peroxidase 4 (GPx4), rendering the cells more sensitive to ferroptosis. JAK1/2 and STAT1 inhibitors could reverse the reduction of SLC7A11, GPx4 and GSH expression induced by IFN-γ, indicating IFN-γ induces ARPE-19 cell ferroptosis via activation of the JAK1-2/STAT1/SLC7A11 signaling pathway. The above results were largely confirmed in IFN-γ-treated mice in vivo . Finally, we used sodium iodate (NaIO 3 )-induced retinal degeneration to further explore the role of ferroptosis in AMD in vivo . Consistent with the role of IFN-γ, treatment with NaIO 3 decreased SLC7A11, GPx4 and SLC40A1 expressions. NaIO 3 -induced RPE damage was accompanied by increased iron, lipid peroxidation products (4-hydroxynonenal, malondialdehyde), and GSH depletion, and ferroptosis inhibitors could reverse the above phenomenon. Taken together, our findings suggest that inhibiting ferroptosis or reducing IFN-γ may serve as a promising target for AMD.
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Frontiers in Bioengineering and Biotechnology
·
2025
·
IF 4.8
Jinxi Wen,Jian Wang,Siqi Wang,Xingping Zhou,You Fu
A one-step hydrothermal method was applied to prepare carbon dots (CDs) with superior fluorescence properties using chitosan as a carbon source. The as-prepared carbon dots were then grafted onto a sodium alginate-gelatin hydrogel film to form a fluorescent hydrogel film (FHGF), emitting at 450 nm under excitation of 350 nm light. In comparison to the CDs, the fluorescence intensity of this film was maintained over 90.0% and the luminescence position remained basically unchanged, caused by the unchanged surface light-emitting structure of the CDs, due to the existence of electrostatic repulsion between the CDs and the hydrogel. Moreover, the tensile-stress of the fluorescent film with 1.0 wt.% of the CDs was increased by 200% to 10.3 Mpa, and the strain was increased from 117% to 153%. The above experimental results are attributed to the hydrogen bonding between the CDs and the sodium alginate-gelatin hydrogel from analyses of the FT-IR spectra. Interestingly, Fe3+ exerted a great quenching effect on this fluorescent film in the concentration range of 0–1.8 μM. The film can be basically used recyclically to detect Fe3+ in solution with a detection limit as low as 0.043 μM. In a word, this work demonstrated an enormous potential of carbon dots in fabricating mechanical and fluorescent properties of the hydrogel and proposed a new detection platform for Fe3+. In view of the promising Fe3+ detection capacity, this hydrogel film can also be applied in oral bacteria surveillance and semi-quantification of ferroptosis in oral cancer.
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ECOTOXICOLOGY AND ENVIRONMENTAL SAFETY
·
2024
·
IF 6.2
Wenli Guo,Jinjin Zhang,Xiaoqian Zhang,Quanzhong Ren,Guangzhe Zheng,Jianxin Zhang,Guoxing Nie
Cadmium (Cd) pollution is considered a pressing challenge to eco-environment and public health worldwide. Although it has been well-documented that Cd exhibits various adverse effects on aquatic animals, it is still largely unknown whether and how Cd at environmentally relevant concentrations affects iron metabolism . Here, we studied the effects of environmental Cd exposure (5 and 50 μg/L) on iron homeostasis and possible mechanisms in common carp. The data revealed that Cd elevated serum iron, transferrin saturation and iron deposition in livers and spleens, leading to the disruption of systemic iron homeostasis. Mechanistic investigations substantiated that Cd drove hemolysis by compromising the osmotic fragility and inducing defective morphology of erythrocytes. Cd concurrently exacerbated hepatic inflammatory responses, resulting in the activation of IL6-Stat3 signaling and subsequent hepcidin transcription. Notably, Cd elicited ferroptosis through increased iron burden and oxidative stress in livers. Taken together, our findings provide evidence and mechanistic insight that environmental Cd exposure could undermine iron homeostasis via erythrotoxicity and hepatotoxicity. Further investigation and ecological risk assessment of Cd and other pollutants on metabolism-related effects is warranted, especially under the realistic exposure scenarios.
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Nano Today
·
2024
·
IF 13.2
Shiwen Duan,Jianmin Gao,Haoqin Ke,Chengquan Huang,Chaoyue Sun,Yujie Ren,Yixue Zhang,Xiumei Jiang,Yinliang Wang,Gang Liu
Mosquitoes are notorious for transmitting arbovirus diseases. Existing genetic-based control strategies only target one of mosquitoes’ flying, blood-sucking and reproduction behaviors and are technically demanding, limiting their real-world application. Therefore, there is an imperative need to identify novel molecular targets for developing multi-effect, easy-to-deploy mosquito control strategies. We herein identified and characterized the function of mosquito iron-sulfur-cluster assembly protein AalbNFS1. Silencing AalbNFS1 with double-strand RNAs (dsNFS1) caused evident metabolic and enzyme activity abnormalities in mosquito tissues and cells. Further analyses revealed that AalbNFS1 deficiency simultaneously reduced mosquitoes’ flying, blood-sucking and reproductive abilities by inducing muscle cell ferroptosis, confirming AalbNFS1 as a multi-effect molecular target for mosquito control purposes. To facilitate the real-world deployment of dsNFS1, a chitosan-tripolyphosphate-dsNFS1 (CS-TPP-dsNFS1) nanosystem was synthesized, generating satisfactory mosquito control effects. Collectively, our study pioneers the research on iron-sulfur-cluster biosynthesis mechanisms in mosquitoes and develops an effective mosquito control nanosystem with promising real-world applicability.
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EUROPEAN JOURNAL OF PHARMACOLOGY
·
2024
·
IF 4.2
Jingjing Lin,Lu Deng,Ailin Qi,Hong Jiang,Di Xu,Yuehui Zheng,Zixuan Zhang,Xiaoman Guo,Beilei Hu,Peijun Li
Hypoxic-ischemic encephalopathy (HIE) is a brain damage caused by perinatal hypoxia and blood flow reduction. Severe HIE leads to death. Available treatments remain limited. Oxidative stress and nerve damage are major factors in brain injury caused by HIE. Catalpol, an iridoid glucoside found in the root of Rehmannia glutinosa, has antioxidant and neuroprotective effects. This study examined the neuroprotective effects of catalpol using a neonatal rat HIE model and found that catalpol might protect the brain through inhibiting neuronal ferroptosis and ameliorating oxidative stress. Behavior tests suggested that catalpol treatment improved functions of motor, learning, and memory abilities after hypoxic-ischemic injury. Catalpol treatment inhibited changes to several ferroptosis-related proteins, including p-PI3K, p-AKT, NRF2, GPX4, SLC7A11, SLC3A2, GCLC, and GSS in HIE neonatal rats. Catalpol also prevented changes to several ferroptosis-related proteins in PC12 cells after oxygen-glucose deprivation. The ferroptosis inducer erastin reversed the protective effects of catalpol both in vitro and in vivo . We concluded that catalpol protects against hypoxic-ischemic brain damage (HIBD) by inhibiting ferroptosis through the PI3K/NRF2/system Xc-/GPX4 axis.
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PESTICIDE BIOCHEMISTRY AND PHYSIOLOGY
·
2024
·
IF 4.2
Bendong Shi,Qiaohan Liu,Chenchen Xu,Ziwei Zhang,Jingzeng Cai
Chlorantraniliprole (CAP) is a bis-amide pesticide used for pest control mainly in agricultural production activities and rice-fish co-culture systems. CAP residues cause liver damage in non-target organism freshwater fish. However, it is unclear whether CAP-exposure-induced liver injury in fish is associated with mitochondrial dysfunction-mediated mitophagy, ferroptosis, and cytokines. Therefore, we established grass carp hepatocyte models exposed to different concentrations of CAP (20, 40, and 80 μM) in vitro. MitoSOX probe, JC-1 staining, immunofluorescence double staining, Fe 2+ staining, lipid peroxidation staining, qRT-PCR, and Western blot were used to verify the physiological regulatory mechanism of CAP induced liver injury. In the present study, the CAP-treated groups exhibited down-regulation of antioxidant-related enzyme activities and accumulation of peroxides. CAP treatment induced an increase in mitochondrial reactive oxygen species (mtROS) levels and altered expression of mitochondrial fission/fusion (Drp1, Fis1, Mfn1, Mfn2, and Opa1) genes in grass carp hepatocytes. In addition, mitophagy (Parkin, Pink1, p62, LC3II/I, and Beclin-1), ferroptosis (GPX4, COX2, ACSL4, FTH, and NCOA4), and cytokine (IFN-γ, IL-18, IL-17, IL-6, IL-10, IL-1β, IL-2, and TNF-α)-related gene expression was significantly altered. Collectively, these findings suggest that CAP exposure drives mitophagy activation, ferroptosis occurrence, and cytokine homeostasis imbalance in grass carp hepatocytes by triggering mitochondrial dysfunction mediated by the mtROS-mitochondrial fission/fusion axis. This study partly explained the physiological regulation mechanism of grass carp hepatocyte injury induced by insecticide CAP from the physiological and biochemical point of view and provided a basis for evaluating the safety of CAP environmental residues to non-target organisms.
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International Journal of Pharmacology
·
2026
·Vol. 22
·期 6
·
IF 0.7
Yachun Guo,Jiahui Zhang,Yanchao Li
Background: Non-small cell lung cancer (NSCLC) remains a leading cause of cancer-related mortality worldwide, and novel therapeutic strategies are urgently needed to overcome treatment resistance. Cordycepin (Cor), a bioactive nucleoside isolated from Cordyceps militaris, exhibits antitumor activity in multiple malignancies. However, whether Cor induces ferroptosis in NSCLC cells and the underlying mechanisms remain unclear. Therefore, this study aimed to investigate the modulatory effects of Cor on ferroptosis in NSCLC cells and to elucidate the underlying molecular and network pharmacology mechanisms. Methods: Human NSCLC A549 cells were treated with Cor (25, 50, and 100 μM). Cell viability was assessed using Cell Counting Kit-8 assays. Ferroptosis involvement was evaluated using ferroptosis inhibitors (ferrostatin-1, deferoxamine, and liproxstatin-1) and other programmed cell death inhibitors. Intracellular reactive oxygen species (ROS), Fe2+ accumulation, lipid peroxidation, glutathione (GSH) levels, and ferroptosis-related proteins were measured using fluorescence probes, spectrophotometric assays, and western blotting. Network pharmacology, protein-protein interaction analysis, Gene Ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analyses, and molecular docking were performed to identify potential molecular targets. Nuclear factor erythroid 2-related factor 2 (Nrf2) and heme oxygenase-1 (HO-1) protein expression was further examined by western blotting. Results: Cor inhibited A549 cell viability in a time- and dose-dependent manner (n = 6). Among the tested death inhibitors, only ferroptosis inhibitors significantly reversed Cor-induced cytotoxicity (p < 0.05, n = 3). Cor treatment elevated intracellular ROS levels, Fe2+ accumulation, and lipid peroxidation while reducing GSH content (p < 0.05, n = 3). At the protein level, Cor downregulated glutathione peroxidase 4 (GPX4) and solute carrier family 7 member 11 (SLC7A11) expression but upregulated transferrin and acyl-CoA synthetase long-chain family member 4 (ACSL4) expression (p < 0.05, n = 3). Database screening identified 28 mutual targets linked to Cor, NSCLC, and ferroptosis. Molecular docking confirmed that Cor spontaneously binds to the Nrf2 and HO-1 proteins encoded by the key pathway genes nuclear factor erythroid 2 like 2 (NFE2L2) and heme oxygenase 1 (HMOX1), which correlated with a significant, dose-dependent downregulation of Nrf2 and HO-1 protein expression (p < 0.05, n = 3). Conclusions: Cordycepin induces ferroptosis in A549 NSCLC cells, characterized by oxidative stress, iron accumulation, lipid peroxidation, and suppression of antioxidant defenses. The Nrf2/HO-1 pathway may contribute to this process and represents a potential therapeutic target for NSCLC.
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ENVIRONMENTAL TOXICOLOGY
·
2024
·
IF 4.4
Lei Huang,Jiayi Wang,Jieqin Yu,Mengxuan Bian,Xingdong Xiang,Guanjie Han,Weisin Chen,Ning Wang,Jun Ge,Shunyi Lu,Jian Zhang
Osteoporosis (OP) can result in slower bone regeneration than the normal condition due to abnormal oxidative stress and high levels of reactive oxygen species (ROS), a condition detrimental for bone formation, making the OP-related bone healing a significant clinical challenge. As the osteogenic differentiation ability of bone marrow mesenchymal stem cells (BMSCs) is closely related to bone regeneration; currently, this study assessed the effects of Picein on BMSCs in vitro and bone regeneration in osteoporotic bone defect in vivo. Cell viability was determined by CCK-8 assay. The production of (ROS), malonaldehyde, superoxide dismutase activities, and glutathione was evaluated by using commercially available kits, and a flow cytometry analysis was adopted to detect macrophage polarization. Osteogenic capacity of BMSCs was evaluated by alkaline phosphatase (ALP) activity, ALP staining, and Alizarin red S staining. The expression of osteogenic-related proteins (OPN, Runx-2, OCN) and osteogenic-related genes (ALP, BMP-4, COL-1, and Osterix) were evaluated by Western blotting and real-time PCR (RT-PCR). In addition, proliferation, migration ability, and angiogenic capacity of human umbilical vein endothelial cells (HUVECs) were evaluated by EdU staining, scratch test, transwell assay, and tube formation assay, respectively. Angiogenic-related genes (VEGF, vWF, CD31) were also evaluated by RT-PCR. Results showed that Picein alleviated erastin-induced oxidative stress, enhanced osteogenic differentiation capacity of BMSCs, angiogenesis of HUVECs, and protects cells against ferroptosis through Nrf2/HO-1/GPX4 axis. Moreover, Picein regulate immune microenvironment by promoting the polarization of M2 macrophages in vitro. In addition, Picein also reduce the inflammation levels and promotes bone regeneration in osteoporotic bone defect in OP rat models in vivo. Altogether, these results suggested that Picein can promote bone regeneration and alleviate oxidative stress via Nrf2/HO-1/GPX4 pathway, offering Picein as a novel antioxidant agent for treating osteoporotic bone defect.
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MOLECULAR PHARMACEUTICS
·
2024
·
IF 4.5
Haonan Tang,Xiao Zhou,Lijuan Liu,Ziyu Wang,Chen Wang,Ningbin Luo,Guanqiao Jin
Erastin can induce ferroptosis in tumor cells as an effective small molecule inhibitor. However, its application is hampered by a lack of water solubility. This study investigated the effects of superparamagnetic iron oxide (SPIO)–erastin–polyethylene glycol (PEG) nanoparticles prepared by loading SPIO–PEG nanoparticles with erastin on ferroptosis. SPIO–erastin–PEG nanoparticles exhibited square and spherical shapes with good dispersibility. The zeta potential and hydrodynamic size of SPIO–erastin–PEG were measured as (−37.68 ± 2.706) mV and (45.75 ± 18.88) nm, respectively. On T2-weighted imaging, the nanosystem showed significant contrast enhancement compared to no-enhancement magnetic resonance imaging (MRI). SPIO–erastin–PEG induced ferroptosis by increasing reactive oxygen species and iron content and promoting the accumulation of lipid peroxides and the degradation of glutathione peroxidase 4. Pharmacokinetic experiments revealed a half-life of 1.25 ± 0.05 h for the SPIO–erastin–PEG solution in circulation. Moreover, significant antitumorigenic effects of SPIO–erastin–PEG have been demonstrated in 5–8F cells and mouse-bearing tumors. These results indicated that the synthesized SPIO–erastin–PEG nanoplatform could induce ferroptosis effects in vitro and in vivo while exhibiting favorable physical characteristics. This approach may provide a new strategy for theranostic nanoplatform for nasopharyngeal cancer.
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FREE RADICAL BIOLOGY AND MEDICINE
·
2024
·
IF 7.1
Qi Wei,Fuxia He,Jiangyan Rao,Xiaoxia Xiang,Li Li,Hongyi Qi
Given the substantial risks associated with ultraviolet B radiation (UVB)-induced solar dermatitis, enhancing current strategies to combat UVB regarding skin diseases is imperative. The cross-talk between ferroptosis and inflammation has been proven to be an essential factor in UVB-induced skin inflammation, whereas detailed process of how their interaction contributes to this remains unclear. Therefore, further investigation of ferroptosis-mediated processes and identification of corresponding inhibitory approaches hold promise for repairing skin damage. Senkyunolide I (Sen I), a bioactive component mainly extracted from the traditional Chinese medicinal plants, Ligusticum chuanxiong Hort. and Angelica sinensis (Oliv.) Diels, has demonstrated efficacy in combating oxidative stress and inflammation. In this study, we utilized UVB-irradiated HaCaT cells as an in vitro model and C57BL/6J mice as an in vivo model of solar dermatitis. Our findings revealed the pivotal roles of autophagy and ferroptosis in inducing skin inflammation, particularly emphasizing the activation of ferroptosis through macroautophagy. Surprisingly, this mechanism operated independently of ferritinophagy, a classical autophagy-driven ferroptosis pathway. Instead, our results highlighted Transferrin Receptor 1 (TfR1), tightly controlled by autophagy, as a crucial mediator of ferroptosis execution and amplifier of subsequent lethal signals. Furthermore, extracellular High Mobility Group Box 1 protein (HMGB1), released following UVB-induced ferroptotic cells from activated autophagic flux, initiated a feedback loop with TfR1, propagating ferroptosis to neighboring cells and exacerbating damage. Remarkably, Sen I administration showed a significant protective effect against UVB damage in both in vitro and in vivo models by interrupting this cascade. Consequently, we have illuminated a novel therapeutic pathway post-UVB exposure and identified Sen I as a potent natural molecule that safeguarded against UVB-induced solar dermatitis by suppressing the autophagy-ferroptosis-HMGB1-TfR1 axis, highlighting a new frontier in photoprotection.
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