ACTA PHARMACOLOGICA SINICA
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2025
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IF 8.4
Guo Qing,Gan Jun,Wang En-ze,Wei Yu-ming,Xu Jie,Xu Yun,Zhang Fei-fei,Cui Meng,Jia Meng-xing,Kong Ming-jian,Tang Qiong-yao,Zhang Zhe
Patients suffering epilepsy caused by the gain-of-function mutants of the hKCNT1 potassium channels are drug refractory. In this study, we cloned a novel human KCNT1B channel isoform using the brain cDNA library and conducted patch-clamp and molecular docking analyses to characterize the pharmacological properties of the hKCNT1B channel using thirteen drugs. Among cinchona alkaloids, we found that hydroquinine exerted the strongest blocking effect on the hKCNT1B channel, especially the F313L mutant. In addition, we confirmed the antitussive drug tipepidine was also a potent inhibitor of the hKCNT1B channel. Subsequently, we proved that these two drugs produced an excellent therapeutic effect on the epileptic model of KCNT1 Y777H mutant male mice; thus, both could be ready-to-use anti-epileptic drugs. On the other hand, we demonstrated that the activation of the KCNT1 channel by loxapine and clozapine was through interacting with pore domain residues to reverse the run-down of the KCNT1 channel. Taken together, our results provide new insights into the mechanism of the modulators in regulating the KCNT1 channel activity as well as important candidates for clinical tests in the treatment of KCNT1 mutant-associated epilepsy.
研究领域:
神经生物学
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药理学
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分子生物学
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DOI
PubMed
高影响因子
Bio-Design and Manufacturing
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2025
·Vol. 8
·期 3
·423-441
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IF 7.6
Mi Xuelian,Ren Ya,Wang Hanbo,Qiang Lei,Kong Weiqing,Wang Hui,Yang Xue,Liu Yihao,Yang Han,Xiao Di,Ma Zhenjiang,Xu Guoxing,Zhang Changru,Wang Jinwu
In the current settings of osteosarcoma research and drug screening, in vitro three-dimensional (3D) models, which overcome the limitations of traditional models, are favored. In in vitro 3D models, tumor microenvironment simulation, particularly of the mechanical microenvironment, is crucial for estimating the biological effects of a tumor. However, current in vitro osteosarcoma model construction is often limited to a single mechanical signal, which fails to simulate the diversity of osteosarcoma mechanical stimuli. In this study, we utilized embedded bioprinting technology and the multiple response properties of calcium ions in soft and hard stiffness systems with osteosarcoma cell biological functions to construct an integrated gradient biomechanical signal-tailored osteosarcoma model (IGBSTOM). We achieved this by printing a fibrinogen bioink containing calcium ions and osteosarcoma tumor spheroids within an extracellular matrix composed of methacryloylated alginate, methacryloylated gelatin, thrombin, and transglutaminase, which is rich in polysaccharides and proteins and exhibits self-healing properties. Our in vitro and in vivo studies showed that the IGBSTOM enhanced tumor stemness, proliferation, and migration, and successfully reproduced the nest-like structure of tumors, providing an in vitro research platform that is more similar to the natural tumor than the existing models. This study proposes a novel IGBSTOM construction and provides a new strategy for the clinical understanding of tumor development, drug screening, and exploration of drug resistance and metastasis mechanisms.
研究领域:
肿瘤学
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生物医学工程
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细胞生物学
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产品关联
DOI
高影响因子
Acta Pharmaceutica Sinica B
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2025
·
IF 14.6
Jingyu Wang,Xiangning Liu,Rongxin Zhu,Ying Sun,Boyang Jiao,Keyan Wang,Yong Jiang,Yong Wang,Chun Li,Wei Wang
Myocardial fibrosis (MF) is a common pathological hallmark of cardiovascular diseases, reflecting shared mechanisms in their progression. However, the lack of reliable MF models that accurately mimic its pathogenesis has hindered drug discovery, highlighting the urgent need for more effective therapeutic agents. Herein, a novel contractile three-dimensional (3D) myocardial tissue model integrating cardiomyocytes, cardiac-fibroblasts, and bone marrow-derived macrophages in collagen hydrogel was developed to simulate the fibrotic changes of cardiovascular disease, and facilitate the screening of anti-MF compounds. The 3D myocardial tissue model exhibited precise, visualizable, and quantifiable contractile characteristics under hypoxia and drug interventions. 76 compounds extracted from the resins of Toxicodendron vernicifluum , a traditional Chinese medicine with clear clinical benefits for fibrotic diseases, were screened for anti-fibrotic activity. Using an in vitro 3D oxygen–glucose deprivation (OGD)-treated myocardial tissue model instead of a two-dimensional transforming growth factor- β treated cardiac-fibroblasts model, two candidates including LQ-40 and SQ-3 exert impressive anti-MF activity, which was further validated in left anterior descending coronary artery ligation-induced MF mouse model. The current results demonstrate the feasibility and advantage of the novel contractile 3D tissue model with multi-cell types in discovering candidates for MF, further stressing the great potential of regulating macrophages in the treatment of MF.
研究领域:
心血管病学
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药理学
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生物医学工程
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产品关联
DOI
PubMed
高影响因子
RESPIRATORY RESEARCH
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2025
·
IF 5
De-zhi Sun,Xi-ru Yang,Cong-shu Huang,Zhi-jie Bai,Pan Shen,Zhe-xin Ni,Chao-ji Huang-fu,Yang-yi Hu,Ning-ning Wang,Xiang-lin Tang,Yong-fang Li,Yue Gao,Wei Zhou
Background High altitude pulmonary edema (HAPE) poses a significant medical challenge to individuals ascending rapidly to high altitudes. Hypoxia-induced cellular morphological changes in the alveolar-capillary barrier such as mitochondrial structural alterations and cytoskeletal reorganization, play a crucial role in the pathogenesis of HAPE. These morphological changes are critical in understanding the cellular response to hypoxia and represent potential therapeutic targets. However, there is still a lack of effective and valid drug discovery strategies for anti-HAPE treatments based on these cellular morphological features. This study aims to develop a pipeline that focuses on morphological alterations in Cell Painting images to identify potential therapeutic agents for HAPE interventions. Methods We generated over 100,000 full-field Cell Painting images of human alveolar adenocarcinoma basal epithelial cells (A549s) and human pulmonary microvascular endothelial cells (HPMECs) under different hypoxic conditions (1%~5% of oxygen content). These images were then submitted to our newly developed segmentation network (SegNet), which exhibited superior performance than traditional methods, to proceed to subcellular structure detection and segmentation. Subsequently, we created a hypoxia scoring network (HypoNet) using over 200,000 images of subcellular structures from A549s and HPMECs, demonstrating outstanding capacity in identifying cellular hypoxia status. Results We proposed a deep neural network-based drug screening pipeline (CPHNet), which facilitated the identification of two promising natural products, ferulic acid (FA) and resveratrol (RES). Both compounds demonstrated satisfactory anti-HAPE effects in a 3D-alveolus chip model (ex vivo) and a mouse model (in vivo). Conclusion This work provides a brand-new and effective pipeline for screening anti-HAPE agents by integrating artificial intelligence (AI) tools and Cell Painting, offering a novel perspective for AI-driven phenotypic drug discovery. Supplementary Information The online version contains supplementary material available at 10.1186/s12931-025-03173-1.
研究领域:
医学
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生物信息学
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药理学
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产品关联
DOI
PubMed
高影响因子
TALANTA
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2020
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IF 5.339
Xia Wang,Xiuzhu Huo,Ran Yang,Zhaohui Li,Yuanqiang Sun,Lingbo Qu,Huajin Zeng
Long and real time imaging of cell membrane is very important for better understanding of cell performances in physiological and pathological processes. Nowadays, fluorescence probe analysis has become an indispensable tool for monitoring cell membrane. Herein, a novel fluorescent probe based on specific recognition of GABA A receptor was developed for imaging cell membrane. The probe synthesized in this work has been successfully applied to image different kinds of cell membrane with some advantages over the reported probes. Moreover, the probe also showed good superiority in the preliminary screening GABA A drugs.
研究领域:
细胞生物学
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药理学
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生物医学工程
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产品关联
DOI
PubMed
高影响因子
APPLIED BIOCHEMISTRY AND BIOTECHNOLOGY
·
2016
·Vol. 182
·期 2
·482-494
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IF 1.606
Bai Yin,Zhou Wen-Di,Mu Xian-Min,Zhang Qian,Yu Chen,Di Bin,Su Meng-Xiang
Human 17β-hydroxysteroid dehydrogenase type 1 (17β-HSD1), a potential target in breast cancer prevention and therapy, was extracted from human placenta and immobilized on nonporous silica (∼5 μm) with a covalent method for the first time. The optimum initial enzyme concentration and immobilization time during the immobilization process were 0.42 mg mL −1 and 12 h, repectively. The binding was confirmed by scanning electron microscope (SEM) and infrared spectroscopy (FT-IR). It could improve the pH, thermal and storage stability compared to free enzyme. Moreover, the immobilized enzyme could be reused at least four times. A screening method based on it coupled with liquid chromatography–time-of-flight mass spectrometer (LC-TOF/MS) was established, and the half-maximal inhibitory concentration (IC 50) of apigenin for the immobilized enzyme was 291 nM. Subsequently, 10 natural products were evaluated leading to inhibition of the activity of 17β-HSD1 at the concentration of 25 μM, and six of them inhibit the activity over 50%.
研究领域:
生物化学
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药物开发
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肿瘤学
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产品关联
DOI
PubMed
高影响因子
CHEMOSPHERE
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2023
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IF 8.8
Shengya Guo,Xiaoxi Zhang,Yong Zhang,Xinghui Chen,Yiwen Zhang,Bingbing Cao,Daozong Xia
Lead (Pb) contamination is a worldwide public health threaten. Besides close restraint of lead exposure, it's emergency to discover compounds that could help to cue toxicities caused by lead. Zebrafish embryos and early larvae can serve as valuable screening tools in early pre-clinical phase of drug screening and research. In order to establish a zebrafish lead poisoning model that could be used for drug screening and research, zebrafish embryos at 6 h post-fertilization (hpf) were treated with lead at different concentrations by soaking intermittently, raised in lead work solution at night while in fish water during the day. After treated for 90 h, death and severe trunk curvature were observed on zebrafish in 640 μM group, obvious dysplasia, blood toxicity, excessive reactive oxygen species (ROS), severe neurotoxicity, such as shorter length of peripheral motor neurons, neuronal apoptosis, and axonal injury, and neurobehavior impairment were induced by lead at 80, 160 and 320 μM, similar to phenotypes reported in rodent. Moreover, the mRNA level of genes related to neurodevelopment, memory, and antioxidation were significantly down regulated, and apoptosis-related genes were up regulated, consistent to zebrafish phenotypic change. Finally, zebrafish were intermittently exposed to 80 μM lead solution to establish the lead poisoning model, and the efficacy of a safe chelating agent Meso-2,3-Dimercaptosuccinic acid (DMSA) was tested at a series of concentrations to validate the zebrafish model. The result showed concentration-dependent decrease of lead content in zebrafish in DMSA treated groups compared with model group. The above data fully demonstrated a zebrafish model of lead poisoning suitable for drug screening was successfully developed, which was expected to provide a rapid and economic tools for discovering antidotes of lead and drugs of neuroprotection.
研究领域:
毒理学
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神经生物学
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药理学
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产品关联
DOI
高影响因子
JOURNAL OF NANOSCIENCE AND NANOTECHNOLOGY
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2016
·Vol. 16
·期 12
·12460-12469
·
IF 1.338
Hu Yinghui,An Jing,Liu Xiujie,Wang Huiheng,Dai Rongji,Deng Yulin
Enzyme immobilization increases the availability of the enzyme to the substrate with a higher turnover over a considerable period. For this purpose, a variety of mesoporous materials with different diameters were synthesized by various methods using different ratios of P123 (template
agent) to 1,3,5-trimethylbenzene (expanding agent). These versatile materials were then characterized by transmission electron microscopy and N2 adsorption–desorption analysis. α-Glucosidase was successfully immobilized on all the synthesized materials, but the
P123/TMB = 4/3-COOH-PMO material had a higher loading rate and enzyme activity. Furthermore, applications of this material were best performed in a column to immobilize the enzymes. Additionally, the synthesized material was further tested using acarbose as a model compound for drug screening.
The immobilized α-glucosidase was packed into a column and connected to HPLC instrument to screen 20 small molecular compounds. Using this method, several drugs that might strongly inhibit α-glucosidase were identified. Therefore, this method can be further used in
drug screening for chemical drugs and traditional Chinese medicines to expedite new drug research.
研究领域:
生物化学
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药理学
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材料科学
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DOI
高影响因子
SENSORS AND ACTUATORS B-CHEMICAL
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2019
·
IF 6.393
Xinlian Chen,Bing Ji,Xinghua Gao,Mengying Zhang,Chang Xue,Bingpu Zhou,Jinbo Wu
In this study, we successively and parallelly slide a solvent strip on a polydimethylsiloxane microwell array to dilute the solution within the microwells. A total of 60 concentration gradients were generated one by one along the sliding direction within minutes while simultaneously forming 60 microwells with the same concentration perpendicular to the sliding direction. Using theoretical calculations, simulated predictions and experimental verification, we could regulate the concentration gradient on the microwell array by tuning the parameters of the sliding head and sliding speed. Afterwards, we cultured human non-small cell lung cancer cells and produced an anticancer drug concentration gradient on the microwell array by this sliding method. The cell viability was examined to demonstrate the potential of this method for high-throughput cell-based drug testing and screening, and this open microwell array method may enable further analysis during a drug-screening process.
研究领域:
生物工程
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药理学
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细胞生物学
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产品关联
DOI
高影响因子
ACS Nano
·
2023
·
IF 17.1
Junfang Xie,Daobo Han,Shuai Xu,Haitong Zhang,Yonghe Li,Mingshan Zhang,Zhichao Deng,Jianguo Tian,Qing Ye
A high-efficiency drug screening method is urgently needed due to the expanding number of potential targets and the extremely long time required to assess them. To date, high throughput and high content have not been successfully combined in image-based drug screening, which is the main obstacle to improve the efficiency. Here, we establish a high-throughput and high-content drug screening method by preparing a superhydrophobic microwell array plate (SMAP) and combining it with protein-retention expansion microscopy (proExM). Primarily, we described a flexible method to prepare the SMAP based on photolithography. Cells were cultured in the SMAP and treated with different drugs using a microcolumn–microwell sandwiching technology. After drug treatment, proExM was applied to realize super-resolution imaging. As a demonstration, a 7 × 7 image array of microtubules was successfully collected within 3 h with 68 nm resolution using this method. Qualitative and quantitative analyses of microtubule and mitochondria morphological changes after drug treatment suggested that more details were revealed after applying proExM, demonstrating the successful combination of high throughput and high content.
研究领域:
药理学
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生物技术
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显微镜技术
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细胞生物学
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产品关联
DOI
PubMed
高影响因子
ACS Nano
·
2025
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IF 16
Keda Shi,Liang Hu,Duote Cai,Xing Liu,Jilin Zheng,Dongxin Xu,Qunchen Yuan,Qianwen Xiong,Haoran Gong,Xiaoyang Zhu,Ning Hu,Chunlian Qin
Cardiac electrophysiology, particularly intracellular action potential (iAP) recordings, is vital for advancing the understanding and treatment of cardiovascular diseases. In this work, we present a 3D-printed flexible nanosilver electrode array (FlexNEA) that enables simple and efficient circuit fabrication within several minutes using a multimaterial electric-field-driven (EFD) micro-jet 3D printing strategy and achieves over 99% success rates in intracellular access through electroporation. The NEA with flexible property creates an enhanced cell-electrode coupling, with the cardiomyocyte membrane wrapping tightly around the nanosilver electrode, leading to superior signal quality in contrast to the conventional planar electrodes. The 3D-printed FlexNEA enables stable, high-fidelity intracellular recordings by multiple consecutive biosafe electroporations over a short or long period of time. Moreover, the platform exhibits a powerful drug screening function by accurately detecting drug-induced iAP alterations, providing a precise and quantitative assessment of ion-channel drug effects. In summary, the 3D-printed FlexNEA device and integrated biosensing-regulating platform present a significant advance in the high-fidelity intracellular recording technology of cardiac electrophysiology. The platform advances the development of low-cost, biocompatible NEA systems for preclinical research in the cardiology and pharmacology fields.
研究领域:
生物医学工程
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心血管生理学
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药理学
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产品关联
DOI
PubMed
高影响因子
Nature Communications
·
2025
·Vol. 16
·期 1
·1-9
·
IF 15.7
Wu Yu,Li Jian,Jiang Wenxuan,Xu Weiqing,Zheng Lirong,Wang Canglong,Gu Wenling,Zhu Chengzhou
Early drug discovery is a time- and cost-consuming task requiring enzymes. Although nanozymes with metal sites akin to metallocofactors display similar activities, the lack of proximal amino acids hinders them from more adequately mimicking enzymes for drug discovery purposes. Hence, the rational design of the nanozyme second coordination sphere is desirable yet remains challenging. Herein, we report a nanozyme featuring atomically dispersed Cu-N 4 sites with proximal hydroxyl groups (CuNC-OH). Experimental and theoretical results reveal that Cu-N 4 site and hydroxyl respectively behave as cofactor and amino acid of the enzymatic pocket to interact with adsorbates, regulating nanozyme activity and inhibition. This mechanism involving dual sites is similar to that of thyroid peroxidases, which enables specific inhibition of CuNC-OH by antithyroid drugs. Based on these findings, a nanozyme-assisted drug discovery kit is established to analyze inhibition features of thyroid peroxidase inhibitors and screen out promising antithyroid drugs with a significant cost reduction compared with traditional enzyme kits.
研究领域:
生物化学
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药物发现
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材料科学
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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）