Polymer Chemistry
·
2024
·Vol. 15
·期 24
·2513-2527
·
IF 4.1
Shuai Yang,Jinhai Xie,Dongdong Wang,Shuangyu Tian,Yaodong Di,Lesan Yan
The distinct variations in the microenvironment between tumor cells and normal cells have facilitated the feasibility of highly specific and efficient drug delivery at tumor sites. This study is based on the elevated levels of glutathione (GSH) and NAD(P)H quinone oxidoreductase (NQO1 enzyme) in the tumor cells, leading to the development of a novel dual-responsive triblock polyurethane (PEG-PTU-SS-PEG) with heightened sensitivity to stimuli. This biodegradable amphiphilic polyurethane contains disulfide bonds responsive to GSH on the main chain and trimethyl locked benzoquinone structures responsive to NQO1 enzyme on the side chains. The polyurethane forms stable micelles through self-assembly and efficiently encapsulates the hydrophobic drug doxorubicin (DOX). Dynamic light scattering (DLS) and transmission electron microscopy (TEM) results indicate that both blank and drug-loaded micelles can be effectively disrupted upon addition of GSH or Na2S2O4 (simulating the NQO1 enzyme environment in vitro). Furthermore, the in vitro drug release behavior of drug-loaded micelles, cellular uptake, and cytotoxicity experiments demonstrate that in the presence of GSH and NQO1 enzyme, polyurethane nanomicelles can achieve specific and efficient drug release, enhance cytotoxicity against tumor cells, and maintain excellent biocompatibility. Therefore, this newly developed polyurethane nanodrug delivery system has tremendous potential in tumor therapy, offering specific drug release and efficient treatment.
研究领域:
药物递送
·
生物材料
·
肿瘤学
✓ 已验证
产品关联
DOI
高影响因子
BIOMACROMOLECULES
·
2023
·
IF 6.2
Jinhai Xie,Shuangyu Tian,Hanning Zhang,Congshu Feng,Yingchao Han,Honglian Dai,Lesan Yan
The design of nano-drug delivery vehicles responsive to tumor microenvironment stimuli has become a crucial aspect in developing cancer therapy in recent years. Among them, the enzyme-responsive nano-drug delivery system is particularly effective, as it utilizes tumor-specific and highly expressed enzymes as precise targets, leading to increased drug release at the target sites, reduced nonspecific release, and improved efficacy while minimizing toxic side effects on normal tissues. NAD(P)H:quinone oxidoreductase 1 (NQO1) is an important reductase associated with cancer and is overexpressed in some cancer cells, particularly in lung and breast cancer. Thus, the design of nanocarriers with high selectivity and responsiveness to NQO1 is of great significance for tumor diagnosis and treatment. It has been reported that under physiological conditions, NQO1 can specifically reduce the trimethyl-locked benzoquinone structure through a two-electron reduction, resulting in rapid lactonization via an enzymatic reaction. Based on this, a novel reduction-sensitive polyurethane (PEG-PTU-PEG) block copolymer was designed and synthesized by copolymerizing diisocyanate, a reduction-sensitive monomer (TMBQ), and poly(ethylene glycol). The successful synthesis of monomers and polymers was verified by nuclear magnetic resonance (1H NMR) and gel permeation chromatography (GPC). Then, the PEG-PTU-PEG micelles were successfully prepared by self-assembly, and their reductive dissociation behavior in the presence of Na2S2O4 was verified by dynamic light scattering (DLS), 1H NMR, and GPC. Next, the model drug doxorubicin (DOX) was encapsulated into the hydrophobic core of this polyurethane micelles by microemulsion method. It was observed that the drug-loaded micelles could also achieve a redox response and rapidly release the encapsulated substances. In vitro cell experiments demonstrated that PEG-PTU-PEG micelles had good biocompatibility and a low hemolysis rate (<5%). Furthermore, in the presence of an NQO1 enzyme inhibitor (dicoumarol), lower drug release from micelles was observed in A549 and 4T1 cells by both fluorescence microscopy and flow cytometry assays, but not in NIH-3T3 control cells. Predictably, DOX-loaded micelles also showed lower cytotoxicity in 4T1 cells in the presence of NQO1 enzyme inhibitors. These results indicate that drug-loaded polyurethane micelles could accomplish specific drug release in the reducing environment in the presence of NQO1 enzymes. Therefore, this study provides a new option for the construction of polyurethane nanocarriers for precise targeting and reductive release, which could benefit the intracellular drug-specific release and precision therapy of tumors.
研究领域:
药剂学
·
肿瘤学
·
生物材料学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
ENVIRONMENTAL TOXICOLOGY AND PHARMACOLOGY
·
2014
·
IF 1.862
Demei Xu,Lihua Hu,Xiaomin Xia,Jianbo Song,Lingrui Li,Erqun Song,Yang Song
Tetrachlorobenzoquinone (TCBQ) is an active metabolite of pentachlorophenol (PCP). Although PCP has been investigated extensively, there are only a few reports describing the toxicity effect of TCBQ, and no report regarding TCBQ-induced liver injury in vivo . In the current study, we aimed to examine the acute hepatic toxicity of TCBQ in the mice model. Chlorogenic acid (CGA) exhibits promising antioxidant activity in the past studies, thus, the second aim of this study was to evaluate the protective effect of CGA on TCBQ-induced liver injury. Our results indicated TCBQ-intoxication caused marked liver cell necrosis and inflammation but not apoptosis, and this damage was alleviated by CGA treatment. Meantime, TCBQ-intoxication enhanced serum ALT, AST activities, TBIL content, hepatic oxidative stress and lipid peroxidation, decreased GSH content and inhibited the activities of antioxidant enzymes. Western blot and immunohistochemical analysis showed that TCBQ marked up-regulated HO-1 and NQO1 expression. On the other hand, pretreatment of CGA reduced TCBQ-induced liver damage remarkably. Taking together, these results revealed that TCBQ has strong hepatic toxic effect, and at least a part of this effect is initiated by free radical and relieved with CGA administration.
研究领域:
毒理学
·
药理学
·
分子生物学
✓ 已验证
DOI
PubMed
高影响因子
CANCER RESEARCH
·
2024
·Vol. 84
·期 21
·3538-3555
·
IF 12.5
Wang Xinzhi,Qu Yi,Xu Qianqian,Jiang Zeyu,Wang Hang,Lin Binyan,Cao Zehong,Pan Yuqi,Li Sheng,Hu Yili,Yang Hui,He Li,Chang Hang,Hang Bo,Wen Hongmei,Wu Hao,Mao Jian-Hua
Metastasis to the lungs is a leading cause of death for patients with breast cancer. Therefore, effective therapies are urgently needed to prevent and treat lung metastasis. In this study, we uncovered a mechanism by which NAD(P)H:quinone oxidoreductase 1 (NQO1) orchestrates lung metastasis. NQO1 stabilized and upregulated peptidyl-prolyl cis-trans isomerase A (PPIA), a chaperone that regulates protein conformation and activity, by preventing its oxidation at a critical cysteine residue C161. PPIA subsequently activated CD147, a membrane protein that facilitates cell invasion. Moreover, NQO1-induced secretion of PPIA modulated the immune landscape of both primary and lung metastatic sites. Secreted PPIA engaged CD147 on neutrophils and triggered the release of neutrophil extracellular traps (NET) and neutrophil elastase, which enhanced tumor progression, invasiveness, and lung colonization. Pharmacological targeting of PPIA effectively inhibited NQO1-mediated breast cancer lung metastasis. These findings reveal a previously unrecognized NQO1-PPIA-CD147-NET axis that drives breast cancer lung metastasis. Inhibiting this axis is a potential therapeutic strategy to limit lung metastasis in patients with breast cancer. Significance: NQO1 stabilizes and promotes the secretion of PPIA to activate CD147 in neutrophils and stimulate NET formation, promoting breast cancer lung metastasis and providing therapeutic targets for this fatal condition.
研究领域:
癌症生物学
·
免疫学
·
分子生物学
✓ 已验证
DOI
高影响因子
AUSTRALIAN JOURNAL OF CHEMISTRY
·
2023
·Vol. 76
·期 8
·465-475
·
IF 1.1
Dingyue Zhang,Lixia Dong,Wenyong Yang,Kui Wang,Dingyue Zhang,Lixia Dong,Wenyong Yang,Kui Wang
Agrimol B is a small molecule isolated from traditional Chinese herbal medicine with a potential anti-cancer effect. However, the molecular target of agrimol B remains unclear. In this report, we found that agrimol B inhibits the growth of hepatocellular carcinoma (HCC) cells. A combination of network pharmacology strategy, bioinformatics analysis, molecular docking and target validation experiments was performed to identify and verify the protein targets of agrimol B in HCC. Bioinformatics analysis suggests that the activity of agrimol B against HCC was related to a cellular response to chemical stress and oxidative stress, folate biosynthesis, the complement and coagulation cascade and FoxO signaling pathway. We further identified 10 core targets through network pharmacology analysis. Among them, NAD(P)H: quinone dehydrogenase 1 (NQO1) was screened as the most promising target based on a molecular docking analysis. The interaction between agrimol B and NQO1 was corroborated by a cellular thermal shift assay. In addition, agrimol B inhibited the growth of HCC cells by decreasing NQO1 activity. Taken together, we identified NQO1 as a molecular target of agrimol B, which provides a new insight into the anti-cancer mechanism of agrimol B in HCC.
研究领域:
癌症研究
·
药理学
·
分子生物学
·
生物信息学
✓ 已验证
产品关联
DOI
高影响因子
IN VITRO CELLULAR & DEVELOPMENTAL BIOLOGY-ANIMAL
·
2025
·
IF 1.7
Sun Jingchi,Zheng Zhousong
Activated microglia are considered to be closely related to brain senescence and the pathogenesis of neurodegenerative diseases. Ginkgo biloba extract (GBE) is widely used to treat cognitive impairment and Alzheimer's disease (AD). This study aims to investigate the active ingredients of GBE and the underlying molecular mechanisms. The active ingredients of GBE in AD treatment were first analyzed by network pharmacology, culminating in the identification of the key ingredient, quercetin, and its targeted protein, NQO1. GO function enriched the oxidative stress pathway, while KEGG enriched the PI3K/Akt/mTOR pathway. Quercetin binding to NQO1 was verified by molecular docking and DARTS analysis. Cytotoxicity assay revealed no significant toxicity of GBE (0–1 mg/mL) and quercetin (0–0.4 μM) over 48 h. Subsequently, we constructed the microglial injury model by H 2 O 2 -induced HMC3 and BV2 cell lines. GBE and quercetin suppressed the senescence characteristics in H 2 O 2 -induced microglia. Further investigation revealed that the expression of NQO1 was downregulated in the injury model, and treatment with GBE and quercetin facilitated the protein expression of NQO1. In addition, silencing NQO1 reduced the promoting effect of quercetin on microglia viability and phosphorylation levels of PI3K, Akt, and mTOR. At the same time, it significantly increased the levels of p53, p21, p16 and β-galactosidase (SA-β-gal). Collectively, GBE mitigated H 2 O 2 -induced microglial injury, which activated the PI3K/Akt/mTOR pathway through the quercetin/NQO1 axis. These findings highlight quercetin/NQO1 signaling as a possible therapeutic target for senescence-related neurodegeneration.
研究领域:
神经生物学
·
药理学
·
分子医学
·
老年医学
·
神经退行性疾病
·
天然药物化学
·
细胞信号转导
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Food Science & Nutrition
·
2025
·Vol. 13
·期 3
·e70105
·
IF 3.8
Heting Zhou,Xinyue Zheng,Shaolin Huang,Xiaomeng Wang,Ting Zhou,Shuwen Zhang,Yihan Ling,Wenxi Wang,Xingjie Li,Shouqian Li,Yongmei Xie,Wenya Yin
Pulmonary fibrosis (PF) is a chronic and progressive lung disease, and oxidative stress plays a critical role in its pathogenesis. Rosa roxburghii Tratt, known for its anti-inflammatory and antioxidant properties, has been shown to alleviate fibrosis. This study aimed to explore whether two Rosa roxburghii fermentation broths (RRFBs) (with different proportions) could attenuate bleomycin (BLM)-induced PF in mice and to elucidate the molecular mechanisms. The results revealed that RRFBs reduced structural lung damage, collagen deposition, and lung inflammation. RRFBs also suppressed fibrotic markers (Collagen I, Vimentin, and α-SMA) while enhancing epithelial marker E-cadherin expression. Additionally, RRFBs alleviated BLM-induced oxidative stress and apoptosis by activating the Nrf2/HO-1/NQO1 signaling pathway and facilitating Nrf2 nuclear translocation. Furthermore, RRFBs attenuated the BLM-induced changes in the gut microbiota; in particular, they decreased the abundance of the pathogenic bacterium Proteus and increased the abundance of the probiotics Ileibacterium and Dubosiella . Spearman correlation analysis revealed a strong association between oxidative stress inhibition and gut microbiota composition. These results indicated that RRFBs could exert lung-protective effects by inhibiting oxidative stress and alleviating intestinal disturbances.
研究领域:
药理学
·
分子生物学
·
微生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
LIFE SCIENCES
·
2024
·
IF 5.2
Kai Yang,Xiaoxiao Yu,Zihao Guo,Zhihao Fang,Hongyu Zhang,Wanyangchuan Zhang,Changxu Liu,Yanchao Ji,Zhichao Dong,Qiang Gu,Jiahao Yao,Chang Liu
Aims Non-alcoholic fatty liver disease (NAFLD) has risen as a significant global public health issue, for which vertical sleeve gastrectomy (VSG) has become an effective treatment method. The study sought to elucidate the processes through which PIM1 mitigates the advancement of NAFLD. The Pro-viral integration site for Moloney murine leukemia virus 1 (PIM1) functions as a serine/threonine kinase. Bioinformatics analysis revealed that reduced PIM1 expression in NAFLD. Methods To further prove the role of PIM1 in NAFLD, an in-depth in vivo experiment was performed, in which male C57BL/6 mice were randomly grouped to receive a normal or high-fat diet for 19 weeks. They were operated or delivered the loaded adeno-associated virus which the PIM1 was overexpressed (AAV-PIM1). In an in vitro experiment, AML12 cells were treated with palmitic acid to induce hepatic steatosis. Key findings The results revealed that the VSG surgery and virus delivery of mice alleviated oxidative stress, and apoptosis in vivo. For AML12 cells, the levels of oxidative stress, apoptosis, and lipid metabolism were reduced via PIM1 upregulation. Moreover, ML385 treatment resulted in the downregulation of the NRF2/HO-1/NQO1 signaling cascade, indicating that PIM1 mitigates NAFLD by targeting this pathway. Significance PIM1 alleviated mice liver oxidative stress and NAFLD induced by High-fat diet by regulating the NRF2/HO-1/NQO1 signaling Pathway.
研究领域:
肝病学
·
分子生物学
·
病理学
·
药理学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
FOOD CHEMISTRY
·
2024
·
IF 8.5
Kuiyou Wang,Kexin Huang,Xueqian Li,Hao Wu,Li Wang,Fengyu Bai,Mingqian Tan,Wentao Su
This study innovatively utilized kelp-derived nanocellulose and sodium caseinate (SC) to prepare fucoxanthin (Fx)-loaded nanoparticles, exploring their efficacy in reducing oxidative stress and inhibiting lipid accumulation. 2, 2, 6, 6-Tetramethylpiperidine-1-oxyl (TEMPO)-mediated oxidation produced well-dispersed, kelp-derived nanocellulose. When these celluloses were mixed with SC at varying mass ratios, the composite nanoparticles showed excellent stability. Specifically, at a TEMPO-oxidized kelp nanocellulose (TKNC) to SC mass ratio of 1:3, the encapsulation efficiency for Fx reached 82.2 %, with a retention of 56.12 % after 14 days of storage. In vitro , the nanoparticles demonstrated good biocompatibility and were efficiently absorbed by cells, significantly enhancing Fx bioavailability . This enhanced delivery efficiency alleviates oxidative stress by activating the Nrf2/HO-1/NQO1 signaling pathways and effectively inhibits lipid droplet formation induced by excessive free fatty acids (FFAs). Moreover, distribution studies in mice revealed effective accumulation of nanoparticles in the intestines and liver, indicating their potential for targeted drug delivery. These findings provide strong experimental support for the use of TKNC and SC as biocompatible materials in nanoparticles for drug delivery and treatment applications.
研究领域:
药理学
·
纳米技术
·
生物医学工程
·
生物化学
·
材料科学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
TALANTA
·
2019
·
IF 4.916
Zhenwei Yuan,Mingjun Xu,Tianze Wu,Xinyi Zhang,Yuanzhi Shen,Umeorah Ernest,Lijuan Gui,Fei Wang,Qing He,Haiyan Chen
As an over-expressed flavoprotein in several kinds of tumor cells, NAD(P)H: quinone oxidoreductase-1 (NQO1) is considered as a potent biomarker in early-stage cancer diagnosis. Developing a fast, selective and sensitive method of monitoring NQO1 on cellular level will greatly promote cancer diagnosis in clinical practice. In this paper, a fast NQO1 responsive fluorescence probe SYZ-30 containing quinone acid and 7-nitro-2,1,3-benzoxadiazole (NBD) fluorophore is constructed. The probe could selectively respond to NQO1 and rapidly emit strong fluorescence in vitro within only 5 min. Notably, the peak fluorescent intensities at 550 nm showed a linear relationship with NQO1 concentrations in the range of 3–30 ng/ml and limit of detection (LOD) was 0.0667 ng/ml. Furthermore, it was validated that the probe has good biocompatibility and could be applied for bio-imaging in NQO1 over-expressed cancer cells, together with its mitochondria targeting ability. Importantly, confocal fluorescence imaging confirmed the NQO1 detection ability on cellular level, which can be used for real-time detection of several cancer subtypes like adenocarcinoma. To conclude, the probe is rapidly responsive, highly sensitive and selective which will potentially become a practical tool for early cancer detection and diagnosis.
研究领域:
癌症生物学
·
生物化学
·
分子生物学
·
生物医学工程
✓ 已验证
DOI
PubMed
高影响因子
JOURNAL OF CONTROLLED RELEASE
·
2022
·
IF 11.467
Binbin Jiao,Kunpeng Liu,Haitao Gong,Zhenshan Ding,Xin Xu,Jian Ren,Guan Zhang,Qingsong Yu,Zhihua Gan
Currently, clinical intravesical instillation chemotherapy has been greatly compromised by the toxicological and physiological factors. New formulations that can specifically and efficiently kill bladder cancer cells are in urgent need to overcome the low residence efficiency and dose limiting toxicity of current ones. The combination of mucoadhesive nanocarriers and cancer cell selective prodrugs can to great extent address these limitations. However, the insignificant endogenous stimulus difference between cancer cells and normal cells in most cases and the high local drug concentration make it essential to develop new drugs with broader selectivity-window. Herein, based on the statistically different NQO1 expression between cancerous and normal bladder tissues, the reactive oxygen species (ROS) activatable epirubicin prodrug and highly potent NQO1 substrate, KP372–1, was co-delivered using a GSH-responsive mucoadhesive nanocarrier. After endocytosis, epirubicin could be promptly activated by the NQO1-dependent ROS production caused by KP372–1, thus specifically inhibiting the proliferation of bladder cancer cells. Since KP372–1 is much more potent than some commonly used NQO1 substrates, for example, β-lapachone, the cascade drug activation could occur under much lower drug concentration, thus greatly lowering the toxicity in normal cells and broadening the selectivity-window during intravesical bladder cancer chemotherapy.
研究领域:
肿瘤学
·
药学
·
纳米技术
·
癌症治疗
✓ 已验证
DOI
PubMed
高影响因子
BIOORGANIC CHEMISTRY
·
2020
·
IF 4.831
Chong Zhang,Yan Qu,Xin Ma,Manping Li,Sen Li,Yue Li,Liqiang Wu
Tumor-specific prodrug treatment renders the exclusive delivery of antitumor agents with the lowest untoward effects. In this work, we reported the synthesis and biological assessment of four NQO1-activatable combretastatin A-4 prodrugs constituted by active drug CA-4, different self-immolating linkers, and NQO1-responsive trigger groups. The in vitro antiproliferative activities showed that prodrug 4 displayed greater selective toxicity toward the tumor cells that overexpressed NQO1, taxol-resistant A549 cells, hypoxia-exposed A549 and HepG2 cells, and incurred lower damage to normal cells in comparison with combretastatin A-4, prodrugs 1 , 2 , and 3 . Moreover, based on a mechanistic study, NQO1 triggered prodrug 4 to effectively liberate the parent drug combretastatin A-4 and kill tumor cells. Furthermore, we also demonstrated that prodrug 4 exerted a stronger anticancer effect and greater safety than combretastatin A-4 under in vivo conditions. Hence, from the above results, NQO1 can be used as a specific delivery system for releasing anticancer agents; besides, prodrug 4 can serve as a candidate lead for developing specific anticancer agents.
研究领域:
药理学
·
肿瘤学
·
药物化学
✓ 已验证
DOI
PubMed
高影响因子
危险品化学品经营许可证（带存储）