BIOORGANIC CHEMISTRY
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2020
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IF 4.831
Jianan Guo,Zhisheng Mi,Xiaoying Jiang,Changjun Zhang,Zili Guo,Linzi Li,Jinping Gu,Tao Zhou,Renren Bai,Yuanyuan Xie
A series of active hybrids combining 3-hydroxypyridin-4(1 H )-one and coumarin pharmacophores were designed and synthesized as potential agents for the treatment of Alzheimer's disease (AD). All the compounds exhibited excellent iron-chelating activities (pFe 3+ = 14.8–19.2) and showed favorable monoamine oxidase B (MAO-B) inhibitory effects compared to the reference drug Pargyline (IC 50 = 86.9 nM). Among them, compound 11 g displayed the best MAO-B inhibitory activity with an IC 50 value of 99.3 nM. Molecular docking analysis showed that compound 11 g could enter the entrance cavity and substrate cavity of MAO-B. Furthermore, the compound 11 g had an excellent antioxidant effect and was capable of protecting from the amyloid- β 1-42 (A β 1-42 ) induced PC12 cell damage. In silico tools were applied for predicting the blood–brain barrier (BBB) penetration and compound 11 g was proved to overcome the brain exposure challenge. In the mice behavioral study, compound 11 g significantly ameliorated cognitive impairment induced by Scopolamine. More importantly, compound 11 g displayed favorable pharmacokinetic profiles in a rat model. In summary, compound 11 g , with both anti-MAO-B and iron-chelating ability, was proved to be a promising potential anti-AD agent for further optimization.
研究领域:
神经科学
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药物化学
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生物化学
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产品关联
DOI
PubMed
高影响因子
JOURNAL OF INORGANIC BIOCHEMISTRY
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2017
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IF 3.348
Qingchun Zhang,Bo Jin,Zhaotao Shi,Xiaofang Wang,Shan Lei,Xingyan Tang,Hua Liang,Qiangqiang Liu,Mei Gong,Rufang Peng
A new tris(dopamine) derivative, containing three dopamine chelate moieties which were attached to a trimesic acid molecular scaffold , has been prepared and fully characterized by NMR , FTIR and HRMS . The solution thermodynamic stability of the chelator with Fe(III), Mg(II), Zn(II) and Fe(II) ions was investigated. Results demonstrated that the chelator exhibited effective binding ability and improved selectivity to Fe(III) ion. The chelator possessed affinity similar to that of diethylenetriaminepentaacetic acid chelator for Fe(III) ion. The high affinity could be attributed to the favorable geometric arrangement between the chelator and Fe(III) ion coordination preference. The chelator also exhibited high antioxidant activity and nontoxicity to neuron-like rat pheochromocytoma cells. Hence, the chelator could be used as chelating agent for iron overload situations without depleting essential metal ions , such as Mg(II) and Zn(II) ions.
研究领域:
药物化学
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生物无机化学
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金属离子螯合研究
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DOI
PubMed
高影响因子
Royal Society Open Science
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2018
·Vol. 5
·期 6
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IF 2.504
Qingchun Zhang,Bo Jin,Xiaofang Wang,Shan Lei,Zhaotao Shi,Jia Zhao,Qiangqiang Liu,Rufang Peng
There is a growing interest in the development of new iron chelators as novel promising therapeutic strategies for neurodegenerative disorders. In this article, a series of mono(catecholamine) derivatives, 2,3-bis(hydroxy)-N-(hydroxyacyl)benzamide, containing a pendant hydroxy, have been synthesized and fully characterized by nuclear magnetic resonance, Fourier transform infrared spectroscopy and mass spectrum. The thermodynamic stability of the chelators with FeIII, MgII and ZnII ions was then investigated. The chelators enable formation of (3 : 1) FeIII complexes with high thermodynamic stability and exhibited improved selectivity to FeIII ion. Meanwhile, the results of 1,1-diphenyl-2-picryl-hydrazyl assays of mono(catecholamine) derivatives indicated that they all possess excellent antioxidant properties. These results support the hypothesis that the mono(catecholamine) derivatives be used as high-affinity chelator for iron overload situations without depleting essential metal ions, such as MgII and ZnII ions.
研究领域:
药理学
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神经科学
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化学
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产品关联
DOI
PubMed
高影响因子
POLYHEDRON
·
2019
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IF 2.284
Qingchun Zhang,Bo Jin,Shufan Feng,Tian Zheng,Xiaofang Wang,Zhicheng Guo,Rufang Peng
There is a growing interest in the development of new iron ligands as novel promising therapeutic strategies for neurodegenerative disorders. In the article, a new tripodal hexadentate tris(dopamine) ligand, containing three dopamine chelate moieties which were attached to a cyanuric chloride molecular scaffold, has been synthesized and fully characterized by NMR, FTIR and MS. The solution thermodynamic stability of the ligand with Fe III , Mg II and Zn II ions was investigated. The results demonstrated that the ligand exhibited effective binding ability and improved selectivity for Fe III ion. The high affinity could be attributed to the favorable geometric arrangement between the ligand and Fe III ion coordination preference. The ligand also exhibited high antioxidant activity. Hence, the ligand could be used as potential chelating agent for iron overload situations.
研究领域:
生物化学
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药物化学
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医学
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产品关联
DOI
高影响因子
Frontiers in Bioengineering and Biotechnology
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2022
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IF 6.064
Liu Peng,Wang Qiang,Li Kuan,Bi Bo,Wen Ying-Fei,Qiu Miao-Juan,Zhao Jing,Li Bin-Bin,Zhang Chang-Hua,He Yu-Long
Iron as an essential element, is involved in various cellular functions and maintaining cell viability, cancer cell is more dependent on iron than normal cell due to its chief characteristic of hyper-proliferation. Despite that some of the iron chelators exhibited potent and broad antitumor activity, severe systemic toxicities have limited their clinical application. Polyaminoacids, as both drug-delivery platform and therapeutic agents, have attracted great interests owing to their different medical applications and biocompatibility. Herein, we have developed a novel iron nanochelator PL-DFX, which composed of deferasirox and hyperbranched polylysine. PL-DFX has higher cytotoxicity than DFX and this effect can be partially reversed by Fe2+ supplementation. PL-DFX also inhibited migration and invasion of cancer cells, interfere with iron metabolism, induce phase G1/S arrest and depolarize mitochondria membrane potential. Additionally, the anti-tumor potency of PL-DFX was also supported by organoids derived from clinical specimens. In this study, DFX-based iron nanochelator has provided a promising and prospective strategy for cancer therapy via iron metabolism disruption.
研究领域:
肿瘤学
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药学
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分子生物学
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产品关联
DOI
PubMed
高影响因子
Communications Biology
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2024
·Vol. 7
·期 1
·1-13
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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
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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
Foods
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2023
·Vol. 12
·期 13
·2521
·
IF 5.2
Xiaobo Li,Miao Zhang,Haizhen Mo,Hongbo Li,Dan Xu,Liangbin Hu
The increasing incidence of diseases caused by highly carcinogenic aflatoxin M1(AFM1) in food demands a simple, fast, and cost-effective detection technique capable of sensitively monitoring AFM1. Recent works predominantly focus on the electrochemical aptamer-based biosensor, which still faces challenges and high costs in experimentally identifying an efficient candidate aptamer. However, the direct electrochemical detection of AFM1has been scarcely reported thus far. In this study, we observed a significant influence on the electrochemical signals of ferric ions at a gold nanoparticle-modified glassy carbon electrode (AuNPs/GCE) by adding varying amounts of AFM1. Utilizing ferricyanide as a sensitive indicator of AFM1, we have introduced a novel approach for detecting AFM1, achieving an unprecedentedly low detection limit of 1.6 × 10−21g/L. Through monitoring the fluorescence quenching of AFM1with Fe3+addition, the interaction between them has been identified at a ratio of 1:936. Transient fluorescence analysis reveals that the fluorescence quenching process is predominantly static. It is interesting that the application of iron chelator diethylenetriaminepentaacetic acid (DTPA) cannot prevent the interaction between AFM1and Fe3+. With a particle size distribution analysis, it is suggested that a combination of AFM1and Fe3+occurs and forms a polymer-like aggregate. Nonetheless, the mutual reaction mechanism between AFM1and Fe3+remains unexplained and urgently necessitates unveiling. Finally, the developed sensor is successfully applied for the AFM1test in real samples, fully meeting the detection requirements for milk.Keywords:aflatoxin M1;electrochemical detection;gold nanoparticles;Fe3+
研究领域:
食品安全
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分析化学
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电化学
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纳米技术
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毒理学
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产品关联
DOI
PubMed
高影响因子
JOURNAL OF NEUROSCIENCE RESEARCH
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2023
·
IF 4.2
Xuying Tan,Ting Zhang,Xuejiao Ding,Xiaopeng Zhao,Qianjun Liu,Zhenglong Xia,Qihua Cao,Feng Yan,Li Chen,Mingwei Zhu,Yaping Tang,Yanyan Song
Oxidative damage and cell death are involved in the pathogenesis of hypoxic–ischemic brain damage (HIBD). Ferroptosis is a newly identified mode of cell death that results from the oxidative damage induced by excessive iron. In HIBD, iron accumulates in brain tissues due to the massive destruction of red blood cells and increased permeability of the blood brain barrier vasculature, which can trigger ferroptosis. Ferroptosis is implicated in various diseases involving neuronal injury; however, the roles of iron and ferroptosis in HIBD have not been identified. In the present study, we investigated the role of iron overload in neuronal ferroptosis both in HIBD rat models and in oxygen- and glucose-deprived (OGD) SH-SY5Y cells. We observed that iron deposition in the cerebral cortex was significantly increased in HIBD rats. Features of ferroptosis such as shrunken mitochondria, increased MDA (malondialdehyde) levels, and reduced solute carrier family 7 member 11 (SLC7A11) and glutathione peroxidase 4 (GPX4) expression were observed in the cerebral cortex of HIBD rats. Administration of an iron chelator in HIBD rats upregulated SLC7A11 expression and alleviated neuronal ferroptosis in cerebral cortex tissue. Additionally, overexpression of SLC7A11 in SH-SY5Y cells increased cell viability and attenuated OGD-induced ferroptosis. Our results demonstrate that iron overload induces neuronal ferroptosis by inhibiting SLC7A11 expression in HIBD. Inhibition of neuronal ferroptosis may be a promising strategy to alleviate brain damage in HIBD.
研究领域:
神经科学
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细胞生物学
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儿科
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药理学
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产品关联
DOI
PubMed
高影响因子
FOOD AND CHEMICAL TOXICOLOGY
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2023
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IF 4.3
Kaiyuan Chen,Yahui Tang,Linhua Lan,Mengxuan Li,Zhongqiu Lu
Acute kidney injury (AKI) induced by diquat (DQ) progresses rapidly, leading to high mortality, and there is no specific antidote for this chemical. Our limited knowledge of the pathogenic toxicological mechanisms of DQ has hindered the development of treatments against DQ poisoning. Pyroptosis is a form of programmed cell death and was recently identified as a novel molecular mechanism of drug-induced AKI. To explore the role of pyroptosis in HK-2 cells exposed to DQ, the plasma membrane damage of the cells was detected by LDH release assay. Western blot was performed to detect the cleavage of GSDME. Proteomics analysis was performed to explore the mechanism of DQ induced nephrotoxicity . FerroOrange probe was used to measure the intracellular Fe 2+ levels. Herein, we show that DQ induces pyroptosis in HK-2 cells. Mechanistically, DQ induces the accumulation of mitochondrial ROS and initiates the cleavage of gasdermin E (GSDME) in an intrinsic mitochondrial pathway. Knockout of GSDME attenuated DQ-induced cell death. Further analysis revealed that loss of FTH1 induces Fe 2+ accumulation, contributing to DQ-induced pyroptosis. Knockdown LC3B could help restore the expression of FTH1 and improve cell viability . Moreover, we found DFO , an iron chelator , could reduce cellular Fe 2+ levels and inhibit pyroptosis. Collectively, these findings suggest an unrecognized mechanism for GSDME-dependent pyroptosis in DQ-induced AKI.
研究领域:
毒理学
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细胞生物学
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肾脏病学
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产品关联
DOI
PubMed
高影响因子
JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY
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2023
·
IF 6.1
Sen Wang,Hui Ren,Chen Fan,Qian Lin,Man Liu,Jun Tian
Mycotoxin ochratoxin A (OTA) is a critical food safety concern due to its nephron-toxic effects and is detected in a wide range of food and feedstuffs. OTA nephrotoxicity is related to oxidative stress and damage. However, the mediator(s) of the excessive oxidative stress is unclear. The current study used human kidney cell lines to investigate whether and how intracellular iron contributed to OTA-induced ROS accumulation and how OTA-induced iron-dependent ferroptotic cell death. Our results showed that OTA treatment affected the cell viability and induced the typical characteristics of cell ferroptosis. Furthermore, gene and protein expression results indicated that OTA disrupted iron homeostasis by upregulating the expression levels of iron importer TFR1 and FTH, while downregulating the expression level of iron exporter FPN and dramatically increasing its negative regulator Hepcidin. The changes were consistent with the induction of intracellular iron accumulation and elevated levels of oxidative stress and lipid peroxidation. Additionally, co-treatment with OTA and an iron chelator significantly improved cell viability, reduced cellular total iron and ROS, and reversed OTA-induced changes in iron metabolism gene expression levels. Interestingly, the addition of a ROS scavenger also reversed cell death and changes in mRNA and protein expression levels of iron metabolism genes but to a lesser degree than that of the iron-chelating agent. Our results revealed that OTA induced ferroptosis in renal cells by disrupting iron homeostasis and increasing ROS.
研究领域:
毒理学
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细胞生物学
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食品安全
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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
·
2021
·
IF 9.229
Lidong Yu,Mingyue He,Sihan Liu,Xinyue Dou,Li Li,Ning Gu,Bingsheng Li,Zhiguo Liu,Guixue Wang,Jianglin Fan
Iron overload is the direct cause of many ferroptosis diseases, and it is essential to maintain iron homeostasis. In this paper, we report the Fe3+ chelation and therapy of the iron overload nonalcoholic fatty liver disease (NAFLD) by the fluorescent egg white-based carbon dots (EWCDs) obtained through the microwave-assisted pyrolysis method. As a high-sensitivity sensor, EWCDs show a high correlation between fluorescence emission and the concentration of Fe3+ (R2 = 0.993) in low concentration ranges of 0–25 μM. In vivo and in vitro, the EWCDs show characteristics of high biocompatibility and specific binding of Fe3+. As a novel type of the nano-iron-chelator, EWCDs can successfully attenuate the production of lethal reactive oxygen species. EWCDs not only alleviate the endoplasmic reticulum stress response but also regulate the NF-κB signaling pathway downstream of the Nrf2 signaling pathway. EWCDs prevent hepatocyte apoptosis, regulate fatty acid metabolism, and alleviate inflammation. Ultimately, they alleviate NAFLD induced by iron overload in zebrafish. This work may provide a new idea and method for the application of carbon dots in the field of disease detection and treatment.
研究领域:
纳米技术
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生物医学工程
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药理学
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病理学
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分子生物学
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肝病学
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产品关联
DOI
PubMed
高影响因子
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