PHARMACOLOGY
·
2019
·
IF 1.615
Chen Xuyang,Li Hui,Luo Hongjun,Lin Zhexuan,Luo Wenhong
Background/Aims: Hydrazone and acylhydrazone derivatives, which are produced from aldehyde reacting with hydrazine or acylhydrazine, have been reported to exhibit antitumor activities. However, the angionenic effects of this kind of derivatives haven’t been elucidated. Here, we synthesized 12 pyridoxal hydrazone and acylhydrazone compounds and investigated their antiangiogenic effects and the underlying mechanisms. Method: 3-(4,5-Dimethylthiazol-2-yl)-2, 5-dipheyltetrazolium bromide assay was used to screen the inhibitory effects of the synthesized compounds on endothelial cells (ECs) proliferation. The compound with best inhibitory effect was further evaluated with wound-healing assay and tube formation assay. Calcein-Am assay was carried out to determine the content of intracellular labile iron pool (LIP). Intracellular reduced glutathione (GSH) was determined by spectrophotometry. Flow cytometry was used to determine cell cycle and apoptosis. Results: Compound 10 (3-hydroxy-5-[hydroxymethyl]-2-methyl-pyridine-4-carbaldehyde-2-naphthalen-1-acetyl hydrazone) showed the best inhibitory effect on human umbilical vascular ECs proliferation, with IC50 value of 25.4 μmol/L. It not only inhibited wound-healing and tube formation of ECs, but also decreased the content of intracellular LIP and GSH. Furthermore, it arrested ECs cycle at S phase and induced cell apoptosis. Conclusions: Compound 10 exhibits antiangiogenic effects by reducing the content of intracellular LIP and GSH, and subsequently arresting cell cycle and inducing cell apoptosis
研究领域:
药理学
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肿瘤学
·
分子生物学
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产品关联
DOI
PubMed
高影响因子
CHEMICO-BIOLOGICAL INTERACTIONS
·
2024
·
IF 4.7
Yan-Ting Lv,Tian-Bin Liu,Yue Li,Zhen-Yong Wang,Cai-Yu Lian,Lin Wang
Cadmium (Cd), a prevalent environmental contaminant, has attracted widespread attention due to its serious health hazards. Ferroptosis is a form of iron-dependent oxidative cell death that contributes to the development of various kidney diseases. However, the mechanisms underlying the occurrence of ferroptosis in Cd-induced renal tubular epithelial cells (TECs) have not been fully elucidated. Hereby, both in-vitro and in-vivo experiments were established to elucidate this issue. In this study, we found that Cd elicited accumulation of lipid peroxides due to intracellular ferrous ion (Fe 2+ ) overload and glutathione depletion, contributing to ferroptosis. Inhibition of ferroptosis via chelation of Fe 2+ or reduction of lipid peroxidation can significantly mitigate Cd-induced cytotoxicity. Renal transcriptome analysis revealed that the activation of heme oxygenase 1 (HO-1) was closely related to ferroptosis in Cd-induced TECs injury . Cd-induced ferroptosis and resultant TECs injury are significantly alleviated due to HO-1 inhibition, demonstrating the crucial role of HO-1 in Cd-triggered ferroptosis. Further studies showed that accumulation of lipid peroxides due to iron overload and mitochondrial ROS (mtROS) generation was responsible for HO-1-triggered ferroptosis in Cd-induced cytotoxicity. In conclusion, the current study demonstrates that excessively upregulating HO-1 promotes iron overload and mtROS overproduction to trigger ferroptosis in Cd-induced TECs injury, highlighting that targeting HO-1-mediated ferroptosis may provide new ideas for preventing Cd-induced nephrotoxicity .
研究领域:
毒理学
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细胞生物学
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肾脏生理学
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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
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分子生物学
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产品关联
DOI
PubMed
高影响因子
ACS Applied Materials & Interfaces
·
2024
·
IF 8.3
Zhenxin Guan,Song Li,Yurong Liu,Xiaokang Zhang,Yunheng Liu,Fangying Zou,Shaojiao Liu,Xinhui Shan,Yu Duan,Li Ma,Jinghui Hu,Jing Chen
Ferroptosis is an iron-dependent cell death pathway triggered by the toxic accumulation of lipid peroxides on cellular membranes. However, an imbalance in iron metabolism in tumor cells leads to the insufficient accumulation of iron ions in the iron pool, which inhibits ferroptosis. Nonspecific delivery of iron species may increase the risk of promoting tumor proliferation as well as trigger undesirable detrimental effects such as anaphylactic reactions in normal tissues. This study found that a constructed self-enhancing targeted nanocarrier can accurately regulate the iron pool levels in tumor cells. We constructed a programmatic targeted enhanced nanotherapy strategy by loading the ferroptosis inducer erastin into a self-enhancing targeted nanocarrier. This nanosystem was more effective at inducing tumor ferroptosis after upregulating the iron pool levels in tumor cells with self-enhancing targeted nanocarriers. Both in vitro and in vivo outcomes demonstrated notable anticancer ferroptosis efficacy, indicating that self-enhancing targeted nanocarriers can effectively regulate the level of the iron pool in tumor cells and promote ferroptosis. The combination of this nanotherapy strategy with self-enhancing targeted chemotherapy nanomedicines can achieve complete tumor clearance. Moreover, this self-enhancing targeted ferroptosis nanotherapy strategy is expected to be beneficial for future progress in the field of cancer self-enhancing targeted therapy.
研究领域:
癌症研究
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纳米技术
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分子生物学
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药学
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治疗学
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产品关联
DOI
PubMed
高影响因子
American Journal of Cancer Research
·
2023
·
IF 5.3
Qi-Tang Huang,Quan-Quan Hu,Zhao-Feng Wen,Yan-Li Li
Since the approval by the Food and Drug Administration (FDA), ferumoxytol and other iron oxide nanoparticles (IONs) have been widely used as iron supplements for patients with iron deficiency. Meanwhile, IONs have also been used as contrast agents in magnetic resonance imaging and as drug carriers. Importantly, IONs have demonstrated a significant inhibitory effect on the growth of tumors, including hematopoietic and lymphoid tumors, such as leukemia. In this study, we further demonstrated the effect of IONs on inhibiting the growth of diffuse large B-cell lymphoma (DLBCL) cells by enhancing ferroptosis-mediated cell death. IONs treatment caused an accumulation of intracellular ferrous iron and the onset of lipid peroxidation in DLBCL cells as well as the suppressed expression of anti-ferroptosis protein Glutathione Peroxidase 4 (GPX4), thereby leading to increased ferroptosis. Mechanistically, IONs increased cellular lipid peroxidation through the generation of ROS via the Fenton reaction and regulating the iron metabolism-related proteins, such as ferroportin (FPN) and transferrin receptor (TFR), which elevated the intracellular labile iron pool (LIP). Hence, our findings suggest the potential therapeutic effect of IONs on the treatment of patients with DLBCL.
研究领域:
肿瘤学
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纳米医学
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血液学
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癌症生物学
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产品关联
DOI
PubMed
高影响因子
PROCESS BIOCHEMISTRY
·
2023
·
IF 4.4
Min Cai,Keqi Gao,Haichan Huang,Xinyue He,Di Jiang,Weihua Jin,Weihong Zhong
A new sulfated polysaccharide (SP7) was obtained and purified from Laminarina japonica with the guidance of kidney protective activity. Analysis of physicochemical features exhibited that SP7 consisted of mannose, amino glucose, rhamnose, glucuronic acid, galactose and fucose at a ratio of 0.82:3.05:2.68:3.11:5.86:1. SP7 had the molecular weight of 4.2 kDa. Cyclophosphamide (CTX) induced oxidative kidney damage mice was used to test the activity and mechanism of SP7 in vivo. Metabolites of CTX caused the over production of reactive oxygen species (ROS). It was found that SP7 inhibited 10 mg/kg CTX-induced renal oxidative damage in mice model. After intraperitoneal injection of SP7 at a dose of 20 mg/kg each day, ferritin heavy chain 1 (FTH1) and glutathione peroxidase 4 (GPX4) protein expression were largely increased ( P < 0.05). TCMK-1 cells incubated with erastin were built as ferroptosis model. Intracellular malondialdehyde (MDA) level was decreased by SP7 treatment time and concentration dependently ( P < 0.05). Electron microscopy showed mitochondria in SP7 treated cells had a 41% increase in length. Test of labile iron pool (LIP) exhibited a 31% decrease of iron concentration in SP7 treated cells. All results proved SP7 would inhibit ferroptosis via downregulating ferritinophagy, which led to a large decrease in kidney oxidative damage.
研究领域:
海洋生物学
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药理学
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生物化学
✓ 已验证
DOI
高影响因子
Theranostics
·
2025
·Vol. 15
·期 17
·9131
·
IF 13.3
Minghao Li,Qiwei Yang,Jie Gao,Xudong Liu,Jihua Shi,Wenzhi Guo,Yi Zhang,Qiwen Yu,Xinzhi Sun,Shuijun Zhang
Background : Acute liver injury (ALI), a highly perilous clinical condition triggered by diverse etiological factors, frequently progresses to acute liver failure with life-threatening consequences. However, due to the limited intervention time window for ALF, donor shortages, challenges in utilizing marginal grafts, surgical complexity and risks, and the high economic burden, developing novel therapeutic strategies targeting ALI-induced ALF has become imperative. Methods : Through transcriptome analysis, we determined that ferroptosis is a key driver in the pathogenesis of ALI. To combat hepatocyte ferroptosis, we designed a novel mitochondria-targeted nanotuner (CPTD) for regulating mitochondrial oxidative stress and iron homeostasis imbalance during ALI. This nanotuner features a cerium oxide (CeO₂) nanozyme core with a polydopamine (PDA) coating, functionalized with triphenylphosphonium (TPP) for mitochondrial targeting and deferoxamine (DFO) for iron chelation. In vitro and in vivo experiments evaluated CPTD's ability to target mitochondria and the labile iron pool (LIP). Results : The nanotuner demonstrates dual regulatory capacity by effectively accumulating in hepatic mitochondria to concurrently scavenge reactive oxygen species (ROS) and sequester labile iron ions, thereby rectifying mitochondrial oxidative stress and iron dyshomeostasis. Comprehensive evaluations across multiple ALI models, mainly including hepatic ischemia-reperfusion injury and acetaminophen-induced hepatotoxicity, revealed that CPTD robustly inhibits ferroptosis, mitigates oxidative damage, attenuates inflammatory responses, and preserves hepatic function. Conclusions : Our findings establish this dual-targeting nanotuner as a promising therapeutic strategy for ALI, providing novel insights into mitochondrial redox and iron homeostasis modulation.
研究领域:
纳米医学
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肝脏病学
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氧化还原生物学
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线粒体生物学
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药物纳米技术
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产品关联
DOI
PubMed
高影响因子
CHEMICAL ENGINEERING JOURNAL
·
2024
·
IF 13.3
Jicheng Jiang,Yan Peng,Liyan Qiu
Ferroptosis is an emerging form of cell death resulting from iron-dependent massive accumulation of lipid peroxides (LPOs). Efficient iron delivery and powerful iron homeostasis disruption remain quite challenging. Herein, we designed a nanovesicle-templated nanogel PCG-Fe/DHA facilitated by the self-assembly of amphiphilic polyphosphazene and the in situ coordination of gallic acid-modified chito-oligosaccharide with Fe 3+ to co-deliver iron and dihydroartemisinin (DHA) for ferroptosis cancer therapy. PCG-Fe/DHA exhibited excellent capability of dual drug loading as well as pH-responsive Fe 3+ release and esterase-responsive DHA release. The concurrent delivery of Fe 3+ and DHA synergistically disrupted intracellular iron homeostasis via the supplementation of exogenous Fe 3+ and DHA-induced ferritin degradation, resulting in a surge in the intracellular labile iron pool to initiate the Fenton reaction. Meanwhile, the intracellular redox homeostasis was disrupted due to the decline of glutathione peroxidase 4 (GPX4) abundance by Fe 3+ -depleting glutathione (GSH). As a result, the intracellular ROS and LPOs were distinctly accumulated, which consequently enhanced ferroptosis of tumor cells. After intravenous injection of PCG-Fe/DHA, the tumor inhibition ratio in 4 T1 breast tumor-bearing mice achieved 76.8 %. In addition the nanogel could target tumor and produce 3.1 times higher magnetic resonance imaging (MRI) signal intensity than free Fe. These evidences indicated that PCG-Fe/DHA platform could provide a dual-modal strategy for ferroptosis cancer therapy and MRI-guided tumor diagnosis.
研究领域:
癌症治疗
·
磁共振成像 (MRI)
·
纳米技术
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细胞生物学
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药学
✓ 已验证
产品关联
DOI
高影响因子
Food & Function
·
2023
·Vol. 14
·期 2
·1087-1098
·
IF 6.1
Chengzhu Song,Dongning Li,Jie Zhang,Xiaoyan Zhao
Imatinib mesylate (IMA) belonging to the selective tyrosine kinase inhibitor family has been proven to induce cardiotoxic effects along with therapeutic strategies. Nrf2-dependent ferroptosis has been implicated in the cardiotoxicity induced by IMA. The present study was designed to investigate the protective effects of berberine hydrochloride (Ber) on cardiac injuries induced by IMA and to explore its potential mechanisms. In H9c2 cells, cell viability, the generation of reactive oxygen species (ROS), mitochondrial membrane potential (MMP) and labile iron pool (LIP) levels were measured. In a mouse model of IMA-induced cardiomyopathy, serum biomarkers and cardiac tissues were examined. A western blot assay was performed to evaluate the expression of ferroptosis-related proteins in vitro and in vivo. Our results indicated that Ber increased cell viability and MMP and decreased cellular ROS and iron levels in comparison to the IMA group of H9c2 cells. In mice, Ber significantly improved cardiac status and attenuated the level of ferroptosis biomarkers including malonaldehyde (MDA) and iron content. Additionally, Ber downregulated the expression of transferrin receptor (TfR) and P53 and upregulated the expression of nuclear factor erythroid 2-related factor 2 (Nrf2), heme oxygenase-1 (HO-1), NAD(P)H quinone oxidoreductase-1 (NQO1), ferritin heavy chain-1 (FTH1), and glutathione peroxidase 4 (GPX4) in H9c2 cells and mice. The present data indicated that Ber has the potential to protect against IMA-induced cardiotoxicity, partly via inhibiting Nrf2-dependent ferroptosis.
研究领域:
药理学
·
心脏病学
·
毒理学
·
细胞生物学
·
分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
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