BME Frontiers
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2026
·
IF 9.1
Zengfeng Guo,Ningfeng Zhang,Junshen Huang,Wang Zhang,Yawei Hu,Shaochu Chen,Ming Gong,Jianhua Zhou,Jiancheng Yang,Jiawen Wu
Objective: This study aimed to investigate the protective effects and underlying mechanisms of baicalein against iron overload-induced osteoblast dysfunction and bone loss. Impact Statement: This research is the first to demonstrate that baicalein, a natural flavonoid, functions as a dual-action agent combining iron chelation and antioxidation to prevent iron overload-induced ferroptosis in osteoblasts, offering a novel therapeutic strategy for iron overload-related osteoporosis. Introduction: Iron overload contributes to osteoblast damage and osteoporosis through ferroptosis, an iron-dependent cell death pathway. Current treatments fail to simultaneously address iron accumulation and bone loss, highlighting the need for effective dual-function therapies. Methods: Using iron dextran-treated MC3T3-E1 osteoblasts and a murine iron overload model, we assessed the effects of baicalein on cell viability, osteogenic differentiation, ferroptosis markers, and the nuclear factor erythroid 2-related factor 2 (Nrf2)/glutathione peroxidase 4 (GPX4) pathway via biochemical assays, Western blot, and micro-computed tomography. Genetic and pharmacological inhibition of Nrf2 were applied to validate the mechanism. Results: Baicalein chelated iron, scavenged reactive oxygen species, and suppressed ferroptosis in osteoblasts, restoring differentiation under iron overload. It activated Nrf2 nuclear translocation and upregulated GPX4/solute carrier family 7-member 11 (SLC7A11) expression. In mice, baicalein reduced iron deposition, oxidative stress, and bone loss, and these effects were abolished by Nrf2 inhibition. Conclusion: Baicalein alleviates iron overload-induced osteoblast ferroptosis and osteoporosis by activating the Nrf2/GPX4 pathway, supporting its clinical potential as a therapeutic agent for iron-related bone disorders.
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INTERNATIONAL IMMUNOPHARMACOLOGY
·
2023
·
IF 5.6
WenBin Liu,ZhengWei Tan,YueChao Zhao,YanNa Zhao,XiaoLing Yu,BoLin Wang,FengLin Shen,Ai Mi,JinJian Lan,RuiLan Gao
Panaxadiol saponin (PND) is a latent targeted drug for the treatment of aplastic anemia (AA). In this study, we examined the effects of PND on ferroptosis in iron-overload AA and Meg-01 cells. We utilized RNA-seq to analyze differentially expressed genes in iron-induced Meg-01 cells treated with PND. The effects of PND or combined with deferasirox (DFS) on iron deposition, labile iron pool (LIP), several ferroptosis events, apoptosis, mitochondrial structure, as well as ferroptosis-, Nrf2/HO-1-, and PI3K/AKT/mTOR pathway-related markers in iron-induced Meg-01 cells were examined by Prussian-blue staining, flow cytometer, ELISA, Hoechst 33342 staining, transmission electron microscope, and Western blot assays, respectively. Additionally, an AA mice model with iron overload was established. Then, the blood routine was assessed, and the number of bone marrow-derived mononuclear cells (BMMNCs) in mice was counted. Also, serum iron, ferroptosis events, apoptosis, histology, T lymphocyte percentage, ferroptosis-, Nrf2/HO-1-, and PI3K/AKT/mTOR signaling-related targets in primary megakaryocytes of AA mice with iron overload were assessed by commercial kits, TUNEL staining, hematoxylin and eosin (H&E) staining, Prussian blue staining, flow cytometer, and qRT-PCR analysis, respectively. PND suppressed iron-triggered iron overload, and apoptosis, and ameliorated mitochondrial morphology in Meg-01 cells. Importantly, PND ameliorated ferroptosis-, Nrf2/HO-1-, and PI3K/AKT/mTOR signaling-related marker expressions in iron-induced Meg-01 cells or primary megakaryocytes of AA mice with iron overload. Moreover, PND ameliorated body weight, peripheral blood cell counts, the number of BMMNCs, and histological injury in the iron-overload AA mice. Also, PND improved the percentage of T lymphocytes in the iron-overload AA mice. PND attenuates ferroptosis against iron-overload AA mice and Meg-01 cells via activating Nrf2/HO-1 and PI3K/AKT/mTOR pathway and is a promising novel therapeutic candidate for AA.
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Science China-Life Sciences
·
2023
·
IF 9.1
Zhang Qian,Ding Haoxuan,Yu Xiaonan,Wang Qiwen,Li Xuejiao,Zhang Ruiqiang,Feng Jie
Iron overload often occurs during blood transfusion and iron supplementation, resulting in the presence of non-transferrin-bound iron (NTBI) in host plasma and damage to multiple organs, but effects on the intestine have rarely been reported. In this study, an iron overload mouse model with plasma NTBI was established by intraperitoneal injection of iron dextran. We found that plasma NTBI damaged intestinal morphology, caused intestinal oxidative stress injury and reactive oxygen species (ROS) accumulation, and induced intestinal epithelial cell apoptosis. In addition, plasma NTBI increased the relative abundance of Ileibacterium and Desulfovibrio in the cecum, while the relative abundance of Faecalibaculum and Romboutsia was reduced. Ileibacterium may be a potential microbial biomarker of plasma NTBI. Based on the function prediction analysis, plasma NTBI led to the weakening of intestinal microbiota function, significantly reducing the function of the extracellular structure. Further investigation into the mechanism of injury showed that iron absorption in the small intestine significantly increased in the iron group. Caco-2 cell monolayers were used as a model of the intestinal epithelium to study the mechanism of iron transport. By adding ferric ammonium citrate (FAC, plasma NTBI in physiological form) to the basolateral side, the apparent permeability coefficient ( Papp ) values from the basolateral to the apical side were greater than 3×10 −6 cm s −1 . Intracellular ferritin level and apical iron concentration significantly increased, and SLC39A8 (ZIP8) and SLC39A14 (ZIP14) were highly expressed in the FAC group. Short hairpin RNA (shRNA) was used to knock down ZIP8 and ZIP14 in Caco-2 cells. Transfection with ZIP14-specific shRNA decreased intracellular ferritin level and inhibited iron uptake. These results revealed that plasma NTBI may cause intestinal injury and intestinal flora dysbiosis due to the uptake of plasma NTBI from the basolateral side into the small intestine, which is probably mediated by ZIP14.
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Nutrients
·
2022
·Vol. 14
·期 21
·4549
·
IF 6.706
Tongtong Ba,Dai Zhao,Yiqin Chen,Cuiping Zeng,Cheng Zhang,Sai Niu,Hanchuan Dai
L-citrulline (L-cit) is a key intermediate in the urea cycle and is known to possess antioxidant and anti-inflammation characteristics. However, the role of L-cit in ameliorating oxidative damage and immune dysfunction against iron overload in the thymus remains unclear. This study explored the underlying mechanism of the antioxidant and anti-inflammation qualities of L-cit on iron overload induced in the thymus. We reported that L-cit administration could robustly alleviate thymus histological damage and reduce iron deposition, as evidenced by the elevation of the CD8+T lymphocyte number and antioxidative capacity. Moreover, the NF-κB pathway, NCOA4-mediated ferritinophagy, and ferroptosis were attenuated. We further demonstrated that L-cit supplementation significantly elevated the mTEC1 cells’ viability and reversed LDH activity, iron levels, and lipid peroxidation caused by FAC. Importantly, NCOA4 knockdown could reduce the intracellular cytoplasmic ROS, which probably relied on the Nfr2 activation. The results subsequently indicated that NCOA4-mediated ferritinophagy was required for ferroptosis by showing that NCOA4 knockdown reduced ferroptosis and lipid ROS, accompanied with mitochondrial membrane potential elevation. Intriguingly, L-cit treatment significantly inhibited the NF-κB pathway, which might depend on restraining ferritinophagy-mediated ferroptosis. Overall, this study indicated that L-cit might target ferritinophagy-mediated ferroptosis to exert antioxidant and anti-inflammation capacities, which could be a therapeutic strategy against iron overload-induced thymus oxidative damage and immune dysfunction.Keywords:L-citrulline;thymus;iron overload;ferritinophagy;ferroptosis
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FREE RADICAL BIOLOGY AND MEDICINE
·
2020
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IF 6.17
Kang Han,Xiaofang Jin,Xin Guo,Guoli Cao,Siyu Tian,Yiming Song,Yuanyuan Zuo,Peng Yu,Guofen Gao,Yan-Zhong Chang
The transcription factor NF-E2-related factor 2 (Nrf2) is a central regulator of cellular antioxidant and detoxification response. The association between Nrf2 activity and iron-related oxidative stress in neurodegenerative diseases has been studied, and Nrf2 was found to transcriptionally regulate the expression of iron transporters and ferroptosis-related factors. However, the role of Nrf2 in age-related motor dysfunction and its link to iron metabolism dysregulation in brain have not been fully elucidated. In this study, with different ages of Nrf2 knockout (KO) and wild type (WT) mice, we investigated the effects of Nrf2 deficiency on brain oxidative stress, iron metabolism and the motor coordination ability of mice. In contrast to the predicted neuroprotective role of Nrf2 in oxidative stress-related diseases , we found that Nrf2 KO remarkably improved the motor coordination of aged mice, which was associated with the reduced ROS level and decreased apoptosis of dopaminergic neurons in substantia nigra (SN) of 18-month-old Nrf2 KO mice . With high-iron and Parkinson's disease (PD) mouse models, we revealed that Nrf2 KO prevented the deposition of brain iron, particularly in SN and striatum, which may subsequently delay motor dysfunction in aged mice. The regulation of Nrf2 KO on brain iron metabolism was likely mediated by decreasing the ferroportin 1 (FPN1) level on brain microvascular endothelial cells , thus hindering the process of iron entry into the brain. Nrf2 may be a potential therapeutic target in age-related motor dysfunction diseases for its role in regulating brain iron homeostasis .
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JOURNAL OF NANOBIOTECHNOLOGY
·
2021
·Vol. 19
·期 1
·1-14
·
IF 10.435
Guo Xiaoyang,Liu Jia,Jiang Lingdong,Gong Wanjun,Wu Huixia,He Qianjun
Background Photothermal therapy (PTT) frequently cause thermal resistance in tumor cells by inducing the heat shock response, limiting its therapeutic effect. Hydrogen sulfide (H2S) with appropriate concentration can reverse the Warburg effect in cancer cells. The combination of PTT with H2S gas therapy is expected to achieve synergistic tumor treatment.Methods Here, sulourea (Su) is developed as a thermosensitive/hydrolysable H2S donor to be loaded into Pd nanocubes through in-depth coordination for construction of the Pd-Su nanomedicine for the first time to achieve photo-controlled H2S release, realizing the effective combination of photothermal therapy and H2S gas therapy.Results The Pd-Su nanomedicine shows a high Su loading capacity (85 mg g−1), a high near-infrared (NIR) photothermal conversion efficiency (69.4%), and NIR-controlled H2S release by the photothermal-triggered hydrolysis of Su. The combination of photothermal heating and H2S produces a strong synergetic effect by H2S-induced inhibition of heat shock response, thereby effectively inhibiting tumor growth. Moreover, high intratumoral accumulation of the Pd-Su nanomedicine after intravenous injection also enables photothermal/photoacoustic dual-mode imaging-guided tumor treatment.Conclusion sThe proposed NIR-responsive heat/H2S release strategy provides a new approach for effective cancer therapy.Graphic abstract
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Advanced Science
·
2019
·Vol. 6
·期 22
·1901694
·
IF 15.804
Xuan Lu,Yang Hu,Jiazhuang Guo,Cai-Feng Wang,Su Chen
All-inorganic halide perovskite nanocrystals (PNCs) have drawn increasing attention owing to their splendid optical properties. However, such nanomaterials suffer from intrinsic instability, greatly limiting their practical application. Meanwhile, environmental regulation has restricted the emissions of volatile organic compounds (VOCs), initiating a search for alternative approaches to PNC synthesis and film forming. Herein, fiber-spinning chemistry (FSC) is proposed for easy-to-perform synthesis of highly stable PNC fibrous films. The FSC process utilizes spinning fibers as reactors, reducing the generation of VOCs. This method enables the fabrication of CsPbX 3 (X = Cl, Br, I) PNCs/poly(methyl methacrylate)/thermoplastic polyurethanes fibrous films at room temperature in one step, exhibiting tunable emission between 450 and 660 nm. Significantly, the in situ generation of PNCs in hydrophobic core–shell nanofibers results in highly improved fluorescence stability. PNCs/polymer fibrous films keep constant in photoluminescence (PL) after storage at atmosphere for 90 d and retain 82% PL after water immersion for 120 h (vs fluorescence quenching in 10 d in air or 5 h in water for pristine PNCs). The PNCs/polymer fibrous films endowed with superior optical stability and great flexibility show promising potentials in flexible optoelectronic applications. This work paves a facile way toward high-performance nanoparticles/polymer fibrous films.
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ECOTOXICOLOGY AND ENVIRONMENTAL SAFETY
·
2025
·
IF 6.1
Jiaxiang Zhang,Haitao Ma,Yongjie Yang,Liyin Liu,Dasheng Luo,Defu Yu,Tao Chen
Excessive intake of essential and toxic metals affects the pathological process of osteoporosis. At present, the effects of single forms of iron (Fe), lead (Pb) and other metals on bone injury have been widely studied. However, these metal elements usually do not exist in the environment in a separate form. They are ingested in various ways and are often found together in the human body. However, the mechanism of bone damage caused by Fe and Pb mixed exposure is still unclear at this stage. At present, the combined analysis of multi-omics is the conventional method to explore the molecular mechanism behind the disease. Therefore, we attempted to combine proteomics and metabolomics to explain the mechanism of bone damage caused by mixed Fe and Pb exposure. Differential proteins and metabolites were found to be predominantly enriched in the JAK-STAT signalling pathway, inflammatory bowel disease (IBD), and osteoclast differentiation. Combined analysis showed that Fpr2, Lifr, Lisofylline, 7-Ketocholesterol, LacCer (d18: 1/14:0) and other substances may be involved in the process of bone injury mediated by mixed metal exposure. In summary, we hypothesise that mixed exposure to Fe and Pb leads to osteoclast activation via the JAK-STAT signalling pathway in situ and indirectly via the gut-bone axis, resulting in bone damage. In general, our study potentially suggests that bone injury induced by mixed exposure of Fe and Pb may be related to osteoclast proliferation mediated by changes in inflammatory levels in vivo .
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Heliyon
·
2024
·
IF 3.4
Fanzhuo Zeng,Anqi Chen,Wei Chen,Shuai Cheng,Sen Lin,Rongcheng Mei,Xifan Mei
Background Spinal cord injury (SCI) is a serious and difficult to treat traumatic disease of the central nervous system. Spinal cord injury causes a variety of detrimental effects, including neuroinflammation and ferroptosis, leading to chronic functional impairment and death. Recent studies have shown that microglia/macrophages (M/Ms) at the injury site remain primarily in the pro-inflammatory state, which is detrimental to recovery. However, information on the factors behind pro-inflammatory polarization skew in the injured spinal cord remains unclear. In this study, we found that Tumor Necrosis Factor-α(TNF-α) ablation protected after SCI by suppressing neuroinflammation and ferroptosis. Though using TNF-α knock out mice (TNF−/−), we induced downregulation of TNF-α in M/Ms and further investigated its effect on SCI outcome. In TNF−/− mice, significant behavioral improvements were observed as early as 7 days after injury. We showed that TNF-α inhibition promote injury-mediated M/Ms polarization from pro-inflammatory to anti-inflammatory phenotype in vivo. Furthermore, accumulated iron in M/Ms after SCI increased the expression of TNF-α and the population of M/Ms to pro-inflammatory phenotype. Moreover, zinc supplement reduced the secondary damage caused by iron overload. In conclusion, we found that knock out of TNF-α promotes recovery of motor function after spinal cord injury in mice by inhibiting ferroptosis and promoting the shift of macrophages to an anti-inflammatory phenotype, indicating that there is great potential for this therapy to SCI.
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MOLECULAR NUTRITION & FOOD RESEARCH
·
2024
·
IF 4.5
Dai Zhao,Yuan Gao,Yiqin Chen,Yingsi Zhang,Yian Deng,Sai Niu,Hanchuan Dai
Scope Oxidative stress caused by iron overload tends to result in intestinal mucosal barrier dysfunction and intestinal microbiota imbalance. As a neutral and nonprotein amino acid, L-Citrulline (L-cit) has been implicated in antioxidant and mitochondrial amelioration properties. This study investigates whether L-cit can alleviate iron overload-induced intestinal injury and explores the underlying mechanisms. Methods and results C57BL/6J mice are intraperitoneally injected with iron dextran, then gavaged with different dose of L-cit for 2 weeks. L-cit treatment significantly alleviates intestine pathological injury, oxidative stress, ATP level, and mitochondrial respiratory chain complex activities, accompanied by ameliorating mitochondrial quality control. L-cit-mediated protection is associated with the upregulation of Glutathione Peroxidase 4 (GPX4) expression, inhibition Nuclear Receptor Coactivator 4 (NCOA4)-mediated ferritinophagy and ferroptosis, and improvement of gut microbiota. To investigate the underlying molecular mechanisms, Intestinal Porcine Epithelial Cell line-J2 (IPEC-J2) cells are treated with L-cit or AMP-activated Protein Kinase (AMPK) inhibitor. AMPK signaling has been activated by L-cit. Notably, Compound C abolishes L-cit's protection on intestinal barrier, mitochondrial function, and antioxidative capacity in IPEC-J2 cells. Conclusion L-cit may restrain ferritinophagy and ferroptosis to regulate iron metabolism, and induce AMPK pathway activation, which contributes to exert antioxidation, ameliorate iron metabolism and mitochondrial quality control, and improve intestinal microbiota. L-cit is a promising therapeutic strategy for iron overload-induced intestinal injury.
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CHEMICAL ENGINEERING JOURNAL
·
2024
·
IF 13.3
Bin Zhang,Xiao-Lin Hou,Xiao-Ting Xie,Lin-Fang Tan,Meng Guan,Dong-Hui Zhao,Sui Zhou,Kai Cheng,Jin-Xuan Fan,Bo Liu
The current limitations of chemodynamic therapy (CDT) are mainly due to the lack of metal ions (Fe 2+ , Cu + , etc.), glutathione overexpression, and insufficient hydrogen peroxide level in the tumor microenvironment. Here, we constructed a safe and effective nanoplatform (abbreviate as MPCF, M: 4T1 cell membranes; P: polydopamine; C: calcium phosphate; F: iron dextran) for tumor CDT applications based on ascorbic acid and iron dextran, which is clinically used in the treatment of iron deficiency anemia. The MPCF was fabricated by encapsulating iron dextran nanoparticles within porous calcium phosphate nanoparticle carriers and surface modifying with polydopamine and 4T1 tumor cell membranes. The MPCF can efficiently accumulate at tumor sites and gradually degrade to release the encapsulated iron dextran nanoparticles in response to the acidic tumor microenvironment. Intraperitoneally injected ascorbic acid not only generated hydrogen peroxide at the tumor site, but also synergistically acted with endogenous glutathione to reduce trivalent iron ions in the iron dextran to divalent iron ions, leading to depletion of the excess glutathione at the tumor site and amplification of oxidative stress effects. In addition, polydopamine-mediated photothermal therapy (PTT) can further enhance the CDT effect. In vitro and in vivo experiments demonstrated that the combination therapy of CDT and PTT based on the MPCF exhibited effective tumor inhibition and good biosafety properties. Therefore, the nanoplatforms prepared with the clinical drug iron dextran provide a new idea for the design of nanoprobes of tumor therapy with clinical translational potential.
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JOURNAL OF APPLIED POLYMER SCIENCE
·
2012
·Vol. 127
·期 1
·733-739
·
IF 1.289
Weidong Zhou,Tao Xu,Xiaowei Wang,Erjuan Zhi,Jun Liu,Wei Zhang,Junhui Ji
In this study, the nanocomposites of poly(butylene succinate) (PBS) and TiO 2 nanofibers were first synthesized via in situ polymerization. Molecular weight, morphology, and thermal properties of the nanocomposites were characterized. As the weight percentage of TiO 2 nanofibers increased from 0 to 2%, the molecular weight of PBS in the nanocomposites decreased gradually compared with that of pure PBS. In morphology, the nanocomposites were constituted by free PBS and PBS-grafted TiO 2 nanofibers (PBS- g -TiO 2 ), which were proved by the Fourier transform infrared, scanning electron microscopy (SEM), and transmission electron microscopy. In addition, the SEM demonstrated the strong interfacial interaction and homogeneous distribution between TiO 2 nanofibers and PBS matrix. The thermal properties determined by differential scanning calorimetry and thermogravimetric analysis included the increasing of cold crystallization temperatures, the melting temperatures, and the thermal stability. Besides, the crystallinity and the rate of crystallization of the nanocomposites were enhanced, which were also observed by the X-ray diffraction. © 2012 Wiley Periodicals, Inc. J. Appl. Polym. Sci., 2013
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