International Journal of Nanomedicine
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2025
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IF 6.5
Yabing Xing,Wentao Hu,Yuxin Li,Yuru Zhang,Yulu Zhang,Binghua Wang,Xinhong Guo
Purpose 2-Methoxyestradiol (2-ME) has been demonstrated to possess extensive antitumor effects; however, various challenges have impeded its clinical utilization. In this study, we aimed to design a novel oral delivery system for 2-ME using a dual-target modification strategy to address the inherent drawbacks associated with poor absorption and rapid elimination, as well as to enhance oral bioavailability and antitumor effects.Methods Mannose(M)-modified zein (MZ) and cysteine(C)-modified zein (CZ) were synthesized. Glucose transporter (GLUT)-targeted adhesive nanoparticles (NPs), designated as 2-ME-CMZ (1:1:9)-NPs, were prepared via a solvent evaporation method using MZ, CZ, and Zein at a mass ratio of 1:1:9. Their in vitro and in vivo properties, including in vitro release, adhesion, antitumor effects etc. were evaluated.Results Compared with 2-ME-NPs, 2-ME-CMZ (1:1:9)-NPs showed a 3.89-fold increase in mucin adsorption in simulated intestinal fluid (SIF), a 0.61-fold extension of mean residence time (MRT), and a 1.2-fold increase in Caco-2 cell uptake, thereby prolonging the maintenance time of effective concentration (MTEC) after single-dose administration by 2.53-fold and enhancing oral bioavailability by 3.7-fold and tumor growth inhibition rate by 1.06-fold. Interestingly, for 2-ME-CMZ (1:1:9)-NPs, their cellular uptake was related to the mediation of multiple subtypes of GLUT with relative specificity, and they significantly enhanced the original cellular uptake pathway of 2-ME-NPs and showed higher tumor distribution than 2-ME-NPs. However, merely modifying 2-ME-NPs with mannose only increased the oral bioavailability of 2-ME-NPs by 0.44-fold.Conclusion Compared with 2-ME-NPs, 2-ME-CMZ (1:1:9)-NPs significantly enhanced absorption through the mediation of multiple subtypes of GLUT, enhancing their original cellular uptake pathway and prolonging absorption time. These findings demonstrated that 2-ME-CMZ (1:1:9)-NPs are an extremely promising oral drug delivery system for 2-ME, and endowing GLUT-targeted drug-loaded nanoparticles with adhesion is an effective strategy for fully leveraging the role of GLUT in mediating oral absorption.
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ACS Applied Materials & Interfaces
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2025
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IF 8.2
Zunjie Zhang,Bingcheng Ge,Mengran Liu,Tianfang Yang,Shuaitong Wang,Yang Liu,Yingjie Yang,Shuyan Gao
The electrocatalytic reduction reaction of nitrate (NO3RR) is anticipated to convert nitrogen-containing pollutants into valuable ammonia products. Copper-based catalysts have received great attention because of their good performance in the NO3RR due to the strong binding energy with *NO3 intermediates. However, the poor H2O dissociation ability of Cu is unable to provide H• in time for the hydrogenation reaction of NOx, thus hindering the electroreduction of the NO3–. Herein, we designed a shell–core nanocube electrocatalyst Cu2O@Ni(OH)2-x (x represents the molar ratio of Ni/Cu) using the liquid phase reduction combined with the etching and precipitation method for electrocatalytic NO3RR. Due to the synergistic effect between the strong nitrate activation ability of Cu and the excellent H2O dissociation ability of Ni(OH)2, Cu2O@Ni(OH)2-3.3% shows an impressive ammonia yield rate (557.9 μmol h–1 cm–2) and Faradaic efficiency (97.4%) at −0.35 V vs. RHE. Operando Raman and Auger electron spectroscopy observe the reduction of Cu2O to Cu during the NO3RR process. Density functional theory calculations combined with electron paramagnetic resonance analysis reveals that Ni(OH)2 can lower the activation energy barrier of H2O dissociation, thereby promoting the generation of H• and accelerating the hydrogenation of *NO during the NO3RR. This research provides an efficient Cu-based catalyst for reducing NO3– and may motivate the development of effective ammonia electrocatalysts for further experimentation.
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FASEB JOURNAL
·
2025
·Vol. 39
·期 11
·e70691
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IF 4.2
Jianfeng Dong,Wen Chen,Shujuan Chang,Nana Liu,Wei Zhu,Li Ma,Jing Qiao,Yuhang Wang,Zhiyong Mao,Jiuhong Kang
Infants born with fetal growth restriction (FGR) are at increased risk of cognitive impairment in later life, yet the underlying mechanisms remain poorly understood, hampering clinical treatment development. Utilizing a FGR mouse model induced by prenatal dexamethasone overexposure, we observed impaired hippocampal dendritic maturation, synaptic plasticity, and hippocampal‐dependent learning and memory in FGR mice. FGR induces DNA hypomethylation in the hippocampal H19/Igf2 imprinted control region, resulting in reduced expression of Igf2, a key metabolic modulator previously implicated in FGR‐related placental and fetal growth. Using a neuron‐specific knockout mouse model, we validated the necessity of Igf2 for dendritic maturation and synaptic plasticity. Importantly, overexpression of Igf2 in the hippocampus of FGR mice improved synaptic plasticity and enhanced learning and memory abilities. Furthermore, running exercise ameliorated DNA hypomethylation driving Igf2 expression levels and counteracted synaptic and cognitive deficits in FGR mice through hippocampal Igf2. These findings unveil a molecular mechanism linking exercise‐induced epigenetic changes in the imprinting gene Igf2 to enhanced synaptic plasticity, ultimately leading to improved cognition in FGR offspring. Our results identify Igf2 as a potential mediator bridging metabolic dysfunction and cognitive impairments in FGR offspring and also propose that exercise represents a promising nondrug intervention for FGR‐related cognitive disorders. Fetal growth restriction (FGR) induces hippocampal DNA hypomethylation and loss of Igf2, contributing to impaired synaptic plasticity and cognitive deficits in offspring. Exercise restores Igf2 levels and rescues these impairments, suggesting a potential therapeutic strategy for FGR‐related cognitive dysfunction.
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JOURNAL OF CELLULAR AND MOLECULAR MEDICINE
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2025
·Vol. 29
·期 6
·e70470
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IF 4.2
Chuchu Xu,Renjun Zhu,Qingfeng Dai,Yaoqing Li,Gengyuan Hu,Kelong Tao,Yuhong Xu,Guangen Xu,Guolin Zhang
The main reason for the failure of chemotherapy therapies based on 5-Fluorouracil (5-Fu) is the development of resistance to 5-Fu in cancer patients, particularly those with colorectal cancer. Tissue inhibitor of metalloproteinases 2 (TIMP-2) has been shown to be associated with colorectal cancer (CRC), but its correlation with 5-Fu resistance in colorectal cancer has not been thoroughly studied. We screen the expression of different cytokines through Cytokine array. CCK-8 assay was conducted to evaluate the IC 50 of 5-Fu and cell proliferation. ELISA and RT-qPCR were performed to detect TIMP-2 expression levels in cells and patient serum. Western blotting was utilised to analyse the differences in the expression of proteins related to signalling pathways in cells. Through cytokine array screening, we found that the expression of TIMP-2 was significantly increased in CRC drug-resistant cell lines. In addition, the expression of TIMP-2 in the serum of patients with CRC resistance to 5-Fu was significantly increased. Subsequent mechanistic experiments showed that TIMP-2 regulated the resistance of CRC cells to 5-Futhrough the JAK–STAT signalling pathway. Moreover, anti-TIMP-2 antibody or small molecule drug LY2784544 targeting the JAK–STAT signalling pathway can effectively reverse the resistance of CRC cells to 5-Fu. It is exactly TIMP-2 that mediates the resistance of CRC to 5-Fu through the JAK–STAT signalling pathway. Targeting drugs for TIMP-2 or the JAK–STAT signalling pathway are expected to be opportunities to reverse 5-Fu resistance in CRC.
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ACS Synthetic Biology
·
2025
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IF 3.9
Bicheng Yu,Wei Song,Shenjie Wang,Wanqing Wei,Guipeng Hu,Xiaomin Li,Cong Gao,Jia Liu,Jian Wen,Jing Wu
2-Pyrrolidone is an important chemical intermediate with broad applications in the materials and pharmaceutical industries. Traditional petrochemical synthesis methods pose significant environmental challenges. In the case of biosynthesis, the limited thermostability of coenzyme A ligase (CaiC) represents a major barrier to industrial-scale production. This study focused on enhancing the thermostability and catalytic efficiency of EcCaiC through protein engineering. Conserved sequences were identified, and flexible regions were targeted for virtual mutagenesis using FoldX and Rosetta. The resulting mutant, M3, exhibited a 7.86-fold increase in half-life(t1/2) at 55 °C and a Tm of 59.3 °C. Additionally, the catalytic efficiency (kcat/Km) of M3 improved by 52.8%, reaching 5.73 mM–1 s–1 compared to the wild type. Subsequently, EcCaiCM3 was introduced into Corynebacterium glutamicum S9114, with targeted knockout of byproduct synthesis genes. Finally, fed-batch fermentation in a 5 L bioreactor achieved a 2-pyrrolidone yield of 58.28 g/L, a glucose conversion rate of 0.32 g/g, and a productivity of 0.97 g/L/h. This work establishes an efficient biosynthetic platform for 2-pyrrolidone, providing a robust foundation for its industrial production.
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CHEMBIOCHEM
·
2024
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IF 2.6
Chunyu Yan,Wei Zhou,Yan Zhang,Xuelian Zhou,Qinglong Qiao,Lu Miao,Zhaochao Xu
In this study, super-resolution structured illumination microscope (SIM) was used to analyze molecular mechanism of endocytic acidification inhibitors in the SARS-CoV-2 pandemic, such as Chloroquine (CQ), Hydroxychloroquine (HCQ) and Bafilomycin A1 (BafA1). We fluorescently labeled the SARS-CoV-2 RBD and its receptor ACE2 protein with small molecule dyes. Utilizing SIM imaging, the real-time impact of inhibitors (BafA1, CQ, HCQ, Dynasore) on the RBD-ACE2 endocytotic process was dynamically tracked in living cells. Initially, the protein activity of RBD and ACE2 was ensured after being labeled. And then our findings revealed that these inhibitors could inhibit the internalization and degradation of RBD-ACE2 to varying degrees. Among them, 100 nM BafA1 exhibited the most satisfactory endocytotic inhibition (~63.9%) and protein degradation inhibition (~97.7%). And it could inhibit the fusion between endocytic vesicles in the living cells. Additionally, Dynasore, a widely recognized dynein inhibitor, also demonstrated cell acidification inhibition effects. Together, these inhibitors collectively hinder SARS-CoV-2 infection by inhibiting both the viral internalization and RNA release. The comprehensive evaluation of pharmacological mechanisms through super-resolution fluorescence imaging has laid a crucial theoretical foundation for the development of potential drugs to treat COVID-19.
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ChemMedChem
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2025
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IF 3.4
Xinlin Zhu,Qin Li,Junhui Wu,Zhiran Ju
Graphical In recent years, the development of COX-2 inhibitors has shifted from a focus on highly selective inhibition to emphasizes more moderate selectivity. This study presents a potent balanced COX-2 inhibitor, compound 21d, which effectively alleviates histological damage and provides protection against DSS-induced colitis. The severe adverse effects associated with imbalanced cyclooxygenase-2 (COX-2) inhibition continue to pose significant challenges in the development of contemporary anti-inflammatory drugs. In recent years, the approach to COX-2 inhibitor drug development has shifted from a focus on highly selective inhibition of COX-2 to a strategy that emphasizes more moderate selectivity. The amino acid sequence and structural similarities between inducible COX-2 and constitutive cyclooxygenase-1 (COX-1) isoforms present both substantial opportunities and challenges for the design of next generation of balanced COX-2 inhibitors. As part of our ongoing research into the discovering novel and safer COX-2 inhibitors, we reported herein a highly potent and balanced COX-2 inhibitor 21 d (IC 50 value=1.35 μM, selectivity profile (IC 50 (COX-1)/IC 50 (COX-2)=22.34)). In vivo assays demonstrated that 21 d significantly alleviated histological damage and provided robust protection against dextran sulfate sodium (DSS)-induced acute colitis.
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JOURNAL OF COLLOID AND INTERFACE SCIENCE
·
2025
·
IF 9.7
Hong Tang,Zixiao Li,Xun He,Hefeng Wang,Meng Yue,Yujie Yuan,Qiuying Dai,Xiaolan Tang,Shengjun Sun,Dongdong Zheng,Yongsong Luo,Mohamed S. Hamdy,Fatma A. Ibrahim,Tingshuai Li,Xuping Sun,Bo Tang
Seawater electrolysis is a facile, economical, and ecologically friendly approach for large-scale hydrogen production. However, the presence of chloride ions (Cl − ) in seawater can cause severe anode corrosion, which hinders its further application. Herein, a heptafluorotantalate (TaF 7 2− ) intercalated NiFe layered double hydroxide on Ni foam (TF-NiFe LDH/NF) is proposed for efficient and durable alkaline seawater oxidation (ASO). Such TF-NiFe LDH/NF requires an overpotential of only 375 mV to achieve a current density ( j ) of 1 A cm −2 and maintains stable operation for 1000 h at a j of 1.5 A cm −2 . In situ Raman characterization and stability tests indicate that TaF 7 2− can not only facilitate the dynamic reconstruction process of the catalyst but also effectively repels Cl − at ampere-level j . This study highlights a novel anion (TaF 7 2− ) intercalation strategy, providing new insights into the design of efficient and stable electrocatalysts, thus offering a new approach to enhance corrosion resistance for ASO.
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COLLOIDS AND SURFACES A-PHYSICOCHEMICAL AND ENGINEERING ASPECTS
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2025
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IF 5.4
Weiwang Chen,Rui Du,Xinrong Guo,Tianyao Jia,Ziling Cai,Xiaomeng Zhou
An aqueous emulsion of 2-bromo-3,3,3-trifluoropropene (2-BTP), referred to as 2-BTP/W, was developed for fire extinguishing applications. It had overcome the immiscibility between 2-BTP and water by using an anionic surfactant. The results showed that a surfactant concentration of 4 % was preferred for achieving a stable, uniformly dispersed emulsion over an extended period. The emulsion displayed a narrow droplet size distribution, with 79 % of the population below 10 μm. Fire suppression performance of the emulsion was then evaluated. The shortest fire extinguishing time for the wood crib and n-heptane pool fires were 3.9 s and 0.8 s, respectively. These were achieved with minimum emulsion consumption of 193.5 mL and 21.3 mL, in conjunction with peak cooling rates of 210 °C/s and 325 °C/s. The synergistic factor ranged from 0.05 to 0.4, significantly lower than that of other reported synergistic agents. By combining rapid chemical inhibition with efficient physical cooling, the emulsion agent offers an enhanced fire suppression performance with reduced agent consumption.
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iScience
·
2022
·
IF 6.107
Yang Liu,Gong-ming Gao,Kai-yuan Yang,Lu-ming Nong
Summary Intervertebral disc (IVD) degeneration, which is common among elderly individuals, mainly manifests as low back pain and is caused by structural deterioration of the nucleus pulposus (NP) due to physiological mechanical stress. NP mesenchymal stem cells (NPMSCs) around the IVD endplate have multidirectional differentiation potential and can be used for tissue repair. To define favorable conditions for NPMSC proliferation and differentiation into chondroid cells for NP repair, the present study simulated periodic mechanical stress (PMS) of the NP under physiological conditions using MSC chondrogenic differentiation medium and recombinant human BMP-2 (rhBMP-2). rhBMP-2 effectively promoted NPMSC proliferation and differentiation. To clarify the mechanism of action of rhBMP-2, integrin alpha 1 (ITG A1) and BMP-2 were inhibited. PMS regulated the BMP-2/Smad1/RUNX2 pathway through ITG A1 and promoted NPMSC proliferation and differentiation. During tissue-engineered NP construction, PMS can effectively reduce osteogenic differentiation and promote extracellular matrix protein synthesis to enhance structural NP recovery.
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CYTOKINE
·
2025
·
IF 3.7
Yuxi Huang,Piaorong Zeng,Tianmin Liu,Mei Xu,Wenyi Tang,Fangyuan Cheng,Zhijuan Zhou,Bairong Chen,Kan Liu,TouKun Chong,Jian Chen
Background Takotsubo syndrome (TTS) and sepsis often co-occur with poor outcomes, yet their underlying molecular mechanisms remain to be elucidated. Transcriptomic analysis is employed to detect diagnostic biomarkers and reveal shared pathophysiological mechanisms in sepsis-associated TTS. Methods Myocardial gene expression data (TTS, sepsis, and controls) from GEO were analyzed to identify shared differentially expressed genes. WGCNA and PPI networks were used for candidate gene selection. Key genes were further refined using random forest and LASSO algorithms. Immune cell infiltration was assessed using CIBERSORT. Myocardial injury and gene expression in rat models were evaluated using HE staining, TUNEL assay, immunohistochemistry, qPCR, and Western blotting. Clinical validation was conducted using plasma samples from the China TTS Registry. t -tests and ANOVA were conducted via GraphPad Prism 8 software. A P -value < 0.05 was considered statistically significant. Results Lipocalin-2 (LCN2) was recognized as an important biomarker through WGCNA, PPI network analysis, and machine learning algorithms, showing strong predictive performance. Its expression was significantly associated with neutrophil infiltration and myocardial injury in TTS. Consistent with the bioinformatics findings, the TTS-sepsis comorbidity model showed elevated mRNA and protein levels of LCN2 in myocardial tissue, accompanied by increased neutrophil infiltration and severe cardiac injury. Clinical validation confirmed elevated plasma LCN2 levels in patients with sepsis-associated TTS, correlating with neutrophil counts, NT-proBNP, and cTnI levels. Conclusion LCN2 is identified as a key inflammatory mediator linking neutrophil-driven inflammation to myocardial injury in sepsis-associated TTS, with dual potential as a diagnostic biomarker and therapeutic target.
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iScience
·
2022
·
IF 6.107
Jian Zhang,Jing Chen,Yufei Lu,Yan Yang,Weize Chen,Bo Shen,Jiachang Hu,Ping Jia,Sujuan Xu,Yiqin Shi,Yichun Ning,Jialin Wang,Yi Fang,Shuan Zhao,Yang Li,Yan Dai,Xiaoyan Zhang,Meng Xiang,Yang Tian,Zhichao Liu,Nana Song,Xiaoqiang Ding
Summary TWIK-related acid-sensitive K + channel-2 (TASK-2, encoded by Kcnk5 ) is essential in cell biological processes, by regulating transmembrane K + balance. In the present study, we aimed to clarify the role of TASK-2 in renal fibrosis and explore the underlying mechanism. We found that TASK-2 level was elevated in the renal tubular UUO- and UIR-induced renal fibrosis as well as in patients with renal tubulointerstitial fibrosis. Knockout of Kcnk5 or inhibition of TASK-2 in renal tubules attenuated G2/M cell-cycle arrest and alleviated renal fibrosis. Mechanistically, demethylase fat mass and obesity-associated protein (FTO) reduced N6-adenosine methylation (m6A) of Kcnk5 mRNA following renal fibrosis. FTO deficiency attenuated the upregulation of TASK-2 and renal fibrosis. The results demonstrated the crucial role of TASK-2 in renal fibrosis, which is conducive to a better understanding of the pathogenesis of renal fibrosis. TASK-2 may be a potential treatment strategy to alleviate the development of renal fibrosis.
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