FITOTERAPIA
·
2023
·
IF 3.4
Nan Zhang,Junwei Zhang,Weiqi Cui,Deqiao Wu,Jingxian Zhang,Bo Wei,Lingbo Qu,Xia Xu
Artemisia argyi H.Lév. & Vaniot, a traditional Chinese medicine with a history spanning over two millennia, has been extensively used in folk medicine to treat dysmenorrhea, uterine bleeding and inflammation. Recent studies have demonstrated that the essential oil extracted from Artemisia argyi H.Lév. & Vaniot, known as AAEO, exhibits significant anti-tumor properties against liver and lung cancers. There is a scarcity of research on the potential impact of AAEO on pancreatic cancer (PC) cells. In this study, UPLC-MS/MS-based metabolomics method was established to evaluate the effect of AAEO on the proliferation of PC cells. The differential compounds included 5-oxoproline, glutamate, γ-glutamylcysteine, glutathione, arachidonic acid, adrenal acid and linoleic acid were detected by metabolomics, enriching in the γ-glutamyl cycle and polyunsaturated fatty acid metabolism, which were closely related to ferroptosis. Meanwhile, AAEO dramatically increased the levels of intracellular iron ion via up-regulation of TFR1, augmented reactive oxygen species and malondialdehyde in a dose-dependent manner by down-regulation of γ-glutamyl cycle through decreasing expressions of SLC7A11. Additionally, β-caryophyllene oxide, one of the main components of AAEO, could covalently bind to Cys in SW1990 cells to form a conjugate Cpo-Cys, resulting in the inhibition of glutathione synthesis. Importantly, the ferroptosis inhibitor deferoxamine significantly blocked the inhibitory effect of AAEO on SW1990 cells. Meanwhile, β-caryophyllene oxide, dihydro-β-ionone and α-bisabolol had strong binding force with GPX4, SLC7A11 and TFR1, respectively. These findings showed that AAEO induced ferroptosis via regulation of γ-glutamyl cycle by SLC7A11 and iron disorders by TFR1. Our study discovered AAEO as a potential therapeutic approach to induce ferroptosis to prevent or treat PC.
研究领域:
肿瘤学
·
药理学
·
代谢组学
·
中医药
✓ 已验证
产品关联
DOI
PubMed
高影响因子
AQUACULTURE
·
2026
·
IF 4.4
Liangliang Mu,Qingliang Zeng,Peiyu Li,Hao Bai,Nuo Chen,Lingyuan Zeng,Jianmin Ye,Xiaoxue Yin
Iron (Fe) is a crucial metal and plays a vital role in a variety of cellular processes. Studies in mammals have indicated that transferrin (TF) and transferrin receptor (TfR), jointly iron ion transport, while also contributing to antibacterial immunity. However, systematic reports on the functions and regulatory mechanisms of these components in teleost fish are lacking. In this study, TF protein was purified and identified from the serum of Nile tilapia ( Oreochromis niloticus ). A range of experimental techniques was employed to demonstrate that OnTF can inhibit the proliferation of pathogenic bacteria both in vivo and in vitro . Meanwhile, OnTF interacts with the OnTfR1 receptor on the cell surface, facilitating phagocytosis and bacterial clearance, thereby providing immune protection to the organism. Notably, OnTfR1 directly influences the secretion of OnHepc through the BMP-SMAD signaling pathway. The increased mortality of tilapia caused by downregulated OnTfR1 expression during pathogenic bacterial infection can be effectively alleviated by supplementing (r)Hepc protein. Moreover, OnTfR1 also played an indispensable role in maintaining the stability of the fish intestinal microecology and resisting pathogen infections. Overall, this study represents the first systematic investigation into the functional roles of molecules involving in iron homeostasis regulation in teleost fish. It elucidates that the OnTF-TfR1 axis, as a core pathway for iron ion uptake and metabolic regulation, plays a significant role in resisting pathogen infections and maintaining the stability of the intestinal microbiota. These findings provide new insights into understanding the functional association between iron metabolism and innate immune defense during adaptive evolution.
✓ 已验证
产品关联
DOI
高影响因子
CHEMICAL ENGINEERING JOURNAL
·
2025
·
IF 13.2
Bowen Jia,Yuchen Yao,Yejia Xu,Yang Zhao,Jing Li,Yumeng Wu,Xiaofeng Zeng,Shijun Hong,Qianqian Li,Xuexia Liu,Chengliang Luo
Traumatic brain injury (TBI) is a major global health issue, causing blood–brain barrier disruption, neuroinflammation, and neuronal damage. Current therapies are limited and failed to address key pathological mechanisms like ferroptosis, oxidative stress, and inflammation, highlighting the need for novel treatments. Recent advances in nanomedicine, particularly nanozymes, offer promising solutions. Copper-based ultrasmall nanozymes, with excellent catalytic activity and biocompatibility, have shown potential in mitigating ferroptosis and oxidative stress. In this study, we developed polyethylene glycol-modified Cu 5.4 O (Cu 5.4 O-PEG), a nanomaterial with superior blood–brain barrier penetration and biocompatibility. Cu 5.4 O-PEG demonstrated no cytotoxicity and significantly reduced oxidative stress and ferroptosis in both in vitro and in vivo models, improving motor and cognitive functions in murine TBI models. The therapeutic effects were mediated through multiple mechanisms, including inhibition of the Fenton reaction, scavenging of reactive oxygen species (ROS), and reducing iron deposition, effectively limiting tissue damage. Proteomic analysis revealed modulation of ferroptosis-related proteins and activation of protective pathways related to transferrin receptor 1 (TfR1). Furthermore, using AAV-mediated knockdown of TfR1 in mice, we observed significant reductions in lipid peroxidation markers such as ACSL4, COX2, and 4HNE, indicating a decrease in iron-induced damage. Histological analysis showed reduced iron deposition, and improved neuronal morphology in TfR1 knockdown mice underwent TBI, indicating knockdown of TfR1 could alleviate TBI-indued ferroptosis and iron-dependent neurodegeneration. Taken together, these data imply that Cu 5.4 O-PEG presents a neuroprotective strategy for improving cerebral recovery after TBI, at least partly by inhibiting TfR1-mediated ferroptosis.
研究领域:
神经科学
·
纳米医学
·
药理学
✓ 已验证
产品关联
DOI
高影响因子
PHYTOMEDICINE
·
2026
·
IF 11.3
Minghui Zhao,Hongfang Mu,Qian Ji,Jiale Song,Fuyixuan Zheng,Tianlong Liu,Wenbin Li,Rong Wang
Background The effects of persistent hypoxic conditions in high-altitude regions on metabolic disorders remain poorly understood and in-depth investigation into its underlying molecular mechanisms is notably insufficient. As a metabolism-associated liver disease, the pathogenesis of non-alcoholic fatty liver disease (NAFLD) under hypoxic conditions urgently requires clarification. Previous studies have demonstrated that resveratrol (Rsv) possesses significant anti-inflammatory, antioxidant, and lipid metabolism-modulating properties, and it can act as an inhibitor of ferroptosis. Yet its precise therapeutic efficacy and mechanism in hypoxic NAFLD remain to be further explored. Objective This study aims to explore the potential mechanism by which Rsv improves the deterioration of NAFLD under hypoxia exposure. Methods Herein, we performed concurrent interventions in both in vivo and in vitro models of NAFLD, comprehensively detecting biochemical indicators (inflammatory factors, oxidative stress markers, liver function), liver histopathological changes, and nucleic acid levels to assess the effects of Rsv. By introducing ferroptosis modulators, we measured core ferroptosis parameters (mitochondrial ultrastructure, Fe²⁺, 4-HNE, LPO levels, and key protein expressions) to define disease progression patterns. By HIF-1α silencing was employed to verify its regulatory roles in ferroptosis-related factors and NAFLD pathogenesis. Co-Immunoprecipitation assays and immunofluorescence co-localization were used to explore protein interactions among ACSL4, TfR1, and HIF-1α. Conclusion Our results demonstrated that high-altitude hypoxia exacerbates NAFLD via inducing ferroptosis; HIF-1α upregulates the expression of key ferroptosis mediators (ACSL4, TfR1), and HIF-1α silencing attenuates ferroptosis. Rsv exerts therapeutic effects against hypoxia-related NAFLD by targeting the HIF-1α-mediated ferroptosis pathway. This study elucidates the pivotal role of HIF-1α-dependent ferroptosis in hypoxia-aggravated NAFLD, identifies the therapeutic targets and mechanisms of Rsv, and provides novel theoretical foundations and potential intervention strategies for clinical management of hypoxia-related NAFLD in high-altitude areas.
✓ 已验证
产品关联
DOI
PubMed
高影响因子
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.
研究领域:
药理学
·
皮肤病学
·
分子生物学
·
细胞生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Communications Biology
·
2024
·Vol. 7
·期 1
·1-13
·
IF 5.2
Lin Hui,Lin Shuaijun,Shi Liuhong,Xu Guangsen,Lin Manjie,Li Supeng,Chen Jiale,Li Zhiquan,Nakazibwe Catherine,Xiao Yunbei,Li Xiaokun,Pan Xuebo,Wang Cong
The acquisition of ectopic fibroblast growth factor receptor 1 (FGFR1) expression is well documented in prostate cancer (PCa) progression, notably in conferring tumor growth advantage and facilitating metastasis. However, how FGFR1 contributes to PCa progression is not fully revealed. Here we report that ectopic FGFR1 in PCa cells promotes transferrin receptor 1 (TFR1) expression and expands the labile iron pool (LIP), and vice versa. We further demonstrate that FGFR1 stabilizes iron regulatory proteins 2 (IRP2) and therefore, upregulates TFR1 via promoting IRP2 binding to the IRE of TFR1. Deletion of FGFR1 in DU145 cells decreases the LIP, which potentiates the anticancer efficacy of iron chelator. Intriguingly, forced expression of IRP2 in FGFR1 depleted cells reinstates TFR1 expression and LIP, subsequently restoring the tumorigenicity of the cells. Together, our results here unravel a new mechanism by which FGFR1 drives PCa progression and suggest a potential novel target for PCa therapy.
研究领域:
肿瘤学
·
细胞生物学
·
分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
VETERINARY MICROBIOLOGY
·
2025
·
IF 2.7
Qing Yang,Shengda Xie,Yundi Zhao,Xinxin Lin,Ning Wei,Miaolei Shi,Ruibing Cao
Japanese encephalitis virus (JEV) is a zoonotic pathogen that can be transmitted to humans and animals via arthropods, causing viral encephalitis. In this study, we investigated the role of transferrin receptor 1 (TfR1) in JEV infection. We found that knocking down TfR1 expression in A549 and HeLa cells significantly inhibited JEV entry, while overexpression of TfR1 in 293 T cells enhanced viral entry. The JEV E protein interacts with TfR1, specifically via the protease-like domain (residues 384–606). Additionally, the hTfR1 soluble ectodomain protein significantly blocked JEV infection in HeLa cells, and ferric ammonium citrate (FAC), an iron supplement, downregulated TfR1 expression and effectively inhibited JEV entry and infection. These findings identify TfR1 as an entry factor for JEV and a potential antiviral target, suggesting that small molecule inhibitors like FAC could offer a promising antiviral strategy.
研究领域:
病毒学
·
分子生物学
·
免疫学
·
传染病学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
JOURNAL OF COLLOID AND INTERFACE SCIENCE
·
2025
·
IF 9.7
Yiran Qian,Xiaoxi Chang,Mingyang Sun,Yunqi Chen,Jiachen Zang,Chenyan Lv,Guanghua Zhao,Tuo Zhang
Bioactive peptides have attracted significant attention for their potential health benefits; however, their oral administration is challenged by degradation from digestive proteases and limited intestinal absorption. In this study, we demonstrated the exceptional gastrointestinal stability of ferritin nanocages, which remained largely intact after 30 min of simulated gastric digestion and were highly resistant to intestinal proteolysis. Consistent with in vitro findings, orally administered ferritin successfully reached the intestinal tract without significant degradation in mice. We engineered a fusion protein by linking a glucagon-like peptide-1 (GLP-1) motif to the C-terminus of heteropolymer ferritin, generating HLG. Through Caco-2 monolayer assays, we confirmed that HLG absorption occurs primarily via TfR1-mediated endocytosis, followed by lysosomal trafficking and subsequent release of bioactive GLP-1. Oral administration of HLG significantly reduced blood glucose levels and food intake in type 2 diabetic mice, whereas the GLP-1 analog exenatide alone showed no such effects. These findings highlight the potential of ferritin-based nanocages as an effective oral delivery platform for bioactive peptides.
研究领域:
纳米医学
·
药剂学
·
分子药理学
·
生物材料
·
消化系统疾病
·
药物递送
·
代谢性疾病
✓ 已验证
产品关联
DOI
PubMed
高影响因子
MOLECULAR PHARMACEUTICS
·
2022
·
IF 5.364
Yixin Dong,Kun Yang,Zicheng Xu,Xun Li,Fei Wang,Yu Zhang
The application of drug delivery systems based on ferritin nanocarrier has been developed as a potential strategy in cancer therapy. The limited permeability of ferritin remains a challenge for drug penetration into the deeper tumor tissues. CendR peptides have been reported to bear tumor-specific penetration by recognizing neuropilin (NRP-1) receptor that overexpressed on a wide range of cancer cells. Herein, we modified CendR peptide L(RGERPPR), its retro-inverso peptide D(RPPREGR), and inverso peptide D(RGERPPR) on the outer surface of human H chain ferritin by sulfhydryl-maleimide coupling reaction. Approximately 45 paclitaxel (PTX) molecules could be loaded into each ferritin inner cavity by a thermal-triggered method at a specific ionic strength. The penetration ability of three peptide-modified ferritin constructs showed that D(RGERPPR)-modified HFtn was able to be engulfed by A549 and MCF-7 tumor cells and spheroids at the highest level. Due to the dual-targeting effect of ferritin and modified peptides, the PTX-loaded nanocomposites could effectively enter the cells with high expression of TfR1 and NRP-1 receptors and enhanced the cytotoxicity against tumor cells. Remarkably, H-D(RGE)-PTX displayed a superior tumor growth suppression efficacy in A549 tumor-bearing nude mice. The inverso CendR peptide-modified HFtn nanocarrier was first generated and could provide an effective dual-targeting platform for treatment of cancers.
研究领域:
药学
·
癌症研究
·
纳米技术
·
分子生物学
✓ 已验证
DOI
PubMed
高影响因子
Acta Pharmaceutica Sinica B
·
2024
·
IF 14.7
Danni Liu,Yaoqi Wang,Qi Sun,Dong Mei,Xiaoling Wang,Yan Su,Jie Zhang,Ran Huo,Yang Tian,Siyu Liu,Shuang Zhang,Chunying Cui
Ferroptosis has received great attention as an iron-dependent programmed cell death for efficient cancer therapy. However, with the accumulation of iron in tumor cells, the antioxidant system is activated by reducing glutathione (GSH) with glutathione peroxidase 4 (GPX4), which critically limits the ferroptosis therapeutic effect. Herein, an iron and GPX4 silencing siRNA (siGPX4) co-encapsulated ferritin nanocage (HFn@Fe/siGPX4) was developed to enhance ferroptosis by disruption of redox homeostasis and inhibition of antioxidant enzyme synergistically. The siGPX4 were loaded into the nanocages by pre-incubated with iron, which could significantly improve the loading efficiency of the gene drugs when compared with the reported gene drug loading strategy by ferritin nanocages. And more iron was overloaded into the ferritin through the diffusion method. When HFn@Fe/siGPX4 was taken up by human breast cancer cell MCF-7 in a TfR1-mediated pathway, the excess iron ions in the drug delivery system could for one thing induce ferroptosis by the production of reactive oxygen species (ROS), for another promote siGPX4 escaping from the lysosome to exert gene silencing effect more effectively. Both the in vitro and in vivo results demonstrated that HFn@Fe/siGPX4 could significantly inhibit tumor growth by synergistical ferroptosis. Thus, the developed HFn@Fe/siGPX4 afforded a combined ferroptosis strategy for ferroptosis-based antitumor as well as a novel and efficient gene drug delivery system.
研究领域:
癌症治疗
·
纳米技术
·
基因递送
·
细胞生物学
·
肿瘤学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Nanoscale
·
2022
·Vol. 14
·期 17
·6449-6464
·
IF 8.307
Ziwei Yuan,Bin Wang,Yilong Teng,William Ho,Bin Hu,Kofi Oti Boakye-Yiadom,Xiaoyang Xu,Xue-Qing Zhang
Gene therapy holds tremendous potential for the treatment of incurable brain diseases including Alzheimer's disease (AD), stroke, glioma, and Parkinson's disease. The main challenge is the lack of effective gene delivery systems traversing the blood–brain barrier (BBB), due to the complex microvessels present in the brain which restrict substances from the circulating blood passing through. Recently, increasing efforts have been made to develop promising gene carriers for brain-related disease therapies. One such development is the self-assembled heavy chain ferritin (HFn) nanoparticles (NPs). HFn NPs have a unique hollow spherical structure that can encapsulate nucleic acid drugs (NADs) and specifically bind to cancer cells and BBB endothelial cells (BBB ECs) via interactions with the transferrin receptor 1 (TfR1) overexpressed on their surfaces, which increases uptake through the BBB. However, the gene-loading capacity of HFn is restricted by its limited interior volume and negatively charged inner surface; therefore, these drawbacks have prompted the demand for strategies to remould the structure of HFn. In this work, we analyzed the three-dimensional (3D) structure of HFn using Chimera software (v 1.14) and developed a class of internally cationic HFn variants (HFn+ NPs) through arginine mutation on the lumenal surface of HFn. These HFn+ NPs presented powerful electrostatic forces in their cavities, and exhibited higher gene encapsulation efficacy than naive HFn. The top-performing candidate, HFn2, effectively delivered siRNA to glioma cells after traversing the BBB and achieved the highest silencing efficacy among HFn+ NPs. Overall, our findings demonstrate that HFn+ NPs obtained by this genetic engineering method provide critical insights into the future development of nucleic acid delivery carriers with BBB-crossing ability.
研究领域:
生物医学工程
·
分子生物学
·
神经科学
·
药学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
International Journal of Nanomedicine
·
2025
·
IF 6.5
Zhecheng Yu,Zeya Zhou,Yunqi Zhao
Background Cancer immunotherapy has achieved great success in breast cancer treatment in recent years. The Programmed Death-1 (PD-1) /Programmed Death-Ligand 1 (PD-L1) immune checkpoint pathway is among the most studied. BMS-1166, a PD-L1 inhibitor, can interfere with PD-1 and PD-L1 interaction. Transferrin Receptor 1 is a transmembrane glycoprotein overexpressed in various cancer cells, including breast cancer, and can specifically interact with the T7 (HAIYPRH) peptide.Purpose This study hypothesized that BMS-1166-loaded T7-modified poly(ethylene glycol)-poly(ε-caprolactone) (PEG-PCL) polymeric micelles (BMS-T7) could block PD-L1 interaction with PD-1, serving as a targeted immunotherapy for TfR1-positive breast cancer.Methods BMS-1166 was encapsulated in T7-PEG-PCL micelle. Particle size and zeta potential were determined by dynamic light scattering. Particle morphology was studied by transmission electron microscopy. The particles were characterized by Fourier transform infrared, thermogravimetric analysis, and differential scanning calorimetry. Drug encapsulation efficiency, loading degree, and release profile were examined by high-performance liquid chromatography. Human breast cancer MDA-MB-231 was used to test the cytotoxicity. Flow cytometry and immunofluorescence imaging were used to study the PD-L1 inhibition in cell surface and exosomes. MDA-MB-231 and Jurkat co-culture studied T-cell activation and apoptosis.Results The particle size of the empty and drug-loaded micelles showed a size distribution with an average diameter of 54.62 ± 2.28 nm and 60.22 ± 2.56 nm, respectively. The encapsulation efficiency of BMS-T7 was 83.89 ± 5.59%. The release half-life of drug-loaded micelles was 48h. The IC50 of BMS-1166 was 28.77 μM in MDA-MB-231 cells. In addition, the BMS-T7 showed a better inhibitory effect on PD-L1 expression in breast cancer cells and exosomes than the naked drug. The formulation significantly restored T-cell function compared to the BMS-1166 treatment.Conclusion These results provide preliminary evidence indicating that BMS-T7 may have the potential to deliver drugs to breast cancer cells via active targeting and hold great promise in cancer immunotherapy drug delivery applications.
研究领域:
肿瘤学
·
药学
·
免疫学
·
纳米技术
✓ 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）