JOURNAL OF CONTROLLED RELEASE
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2024
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IF 10.5
Mengjuan Sun,Chang Liu,Ji Liu,Jing Wen,Tianjiao Hao,Daquan Chen,Yan Shen
Thrombus-induced cardiovascular diseases threaten human health. Current treatment strategies often rely on urokinase plasminogen activator (uPA) for its efficacy, yet it has such limiting factors as short half-life, lack of thrombus targeting, and systemic side effects leading to unintended bleeding. In addition, thrombolytic interventions can trigger inflammation-induced damage at thrombus sites, which affects endothelial function. To address these challenges, Fer-1/uPA@pep-CREKA-Lipo (Fu@pep-CLipo) has been developed. This system achieves precise and efficient thrombolysis while enhancing the thrombus microenvironment and mitigating ischemia-reperfusion injury, with exceptional thrombus targeting ability via the strong affinity of the Cys-Arg-Glu-Lys-Ala (CREKA) peptide for fibrin. The Cys-Nle-TPRSFL-DSPE (pep) could respond to the thrombus microenvironment and fixed-point cleavage. The uPA component linked to the liposome surface is strategically cleaved upon exposure to abundant thrombin at thrombus sites. Importantly, the inclusion of Fer-1 within Fu@pep-CLipo contributes to reactive oxygen species (ROS) scavenging and significantly improves the thrombus microenvironment. This innovative approach not only achieves highly efficient and precise thrombolysis but also positively influences the expression of eNOS protein while suppressing inflammatory factors like TNF-α and IL-6. This dual action contributes to improved thrombus inflammatory microenvironment and mitigated ischemia-reperfusion injury.
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SEPARATION AND PURIFICATION TECHNOLOGY
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2024
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IF 8.1
Dongzhou Wang,Ze Wang,Xiaojun Ren,Yunfeng Li,Yuxuan Zhang,Hao Liang,Lei Li,Yuechen Zhao,Shunzi Jin,Yannan Shen,Quan Lin,Tiejun Wang
Radiotherapy (RT) is one of the most widely used treatment strategies for cervical cancer. However, radiation resistance poses a significant challenge in clinical practice, leading to poor prognosis and cancer-related deaths following RT. Herein, the multifunctional bimetallic nanoplatform Au/Fe nanodots (Au/FeNDs) were constructed to serve as an excellent radiosensitizer and reverse radiation resistance, aiming to enhance the therapeutic efficiency of RT. Au/FeNDs can generate a sufficient amount of reactive oxygen species through the Fenton reaction, thus achieving chemodynamic therapy (CDT). This in turn facilitates the damage of biomacromolecules such as DNA and lipids, promoting oxidative damage and inducing ferroptosis of tumor cells. Further, Au/FeNDs can also deposit more X-ray energy, increase DNA damage, and induce cell cycle arrest in the radiosensitive G2/M phase, thus achieving RT-CDT-ferroptosis trifunctional synergistic therapy to enhance RT efficiency. In addition, Au/FeNDs display remarkable performance as a contrast agent for computed tomography, which can be used to differentiate the boundary between tumors and normal tissues, facilitating precise RT of tumors. In conclusion, the developed nanodots have the potential to overcome radiation resistance through their ability to induce oxidative damage and ferroptosis, suggesting their potential translational value in clinical applications.
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Journal of Natural Medicines
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2024
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IF 2.5
Cao Yongyi,Wang Yu,Li Yueyang,Liu Sihan,Wang Lizhe,Zhou Li,Zhu Ting
Ferroptosis is a unique programmed cell death driven by iron-dependent phospholipid peroxidation. Tumor cells that escape from the conventional therapies appear more sensitive to ferroptosis. Therefore, it is extremely urgent to find safe and efficient active ingredients that induce ferroptosis in tumor cells. Herein, we identified that angelic acid, as a potent anti-tumor active ingredient in Angelica sinensis , profoundly sensitizes CRC cells to ferroptosis via a natural compound library screen. We revealed that angelic acid treatment is sufficient to predispose CRC cells to ferroptosis phenotype, evidenced by malondialdehyde (MDA) accumulation, lipid peroxidation, and upregulation of ferroptosis-associated markers CHAC1 and PTGS2, which is abolished by ferroptosis inhibitor Fer-1. Moreover, the results of network pharmacology showed that NRF2 is critical for angelic acid-mediated CRC cell ferroptosis. Mechanistically, angelic acid exerted its ferroptosis induction via directly binding and facilitating the degradation of NRF2. In addition, the syngeneic mouse models revealed that angelic acid boosts CRC cell sensitivity to ferroptosis inducer sulfasalazine with essentially no toxicity in vivo. Collectively, our findings highlighted a previously unrecognized anti-tumor mechanism of angelic acid and represented an appealing therapeutic strategy for CRC treatment. Graphical abstract
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CHEMICAL ENGINEERING JOURNAL
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2024
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IF 13.3
Mengran Xu,Fuxuan Lai,Hu Liu,Delin Hu,Yexiang Sun,Fenfen Li,Min Sun,Na Lv,Bensheng Qiu,Yueyin Pan,Yi Hu
Ferroptosis, a relatively recently discovered form of programmed cell death, has garnered considerable attention in the field of cancer drug discovery. However, effectively inducing ferroptosis at tumor sites and maximizing its therapeutic efficacy remains a formidable challenge. In the present study, we constructed the MIL-53@cMBP@ST/Ce6 (MMSC) nanocomplex to enhance the therapeutic efficacy of a ferroptosis-inducing drug. This was accomplished by modifying the cMBP peptide and encapsulating a small molecular ferroptosis inducer, sorafenib tosylate (ST), along with a photosensitizer, Chlorin e6 (Ce6), within the iron-based nanozyme MIL-53, which exhibits multiple enzyme-like activities. The glutathione (GSH) oxidase-like activity of MIL-53 depletes GSH, which is known to contribute to ferroptosis resistance in tumors. The catalase-like activity of MIL-53 catalyzes the decomposition of H 2 O 2 within the tumor, yielding oxygen to enhance the effect of photodynamic therapy. Concurrently, the photodynamic effect of MMSC generates singlet oxygen ( 1 O 2 ), further amplifying ferroptosis. Additionally, modification of the cMBP peptide enabled MMSC to attenuate the MET pathway in MET-overexpressing tumors, thereby decreasing the antioxidant capacity of these cells to promote ferroptosis. Notably, transcriptomic analysis revealed that PDT enhances the ferroptosis pathway and modulates the expression of ferroptosis-related genes and MET signaling pathways-related genes, while Western Blot results confirmed the inhibition of GPX4 protein, a critical regulator of ferroptosis. In vivo, MMSC demonstrated a tumor-specific accumulation effect, as evidenced by fluorescence imaging, and significantly inhibited tumor growth by alleviating the hypoxic tumor microenvironment and enhancing ferroptosis at the tumor site. This study presents a novel strategy for the mechanistic investigation of augmented ferroptosis in tumor therapy.
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JOURNAL OF CONTROLLED RELEASE
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2025
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IF 11.5
Anning Yang,Hongwen Zhang,Huiping Zhang,Nan Li,Cong Chen,Xiaoling Yang,Jue Tian,Jianmin Sun,Guizhong Li,Yue Sun,Bin Liu,Yideng Jiang
Atherosclerosis (AS) therapy has been commonly based on lipid-lowering agents ( e.g. , statins), supplemented by other therapies, such as anti-inflammatory agents and antioxidants, through traditional Chinese herbs. Ferroptosis, a form of regulated cell death characterized by iron-dependent lipid peroxidation, has been implicated in the progression of AS, particularly in macrophages. In the study, we constructed a macrophage targeted hybridization nanodrug of HMLRPP NPs, which used Pit-loaded Poly(lactic- co -glycolic) acid (PLGA) nanoparticles and Res-loaded liposomes (Lipo) as nano-core, then, coated with a macrophage membrane hybridized by hyaluronic acid (HA). The nanodrug prolonged blood circulation time and achieved optimal Res and Pit accumulation in the atherosclerotic plaques by effectively evading immune system clearance. In vivo studies demonstrated that HMLRPP NPs significantly attenuated plaque progression, characterized by decreased plaque area, less lipid deposition, and increased collagen. Meanwhile, HMLRPP NPs inhibited macrophage ferroptosis by decreasing the expression of β-Hydroxybutyrate dehydrogenase 1 (BDH1), Orosomucoid 1 (ORM1) and enhancing the expression of Ribosomal protein S27-like (RPS27L), which resulted in the alleviation of lipid accumulation and inflammation. Our data suggest that the HMLRPP nanodrug delivery system with ferroptosis-regulating capability provides a feasible therapeutic strategy for atherosclerosis.
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Advanced Healthcare Materials
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2024
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IF 10
Mingjie Rong,Jian Liu,Lehui Lu
Nanozymes show great potential in facilitating tumor ferroptosis by upregulation of reactive oxygen species (ROS) and downregulation of glutathione (GSH). However, mild acidity (pH 6.5–6.9) of tumor microenvironment severely restricts the activity of nanozymes. Although lysosomes as acidic organelles (pH = 3.5–5.5) are hopeful for improving enzyme-like activity, most reported nanozymes are not capable of effectively accumulating in the lysosomes. Herein, an acid-responsive self-assembly strategy based on iron phthalocyanine-rich covalent organic framework nanosheets (COF FePc NSs) is developed, which enables lysosomal targeting aggregation of COF FePc NSs due to the existence of abundant negative hydroxyl groups and rigid structure. Meanwhile, COF FePc NSs display exceptional multienzyme-mimic performance at lower pH to efficiently generate ROS to cause lysosome damage and apoptosis by synergistic photothermal effect. Subsequently, the released COF FePc with GSH oxidase-mimicking activity can consume GSH to promote ferroptosis. This is the first report of a 2D COF using its own properties to achieve lysosomal self-assembly. Overall, the work provides a new paradigm for the development of lysosome-targeted nanosystems.
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BRAZILIAN JOURNAL OF MEDICAL AND BIOLOGICAL RESEARCH
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2024
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IF 1.9
Lin Shuai,Cai Hui,Song Xuemei
The objective of this study was to explore the effects and mechanisms of the combination of isobavachalcone (IBC) and doxorubicin (DOX) on the progression of anaplastic thyroid cancer (ATC). Cell viability of 8505C and CAL62 cells was observed by CCK-8 assay. Kits were used to detect the presence of reactive oxygen species (ROS), glutathione (GSH), malondialdehyde (MDA), and cellular iron. Protein expression of solute carrier family 7 member 11 (SLC7A11) and glutathione peroxidase 4 (GPX4) was detected using western blot, and CD31 was detected through immunofluorescence. Tumor xenograft models of 8505C cells were constructed to observe the effect of IBC and DOX on ATC growth in vivo. The co-administration of IBC and DOX exhibited a synergistic effect of suppressing the growth of 8505C and CAL62 cells. The concurrent use of IBC and DOX resulted in elevated iron, ROS, and MDA levels, while reducing GSH levels and protein expression of SLC7A11 and GPX4. However, the Fer-1 ferroptosis inhibitor effectively counteracted this effect. In vitro and in vivo, the inhibitory effect on ATC cell proliferation and tumor growth was significantly enhanced by the combination of IBC and DOX. The combination of IBC and DOX can inhibit the growth of ATC by activating ferroptosis, and might prove to be a potent chemotherapy protocol for addressing ATC.
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TRANSITION METAL CHEMISTRY
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2025
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IF 1.7
Feng Qiying,Zhou Lin,Tian Shuang,Yang Jiawan,Liu Yunjun
Herein, we reported the synthesis and characterization of two new iridium(III) complexes [Ir(ppy) 2 (fpp)](PF 6 ) (Ir1a, ppy = 2-phenylpyridine, fpp = 2-(2,2-difluorobenzo[1,3]dioxol-5-yl-1H-imidazo[4,5-f][1,10]phenanthroline) and [Ir(bzq) 2 (fpp)](PF 6 ) (Ir1b, bzq = benzo[h]quinoline) through high resolution mass spectrometry (HRMS), 1 H NMR and 13 C NMR. The cytotoxicity in vitro of Ir1a and Ir1b on normal NIH3T3 cells and cancer SGC-7901, A549, SK-Hep1 cells was tested using MTT (3-(4,5-dimethylthiazole-2-yl)-diphenyltetrazolium bromide) method. Ir1a exhibits high cytotoxicity on SGC-7901 cells (IC 50 = 2.7 ± 0.7 µM), whereas Ir1b shows moderate cytotoxicity toward the selected cancer cells. The ROS content was investigated using a fluorescence probe of 2′,7′-dichlorodihydrofluorescein diacetate (DCHF-DA), the results show that Ir1a and Ir1b elevate ROS content. The co-localization and the change of mitochondrial membrane potential were explored. Apoptotic studies using Annex V/PI double staining method demonstrate that Ir1a and Ir1b can efficiently cause apoptosis. Ir1a and Ir1b inhibit the cell proliferation at the G2/M period. Additionally, lipid peroxidation and downregulation of ferritin protein suggest that Ir1a and Ir1b can trigger ferroptosis.
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ACS Nano
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2025
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IF 16
Lei Shu,Peili Luo,Chuanyu Ren,Ziwei Lai,Xuejuan Zhang,Chuanbin Wu,Xin Pan,Zhengwei Huang
The application of ferroptosis inducer FIN56 to decrease antioxidant levels in lung adenocarcinoma (LUAD) is a promising tumor eradication technique. However, several obstacles reduce the efficacy of ferroptosis therapy including insufficient oxidative stress from monotherapy and restricted drug retention in tumor tissues. To address these challenges, we developed an inhalable hybrid liposome in which FIN56 and piperlongumine (PPL) are coloaded into silk fibroin nanoparticles to overcome the limitation of the poor therapeutic effect of single-drug ferroptosis. Subsequently, lipids containing hyaluronic acid were added to the hybrid liposome to enable it to specifically target the overexpressed CD44 receptors on the surface of LUAD cells and solve the problem of insufficient active targeting of silk fibroin nanoparticles. Compared to conventional intravenous formulations, the as-synthesized formulation FP@SLCDH increased pulmonary accumulation by 13.6-fold and lipid peroxidation products by 2.14-fold. FIN56 prompts tumor-specific ferroptosis by inhibiting glutathione peroxidase 4 (GPX4) and glutathione (GSH), whereas PPL further augments this effect by increasing intracellular reactive oxygen species levels and facilitating ferritin degradation to release Fe ions from ferritin. The role of autophagy in promoting ferroptosis and therapeutic efficacy was validated in an orthotopic LUAD tumor model. The real-time tracking of targeted retention of FP@SLCDH in LUAD cells is also possible using an aggregation-induced emission probe, which is facilitated as a “double-lock logic gate fluorescence probe”. This probe emits fluorescence signals only after entering cancer cells and arriving at the mitochondria. To summarize, our proposed hybrid liposomes represent a significantly enhanced pulmonary strategy for LUAD therapy.
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JOURNAL OF VIROLOGY
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2025
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IF 3.8
Xiaohan Chen,Yipeng Pang,Fructueux Modeste Amona,Zilu Liu,Fang Wang,Yuan Liang,Jiachen Yang,Wanhan Zhang,Xingtang Fang,Xi Chen
Porcine reproductive and respiratory syndrome virus (PRRSV) is a highly contagious pathogen that causes substantial economic losses in the global swine industry, primarily by impairing reproductive performance and respiratory health. However, current therapeutic approaches remain limited in effectively controlling PRRSV infection. Here, we present self-assembled cyanidin-3-O-glucoside (C3G)-based nanoparticles (C3G-Cs-SeNPs) as a promising antiviral agent against PRRSV infection. These nanoparticles demonstrated excellent stability and biocompatibility, with minimal cytotoxicity in Marc-145 cells. C3G-Cs-SeNPs significantly reduced ROS levels in PRRSV-infected cells, enhancing the antioxidant capacity and mitigating oxidative stress. In addition, they effectively inhibited key stages of the PRRSV lifecycle, including viral internalization and replication, leading to a marked decrease in viral proliferation. Moreover, C3G-Cs-SeNPs alleviated ferroptosis by restoring redox homeostasis through enhanced antioxidant enzyme activity. Mechanistically, these nanoparticles potentially activate the SIRT1/Nrf2/HO-1 signaling pathway, which plays a critical role in regulating inflammation and ferroptosis in PRRSV-infected cells. These findings suggest that C3G-Cs-SeNPs could serve as a novel therapeutic approach to modulate inflammation, ferroptosis, and viral replication in respiratory viral infections. Our study highlights the therapeutic potential of C3G-Cs-SeNPs in combating PRRSV infection, with important implications for viral infection management and respiratory disease treatment.
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TISSUE & CELL
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2025
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IF 2.5
Xiaoxue Zhao,Bingyu Zhang,Sining Duan,Tengfei Wu,Xiaojiao Yang,Yuxiang Liu
Growing evidence demonstrated the involvement of ferroptosis in the pathogenesis of myocardial ischemia/reperfusion injury (MIRI). The nature compound Wedelolactone (Wed) exhibits anti-ferroptosis effects. The current study aims to explore the impact of Wed on MIRI and reveal whether Wed could protect cardiomyocytes from ferroptosis. Rats underwent cardiac IR operation, and H9c2 cardiomyocytes were subjected to oxygen-glucose deprivation/reoxygenation (OGD/R). Rats or cell in Wed-treated group were subdivided into 2 different dose regimens: low and high. Wed intervention alleviated myocardial infarction and left ventricle dysfunction, and diminished the levels of biochemical markers for cardiac injury caused by cardiac IR. The content of Fe 2+ and MDA, 4-HNE expression, and ROS production were increased in infarct zone, as well as GSH content, GSH-Px activity, and the levels of ferroptosis-related proteins were reduced. Treatment with Wed reversed the aforementioned changes. Similar results were observed in vitro experiments. Molecular docking analysis showed good binding affinity between Wed and the target protein METTL3. In OGD/R-induced H9c2 cells, Wed downregulated METTL3 protein expression and further blocked METTL3-mediated m 6 A modification of BRD4 mRNA. Overexpression of METTL3 reversed the antagonistic effect of Wed on cardiomyocyte ferroptosis. Collectively, our findings uncovered that Wed showed anti-ferroptosis effects in cardiomyocytes through downregulating the METTL3/BRD4 axis, thereby ameliorating MIRI.
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CHEMICAL ENGINEERING JOURNAL
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2025
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IF 13.2
Shichen Zhang,Lei Guo,Yixin Tang,Yixing Wang,Heshi Liu,Chang Liu,Xiuzhang Yan,Congcong Duan,Huanyan Dai,Bing Han,Caina Xu
Conventional treatments for head and neck squamous cell carcinoma (HNSCC) cause severe side effects and functional impairment. Chemodynamic therapy (CDT), a reactive oxidative stress (ROS)-based therapy, exploits H 2 O 2 in the tumor micro-environment to produce large amounts of cytotoxic ROS to destroy cancer cells. Monotonic CDT efficacy is severely constrained by slow Fenton kinetics and insufficient intra-tumoral H 2 O 2 content. In order to overcome these barriers, a multifunctional self-reinforced nanoreactor, MAGFH, was developed for the eradication of HNSCC. This nano-system employed an Fe-based metal-organic framework, MIL-100, to deliver artesunate (ART) for the exertion of H 2 O 2 -independent CDT. A gallic acid (GA)-Fe 3+ metal-polyphenol network (MPN) coating was introduced to enhance the Fenton reaction by accelerating iron redox cycling while conferring photothermal therapy (PTT) effect. Hyaluronic acid (HA) was covered on the outermost layer to enable the tumor targeting. Following endocytosis into cancer cells, the released Fe 3+ was reduced into Fe 2+ by the consumption of glutathione (GSH), thereby catalyzing the production of hydroxyl radicals ( OH) via the Fenton reaction. The GA-Fe network functioned as an amplifier for the iron redox cycle. Concurrently, the activation of ART by Fe 2+ led to the generation of highly cytotoxic superoxide anions ( O 2 − ) and C-centered free radicals ( C). The near infrared laser (808 nm) irradiation synergistically enhanced ROS generation and GSH depletion, resulting in the high accumulation of ROS and the dysregulation of redox homeostasis, subsequently inducing cell apoptosis and ferroptosis. In addition, the introduction of the GA-Fe MPN conferred both photoacoustic imaging (PAI) and T 1 magnetic resonance imaging (MRI) capabilities, enabling the integration of therapeutics and diagnosis. Collectively, this work established a PAI/MRI-guided nanoplatform for self-amplifying CDT/PTT against HNSCC via dual induction of apoptosis-ferroptosis.
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