Chemical Biology & Drug Design
·
2024
·Vol. 103
·期 3
·e14511
·
IF 3.2
Yongpeng Shen,Yilin Cheng,Haotian Hu,Yufeng Liu,Yujie Li,Tianyu Zhu,Defeng Xu,Hang Hu
Docetaxel (DTX) is a semi-synthetic analogue of paclitaxel which has attracted extensive attention in the treatment of cancer. However, the current clinically used DTX formulations display low tumor targeting ability, leading to unsatisfactory therapeutic outcomes with adverse effects, which poses significant challenges to the clinical application. In this study, three galactosamine (Gal) and docetaxel conjugates with different linkers were synthesized, namely DTX-(suc-Gal) 2 , DTX-(DTDPA-Gal) 2 , and DTX-(DSeDPA-Gal) 2 . These three conjugates were characterized by 1 H NMR, FT-IR and HRMS. The in vitro drug release study shows that DTX-(DTDPA-Gal) 2 and DTX-(DSeDPA-Gal) 2 exhibit glutathione (GSH)-responsive drug release and DTX-(DSeDPA-Gal) 2 displays higher GSH-responsiveness. The in vitro antitumor activity study shows that DTX-(DTDPA-Gal) 2 and DTX-(DSeDPA-Gal) 2 exhibit enhanced cytotoxicity, cell apoptosis rate and G2/M phase arrest against HepG2 cells as compared to DTX-(suc-Gal) 2 , DTX-(DSeDPA-Gal) 2 displays the highest cytotoxicity, cell apoptosis rate and G2/M phase arrest among these three conjugates. In addition, DTX-(DSeDPA-Gal) 2 exhibits higher selectivity to HepG2 cells as compared to free DTX. The DTX-(DSeDPA-Gal) 2 developed in this study has been proven to be an effective DTX conjugate for selective killing hepatoma cells.
研究领域:
药理学
·
肿瘤学
·
化学
·
药物递送系统
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DOI
PubMed
高影响因子
Anti-Cancer Agents in Medicinal Chemistry
·
2013
·Vol. 13
·期 8
·1280-1290
·
IF 2.61
Wen Hua Yang,Zhen Zhang,Yang Hu Sima,Jian Zhang,Jian Wen Wang
Glaucocalyxin (Gla) A-C are major ent-kauranoid diterpenoids isolated from Rabdosia japonica var. glaucocalyx, a plant used in Chinese traditional medicine as an antitumor and anti-inflammatory agent. The present investigation was carried out to observe whether cellular reduced glutathione (GSH) plays important roles in Gla -induced cytotoxicity. Among major ent-kauranoid diterpenoids isolated, Gla A and B dose-dependently decreased the growth of HL-60 cells with an IC50 of approximately 6.15 and 5.86 µM at 24 h, respectively. Both Gla A and B could induce apoptosis, G2/M-phase cycle arrest, DNA damage and the accumulation of reactive oxygen species (ROS) in HL-60 cells. Moreover, Gla A, B caused rapid decrease of the intracellular GSH content, while inhibition of cellular GSH synthesis by buthionine sulfoximine (BSO) augmented the induced cytotoxicity and apoptosis in HL-60 cells. On the other hand, the administration of GSH or GSH precursor N-acetyl-cysteine (NAC) could rescue Gla A, B-depleted cellular GSH, and abrogate the induced cytotoxicity, G2/M-phase cycle arrest, DNA damage and ROS accumulation in HL-60 cells. Furthermore, Gla A, B decreased the activity of the GSH-related enzymes including glutathione reductase (GR) and glutathione peroxidase (GPX). These data suggest that the intracellular GSH redox system plays important roles in regulating the Gla A, B-induced cytotoxicity on HL-60 cells.
研究领域:
药理学
·
生物化学
·
肿瘤学
·
细胞生物学
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天然产物化学
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DOI
高影响因子
ECOTOXICOLOGY AND ENVIRONMENTAL SAFETY
·
2025
·
IF 6.1
Huiqi Li,Qizhuan Lin,Huanpeng Liu,Zheyan Chen,Xueliang Zhang,Liyuan Jin,Renyi Peng,Huanzhi Jin
Polystyrene nanoplastics (PS-NPs) and copper ions (Cu²⁺) are common environmental pollutants, yet their combined toxicological effects remain poorly understood. This study demonstrates that PS-NPs act as carriers of Cu²⁺, facilitating intracellular accumulation and inducing cuproptosis, a recently identified form of regulated cell death. Using zebrafish larvae and Hep G2 cells, we showed that co-exposure to PS-NPs and Cu²⁺ disrupted copper homeostasis, promoted DLAT oligomerization, impaired mitochondrial structure and function, and activated the cuproptosis pathway. Molecular docking revealed stable binding of PS-NPs and Cu²⁺ to the key regulator FDX1, further aggravating cuproptosis. FDX1 overexpression experiments confirmed its pivotal role, as enhanced expression significantly increased DLAT aggregation and cell death. This study is the first to reveal the molecular mechanism by which PS-NPs mediate FDX1-dependent cuproptosis via a “Trojan horse” effect. These findings provide novel insights into the mechanisms of nanoplastics–heavy metal co-exposure and offer a potential molecular target for mitigating environmental toxicity.
研究领域:
环境毒理学
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细胞生物学
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纳米毒理学
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生物化学
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分子生物学
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DOI
PubMed
高影响因子
STEROIDS
·
2014
·
IF 2.716
Bin Yu,Ping-Ping Qi,Xiao-Jing Shi,Li-Hong Shan,De-Quan Yu,Hong-Min Liu
A series of novel steroidal pyran–oxindole hybrids were efficiently synthesized in a single operation through the vinylogous aldol reaction of vinyl malononitrile 3 with substituted isatins involving the construction of C–C and C–O bonds. Some compounds displayed moderate to good cytotoxicity against T24, SMMC-7721, MCF-7 and MGC-803 cells. Compounds 4f and 4i were more potent than 5-Fu against T24 and MGC-803 cells with the IC 50 values of 4.43 and 8.45 μM, respectively. Further mechanism studies indicated that compound 4i induced G2/M arrest and early apoptosis in a concentration- and time-dependent manner.
研究领域:
药物化学
·
肿瘤学
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合成化学
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产品关联
DOI
PubMed
高影响因子
ACS Applied Bio Materials
·
2019
·
IF 0
Hongyan Cui,Jing Xia,Liuwei Zhang,Ming Qian,Hao Wang,Jingyun Wang,Qixian Chen
The surface properties of drug/gene delivery systems are critical important to their ultimate therapeutic performance. In the present studies, cytoplasmic membranes deriving from cancerous cells (Hep-G2) were attempted as the external integument onto the polycationic theranostic DNA delivery systems with the aim of diminishing unfavorable biointerfacial reactions of nanomedicine. Herein, a multiple of polycationic oligoethylenimine (OEI) segments were installed onto the surface of luminescent carbon quantum dots (CQD, facile bioimaging utilities) for complexation with plasmid DNA (pDNA) into DNA delivery constructs, followed by surface integument by cytoplasmic membranes. The subsequent investigations verified this strategic integument capable of shielding the unfavorable surface positive net charge of the polycationic DNA delivery constructs and thereby markedly diminishing the potential nonspecific reactions in biological milieu. Leadingly, improved biocompatibilities as well as additional protection of inner vulnerable DNA cargos from enzymatic degradation, have been accomplished. More importantly, preferential affinities to the homologous cells were identified as a result of this membrane integument based on facile fluorescence quantification for the intracellular CQD. Significant higher cellular uptake efficiency for the polycationic constructs based on Hep-G2 membrane integument was confirmed in the homologous Hep-G2 cells in contrast to the heterologous MCF-7 and HeLa cells (approximately 4-fold). Note that this homologous privilege was observed for the delivery constructs not only from cancerous HeLa and MCF-7 membrane integuments but also normal cells (COS-7), heralding the intriguing potentials of this membrane-integument strategy in pursuit of targeting functions. Eventually, gene expression activities were also determined to prevail in the homologous cells. Therefore, our proposed surface integument strategy by homologous cell membrane could imply an alternative facile and versatile avenue in construction of active-targeted nanomedicine.
研究领域:
分子生物学
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纳米医学
·
基因工程
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癌症研究
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药物递送系统
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产品关联
DOI
PubMed
ENVIRONMENTAL SCIENCE & TECHNOLOGY
·
2021
·
IF 9.028
Yun Wu,Wenzhe Wei,Jiayi Luo,Yang Pan,Mengting Yang,Ming Hua,Wenhai Chu,Chendong Shuang,Aimin Li
In recent years, dozens of halogenated disinfection byproducts (DBPs) with cyclic structures were identified and detected in drinking water globally. Previous in vivo toxicity studies have shown that a few new cyclic DBPs possessed higher developmental toxicity and growth inhibition rate than common aliphatic DBPs; however, in vitro toxicity studies have proved that the latter exhibited higher cytotoxicity and genotoxicity than the former. Thus, to provide a more comprehensive toxicity comparison of DBPs from different endpoints, 11 groups of cyclic DBPs and nine groups of aliphatic DBPs were evaluated for their comparative in vitro and in vivo toxicity using human hepatoma cells (Hep G2) and zebrafish embryos. Notably, results showed that the in vitro Hep G2 cytotoxicity index of the aliphatic DBPs was nearly eight times higher than that of the cyclic DBPs, whereas the in vivo zebrafish embryo developmental/acute toxicity indexes of the cyclic DBPs were roughly 48–50 times higher than those of the aliphatic DBPs, indicating that the toxicity rank order differed when different endpoints were applied. For a broader comparison, a Pearson correlation analysis of DBP toxicity data from nine different endpoints was conducted. It was found that the observed Hep G2 cytotoxicity and zebrafish embryo developmental/acute toxicity in this study were highly correlated with the previously reported in vitro CHO cytotoxicity and in vivo toxicity in aquatic organisms (P < 0.01), respectively. However, the observed in vitro toxicity had no correlation with the in vivo toxicity (P > 0.05), suggesting that the toxicity rank orders obtained from in vitro and in vivo bioassays had large discrepancies. According to the observed toxicity data in this study and the candidate descriptors, two quantitative structure–activity relationship (QSAR) models were established, which help to further interpret the toxicity mechanisms of DBPs from different endpoints.
研究领域:
环境科学
·
毒理学
·
化学工程
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产品关联
DOI
PubMed
高影响因子
Scientific Reports
·
2016
·Vol. 6
·期 1
·1-13
·
IF 5.228
Wu Xunxun,Chen Xiaofei,Jia Dan,Cao Yan,Gao Shouhong,Guo Zhiying,Zerbe Philipp,Chai Yifeng,Diao Yong,Zhang Lei
Traditional Chinese Medicine (TCM) has been developed for thousands of years and has formed an integrated theoretical system based on a large amount of clinical practice. However, essential ingredients in TCM herbs have not been fully identified, and their precise mechanisms and targets are not elucidated. In this study, a new strategy combining comprehensive two-dimensional K562/cell membrane chromatographic system and in silico target identification was established to characterize active components from Indigo naturalis , a famous TCM herb that has been widely used for the treatment of leukemia in China, and their targets. Three active components, indirubin, tryptanthrin and isorhamnetin, were successfully characterized and their anti-leukemia effects were validated by cell viability and cell apoptosis assays. Isorhamnetin, with undefined cancer related targets, was selected for in silico target identification. Proto-oncogene tyrosine-protein kinase (Src) was identified as its membrane target and the dissociation constant (Kd) between Src and isorhamnetin was 3.81 μM. Furthermore, anti-leukemia effects of isorhamnetin were mediated by Src through inducing G2/M cell cycle arrest. The results demonstrated that the integrated strategy could efficiently characterize active components in TCM and their targets, which may bring a new light for a better understanding of the complex mechanism of herbal medicines.
研究领域:
药理学
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肿瘤学
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中医
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色谱学
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生物信息学
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产品关联
DOI
PubMed
高影响因子
EUROPEAN JOURNAL OF PHARMACEUTICAL SCIENCES
·
2018
·
IF 3.466
Ali Fan,Jiali Wei,Mengru Yang,Qing Zhang,Yaliang Zhang,Qingwang Liu,Ning Li,Di Zhao,Yang Lu,Junxiu Li,Jie Zhao,Shuhua Deng,Bingjie Zhang,Hailiang Zhu,Xijing Chen
YMR-65, 5-(5-bromo-1-methyl-1H-indol-3-yl)-3-(3-methoxyphenyl)-4, 5-dihydro-1H-pyrazole-1-carboxamide, is a potential tubulin inhibitor exhibiting good anticancer activity. In our study, we illustrated the biological activities in HepG2 cells and the pharmacodynamic and pharmacokinetic profiles were evaluated in murine H22 hepatoma-bearing mice. Molecular docking assay and colchicine competition assay indicated that YMR-65 could bind tightly to the colchicine binding site of tubulin. Further investigation demonstrated that YMR-65 arrested cells in the G2/M phase of cell cycle and induced apoptosis in HepG2 cells. Compared with control group, the tumor growth inhibition determined by final relative volume of tumor/the initial tumor volume were 32.57%, 24.00% and 34.95%, respectively, for YMR-65 (10 mg/kg), YMR-65 (20 mg/kg) and CA4P (10 m/kg) groups. Besides there were no obvious body change or tissue damage (enhanced by histopathology study). YMR-65 administration at 10 and 20 mg/kg in H22 tumor-bearing mice resulted in 1.87- and 1.80-fold longer half time (t 1/2 ) and 0.36- and 0.78-fold lower area under concentration-time curve (AUC 0–∞ ) in plasma in contrast with normal mice at 10 mg/kg. Furthermore, YMR-65 showed a wide distribution to various tissues or tumor and the highest distribution index (the ratio of AUC tissue or tumor /AUC plasma ) was found in tumor, which implied that it might accumulate in tumor after administration. In brief, our results indicated that YMR-65 was a promising candidate with high antitumor efficacy and low tissue damage.
研究领域:
肿瘤学
·
药理学
·
分子生物学
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产品关联
DOI
PubMed
高影响因子
JOURNAL OF SEPARATION SCIENCE
·
2016
·Vol. 39
·期 19
·3789-3797
·
IF 2.741
Jiao Zhao,Yan Zhu,Yang Jiao,Jinyan Ning,Yaling Yang
A novel two-step extraction technique combining ionic-liquid-based dispersive liquid–liquid microextraction with magnetic solid-phase extraction was developed for the preconcentration and separation of aflatoxins in animal feedstuffs before high-performance liquid chromatography coupled with fluorescence detection. In this work, ionic liquid 1-octyl-3-methylimidazolium hexafluorophosphate was used as the extractant in dispersive liquid–liquid microextraction, and hydrophobic pelargonic acid modified Fe 3 O 4 magnetic nanoparticles as an efficient adsorbent were applied to retrieve the aflatoxins-containing ionic liquid. Notably, the target of magnetic nanoparticles was the ionic liquid rather than the aflatoxins. Because of the rapid mass transfer associated with the dispersive liquid–liquid microextraction and magnetic solid phase steps, fast extraction could be achieved. The main parameters affecting the extraction recoveries of aflatoxins were investigated and optimized. Under the optimum conditions, vortexing at 2500 rpm for 1 min in the dispersive liquid–liquid microextraction and magnetic solid-phase extraction and then desorption by sonication for 2 min with acetonitrile as eluent. The recoveries were 90.3–103.7% with relative standard deviations of 3.2–6.4%. Good linearity was observed with correlation coefficients ranged from 0.9986 to 0.9995. The detection limits were 0.632, 0.087, 0.422 and 0.146 ng/mL for aflatoxins B 1 , B2, G1, and G2, respectively. The results were also compared with the pretreatment method carried out by conventional immunoaffinity columns.
研究领域:
分析化学
·
食品安全
·
环境科学
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产品关联
DOI
PubMed
高影响因子
Scientific Reports
·
2025
·Vol. 15
·期 1
·1-18
·
IF 3.9
Su Rishun,Chen Jia,Dai Chen,Yin Songcheng,Chen Haoming,Sun Xuezeng,Fang Zhaoxin,Zhang Changhua,Chen Jingyao,Gu Liang
G2/M checkpoint and P53 pathway are essential in regulating the cell cycle and proliferation of cells, which is related to the progress of tumors. Here, we carried out an integrative analysis of the prognostic genes of these pathways in gastric cancer (GC) and thus developed a molecular subtype. We identified prognostic differential expression genes (PDEGs) of G2/M checkpoint and P53 pathways between normal and tumor tissue in TCGA-STAD and developed a molecular subtype based on PDEGs. Meanwhile, the clinical significance of the molecular subtype was further explored. In addition, a comprehensive model and nomogram based on PDEGs score were constructed and validated by GSE26901 and GSE13861. Gastric cancer cell lines and patients’ specimens were used to validate the expression of selected genes.19 PDEGs were identified from these pathways in TCGA-STAD. Ulteriorly, a PDEGs score model consisting of 4 genes (PVT1, F2R, INCENP, IRAK1) was generated to classify patients into high- and low- PDEGs score subgroups. Patients in low PDEGs score groups had a better prognosis and a higher tumor mutational burden and may be more sensitive to chemotherapy and immunotherapy. Notably, the combination of PDEGs score and clinical features showed a pleasing survival prediction ability. In the GSE13861 cohort, the PDEGs score and its derivative model were confirmed with significant predictive effects in overall survival. Furthermore, these genes were significantly upregulated in both GC cell lines and tumor tissues and F2R was the hub gene resulting in poor survival. This paper has provided a distinct insight for tumor classification predicting prognosis more accurately and having the potential to instruct the use of chemotherapy and immunotherapy for patients with GC.
研究领域:
癌症研究
·
分子生物学
·
生物信息学
·
基因组学
·
肿瘤学
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计算生物学
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医学遗传学
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产品关联
DOI
PubMed
高影响因子
JOURNAL OF APPLIED TOXICOLOGY
·
2021
·Vol. 42
·期 2
·230-243
·
IF 3.446
Yan-ping Liu,Xiao-yan Yuan,Xun-ya Li,Ye Wang,Zhan-bing Sun,Wei-hua Deng,Yuan-di Lei,Lian Huang,Tian-yi Jiang,Zhao-hui Zhang
Beryllium and its compounds are systemic toxicants that are widely applied in many industries. Hydrogen sulfide has been found to protect cells. The present study aimed to determine the protective mechanisms involved in hydrogen sulfide treatment of 16HBE cells following beryllium sulfate-induced injury. 16HBE cells were treated with beryllium sulfate doses ranging between 0 and 300 μM BeSO 4 . Additionally, 16HBE cells were subjected to pretreatment with either a 300 μM dose of sodium hydrosulfide (a hydrogen sulfide donor) or 10 mM DL-propargylglycine (a cystathionine- γ -lyase inhibitor) for 6 hr before then being treated with 150 μM beryllium sulfate for 48 hr. This study illustrates that beryllium sulfate induces a reduction in cell viability, increases lactate dehydrogenase (LDH) release, and increases cellular apoptosis and autophagy in 16HBE cells. Interestingly, pretreating 16HBE cells with sodium hydrosulfide significantly reduced the beryllium sulfate-induced apoptosis and autophagy. Moreover, it increased the mitochondrial membrane potential and alleviated the G2/M-phase cell cycle arrest. However, pretreatment with 10 mM DL-propargylglycine promoted the opposite effects. PI3K/Akt/mTOR and Nrf2/ARE signaling pathways are also activated following pretreatment with sodium hydrosulfide. These results indicate the protection provided by hydrogen sulfide in 16HBE cells against beryllium sulfate-induced injury is associated with the inhibition of apoptosis and autophagy through the activation of the PI3K/Akt/mTOR and Nrf2/ARE signaling pathways. Therefore, hydrogen sulfide has the potential to be a promising candidate in the treatment against beryllium disease.
研究领域:
毒理学
·
细胞生物学
·
药理学
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产品关联
DOI
PubMed
高影响因子
BIOMATERIALS
·
2015
·
IF 8.557
Yang Wang,Ruibo Zhao,Shibing Wang,Zhaoming Liu,Ruikang Tang
Multidrug resistance is one of major obstacles to the effective cancer chemotherapy. To address this issue, we developed the effective circumvention of multidrug resistance in cancer cells by a yolk-shell Fe 3 O 4 @MgSiO 3 nanoplatform with the polymerpoly(ethylene glycol) and folic acid modifications can achieve active targeted delivery of anti-cancer drug by using combined magnetic and ligand targeting . The direct intracellular drug delivery of doxorubicin by nanocarrier was much more effectively than free DOX for multidrug resistant Hep-G2/MDR cancer cells. Besides the excellent biocompatibility, high drug loading efficiency, dual-targeting delivery, and controlled releasing behavior, in vivo experiments demonstrate that this nanocarrier can specifically deliver and concentrate doxorubicin hydrochloride in tumor sites to overcome drug resistance. It follows an alternative strategy for effective chemotherapy against drug resistant cancers by using rationally designed nanomaterial .
研究领域:
癌症研究
·
纳米技术
·
药学
·
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）