Biomaterials Science
·
2016
·Vol. 5
·期 1
·77-88
·
IF 3.614
Chun Li,Junqing Hu,Wenyao Li,Guosheng Song,Jia Shen
Our previous work reported the development of a proteasome inhibitor, bortezomib (BTZ) encapsulated hollow mesoporous silica nanospheres (HMSNs), as a biocompatible and effective drug-delivery system for non-small cell lung cancer (NSCLC) therapy. Then we found that the tumor-suppressing effect of BTZ or HMSNs-BTZ was compromised in p53 null/mutant NSCLC. In fact, clinical studies have shown a beneficial effect of the combination of p53 gene therapy and chemotherapeutic drugs for patients with NSCLC, especially with the p53 gene null/mutant NSCLC. But there are some safety and toxicity concerns that face the use of gene delivery viral vectors. Here, HMSN-based co-delivery of BTZ and the tumor-suppressor gene p53 was developed for p53 signal impaired NSCLC therapy. The result of the cell viability assay on p53-mutant H1299 cells showed that the half-maximum inhibiting concentration (IC50) of HMSN-PEI-BTZ-p53 was 51% or 25% of that for HMSN-BTZ in 72 or 96 h treatment, respectively. Live/dead staining assay for treated H1299 cells exhibited wider distribution, and higher dead staining was prominent in the HMSNs-PEI-BTZ-p53 group when compared to that of the HMSNs-BTZ group with equivalent BTZ concentration, which was consistent with accumulated p53 expression. Furthermore, the Annexin V-FITC/PI assay suggested restored p53 expression by HMSNs-PEI-BTZ-p53 induced activation of early apoptosis which contributed to enhanced later cell death. Western blotting and real time PCR results showed that several p53 downstream genes responded strongly and synergistically to BTZ function and p53 restored expression (accumulation of p21 and bax, activation of caspase 3, down-regulation of Bcl-2, etc.). Restoration and re-activation of the p53 signal pathway was the basic molecular mechanism for enhanced efficacy of HMSNs-PEI-BTZ-p53 on p53-mutant NSCLC cells.
研究领域:
肿瘤学
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药学
·
纳米技术
·
分子生物学
·
癌症治疗
✓ 已验证
产品关联
DOI
PubMed
高影响因子
OTOLOGY & NEUROTOLOGY
·
2024
·
IF 1.9
Li Yingying,Xu Hui,Shi Jinping,Li Cong,Li Mengxin,Zhang Xiaoling,Xue Qing,Qiu Jingjing,Cui Limei,Sun Yan,Song Xicheng,Chen Liang
Background Gentamicin is a commonly used aminoglycoside antibiotic, with ototoxicity as a significant side effect. Ferroptosis, an iron-dependent form of cell death, has been implicated in a variety of disorders. Whether ferroptosis impacts gentamicin ototoxicity is not yet known. The current work used an in-vitro model to examine the influence of gentamicin-induced ferroptosis on cochlear hair cell damage and probable molecular biological pathways. Methods House Ear Institute-Organ of Corti 1 (HEI-OC1) cells were treated with different concentrations of gentamicin for 24 hours, with or without ferrostatin-1 pretreatment, to observe gentamicin-induced ferroptosis. The role of p53/solute carrier family 7 member 11 (SLC7A11)/glutathione peroxidase 4 (GPX4) signaling in gentamicin-induced ferroptosis was explored by pretreating cells with the p53 inhibitor pifithrin-α (PFT-α). We investigated the effect of gentamicin on cells by assessing cell viability. Cellular proteins were isolated and Western blots were performed to detect changes in the expression of p53, SLC7A11, and GPX4. Fluorescence staining was used to assess levels of reactive oxygen species. An enzymatic detection kit was used to detect glutathione, Fe, and malondialdehyde markers. Results Gentamicin reduced cell viability, glutathione content, and SLC7A11 and GPX4 protein levels, and increased levels of p53 protein, reactive oxygen species, malondialdehyde, and Fe. These effects were largely blocked by pretreatment with ferrostatin-1. Pretreatment with the p53 inhibitor PFT-α prevented the gentamicin-induced reduction in SLC7A11 and GPX4, which alleviated several features of ferroptosis including glutathione depletion, iron overload, and lipid peroxidation build-up. Conclusion Gentamicin induces ferroptosis in the HEI-OC1 cell line, and the mechanism may be related to the p53/SLC7A11/GPX4 signaling pathway.
研究领域:
耳科学
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细胞生物学
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分子生物学
✓ 已验证
DOI
高影响因子
Frontiers in Cell and Developmental Biology
·
2020
·
IF 5.186
Xu Chenxi,Zhuang Jianjian,Zhang Xiaobo
P53 is a transcriptional factor that plays important roles in apoptosis and is mutated in more than 50% of tumor cells. However, the restoration of mutated p53 to the level similar to wild-type p53 by a natural compound has not been explored intensively. In this study, the 2-[(4-hydroxybenzyl) amino] phenol (HBAP) compound, obtained from deep-sea virus-challenged thermophile Geobacillus sp. E263, interacted specifically with the mutated p53 protein. HBAP was able to induce apoptosis of p53-mutated breast cancer cells, but not normal breast cells and p53-unmutated breast cancer cells. HBAP activated the mutant p53 transcriptional activity by restoring the function of mutant p53 to that of wild-type p53. Further analysis indicated that HBAP bound only to the DNA binding domain of mutant p53 and that the interaction was dependent on the HBAP hydroxyl groups. In vivo data demonstrated that HBAP was toxicity-free and could suppress tumor growth by inducing tumor cell apoptosis. Therefore our findings revealed that recovering mutated p53 function to that of wild-type p53 caused by HBAP triggered cancer cell apoptosis and that metabolites from deep-sea virus-challenged thermophiles could be a promising source of anti-tumor drugs.
研究领域:
肿瘤学
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分子生物学
·
药理学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS
·
2018
·
IF 2.559
Jianhao Xu,Cunjin Su,Fenglun Zhao,Jialong Tao,Duanmin Hu,Aiming Shi,Jie Pan,Yusong Zhang
Paclitaxel (PTX) is a first-line chemotherapy drug for advanced non-small cell lung cancer (NSCLC). The long-chain non-coding RNA maternally expressed gene 3 (MEG3) is a recognized tumor suppressor . This study aimed to explore the effects of PTX on the expression of MEG3 and its anti-tumor mechanism in lung cancer cells. 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assays were performed to determine cell proliferation . Quantitative polymerase chain reaction was used to determine the levels of MEG3 expressions. Western blot and immunofluorescence were used to detect protein levels. Small interfering RNA or pCDNA-MEG3 transfection was used to downregulate or upregulate MEG3 expression. Dichlorof luorescein diacetate was used to detect intracellular reactive oxygen species. Flow cytometry was used to analyze apoptosis. PTX significantly inhibited the proliferation of NSCLC cells and increased the expressions of MEG3 and P53. The downregulation of MEG3 attenuated PTX-induced cytotoxicity, whereas upregulation of MEG3 induced cell death and increased P53 expression. The inhibition of P53 caused no effect on the upstream MEG3 expression. Our results suggest that the MEG3-P53 pathway is involved in the apoptosis of A549 cells induced by PTX.
研究领域:
肿瘤学
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分子生物学
·
药理学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
FEBS LETTERS
·
2018
·Vol. 592
·期 20
·3438-3445
·
IF 2.999
Dongxin Zhao,Kui Lu,Guangbin Liu,Li Ma,Hanjing Zhu,Juan He
Mutations in breast cancer susceptibility gene 2 ( BRCA2 ) can lead to chromosomal instability and result in breast cancer, which is strongly associated with p53 mutations. Here, based on the crystal structure of BRC4 and p53, the spatial structure of BRC2 and p53 (171–192) was simulated, providing structural basis for the site-specific mutation of BRC2. The BRC analogous peptides and p53 (171–192) were synthesized, and the interaction between the mutant peptide and p53 (171–192) was studied using circular diachronic spectroscopy and fluorescence spectroscopy. The results show that the mutations of amino acid residues constituting the BRC2 α-helix significantly affect the structure and interaction of BRC analogs and p53 (171–192), which provides support for understanding the structure of the BRC repeat motifs and its interaction pattern with p53.
研究领域:
分子生物学
·
癌症研究
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生物化学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
ECOTOXICOLOGY AND ENVIRONMENTAL SAFETY
·
2024
·
IF 6.2
Weitao Hu,Guilan Chen,Wenbin Yuan,Chen Guo,Fasheng Liu,Shouhua Zhang,Zigang Cao
Iprodione is an effective and broad-spectrum fungicide commonly used for early disease control in fruit trees and vegetables. Due to rainfall, iprodione often finds its way into water bodies, posing toxicity risks to non-target organisms and potentially entering the human food chain. However, there is limited information available regarding the developmental toxicity of iprodione specifically on the liver in existing literature. In this study, we employed larval and adult zebrafish as models to investigate the toxicity of iprodione. Our findings revealed that iprodione exposure led to yolk sac edema and increased mortality in zebrafish. Notably, iprodione exhibited specific effects on zebrafish liver development. Additionally, zebrafish exposed to iprodione experienced an overload of reactive oxygen species, resulting in the upregulation of p53 gene expression. This, in turn, triggered hepatocyte apoptosis and disrupted carbohydrate/lipid metabolism as well as energy demand systems. These results demonstrated the substantial impact of iprodione on zebrafish liver development and function. Furthermore, the application of astaxanthin (an antioxidant) and p53 morpholino partially mitigated the liver toxicity caused by iprodione. To summarize, iprodione induces apoptosis through the upregulation of p53 mediated by oxidative stress signals, leading to liver toxicity in zebrafish. Our study highlights that exposure to iprodione can result in hepatotoxicity in zebrafish, and it may potentially pose toxicity risks to other aquatic organisms and even humans.
研究领域:
毒理学
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环境科学
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分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Nutrients
·
2022
·Vol. 14
·期 11
·2332
·
IF 6.706
Meng-Ling Zhang,Qian Yang,Yan-Di Zhu,Ya-Di Zhang,Rui Zhang,Jian Liu,Xiao-Yan Zhao,Qin-Yu Dang,Dong-Xu Huang,Ming-Yuan Zhang,Yu-Chen Wei,Zhuo Hu,Xia-Xia Cai,Li-Fang Gao,Yang Shan,Huan-Ling Yu
In this study, we aimed to evaluate the effect of Nobiletin (NOB) on the placenta of Sprague–Dawley (SD) rats that had undergone reduced uterine perfusion pressure (RUPP) surgery and to evaluate the safety of NOB intervention during pregnancy. The results showed that NOB alleviated placental hypoxia, attenuated placental cell apoptosis, and inhibited placental damage in RUPP rats. No side effect of NOB intervention during pregnancy was observed. BeWo cell lines with P53 knockdown were then constructed using lentiviral transfection, and the P53 signaling pathway was found to be essential for NOB to reduce hypoxia-induced apoptosis of the BeWo cell lines. In summary, NOB attenuated hypoxia-induced placental damage by regulating the P53 signaling pathway, and those findings may contribute some insights into the role of NOB in placental development and the prevention of placental-related diseases.Keywords:Nobiletin;placenta;hypoxia;RUPP;P53 signaling pathway
研究领域:
药理学
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妇产科学
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分子生物学
✓ 已验证
DOI
PubMed
高影响因子
RSC Advances
·
2015
·Vol. 5
·期 128
·105901-105907
·
IF 3.84
Guan-Hai Wang,Hui-Kang Yang,Yi Zhao,Da-Wei Zhang,Li-Ming Zhang,Jian-Tao Lin
In this work, novel biodegradable cationic micelles were prepared based on poly-(N-ε-carbobenzyloxy-L-lysine) (PZLL) and chitosan (CS) by click reaction, and applied for co-delivery of doxorubicin (DOX) and p53 plasmid. The structure of the copolymer was characterized by 1H NMR and FTIR. The loading amount of DOX in the micelles was 12.8%. Fluorescence spectra confirmed that DOX interacted via π–π stacking with micelles when DOX was encapsulated into the micelles. In particular, its complexation with plasmid DNA was investigated using agarose gel electrophoresis, flow cytometry, zeta potential, and particle size analyses as well as transmission electron microscopy observations. The results showed that the copolymers have a strong pDNA condensation ability and provide protection of pDNA against deoxyribonuclease I degradation. CS-g-PZLL/DOX/p53 nanoparticles showed good gene transfection efficiency in vitro. Fluorescence images and flow cytometry tests revealed that p53 and DOX could be efficiently transported into Hela tumor cells simultaneously, and the optimum N/P ratio for p53 transfection was 20/1. For co-delivery analysis, the obtained CS-g-PZLL/DOX/p53 complexes showed a better inhibitory effect on Hela tumor cells than DOX or p53 used singly.
研究领域:
药剂学
·
肿瘤学
·
生物材料学
✓ 已验证
产品关联
DOI
高影响因子
BIOSENSORS & BIOELECTRONICS
·
2015
·
IF 6.409
Zonghua Wang,Jianfei Xia,Daimin Song,Feifei Zhang,Min Yang,Rijun Gui,Lin Xia,Sai Bi,Yanzhi Xia
A versatile label-free quadruple signal amplification biosensing platform for p53 gene (target DNA) detection was proposed. The chitosan–graphene (CS–GR) modified electrode with excellent electron transfer ability could provide a large specific surface for high levels of AuNPs-DNA attachment. The large amount of AuNPs could immobilize more capture probes and enhance the electrochemical signal with the excellent electrocatalytic activity . Furthermore, with the assist of N.BstNB I (the nicking endonuclease), target DNA could be reused and more G-quadruplex-hemin DNAzyme could be formed, allowing significant signal amplification in the presence of H 2 O 2 . Such strategy can enhance the oxidation–reduction reaction of adsorbed methylene blue (MB) and efficiently improve the sensitivity of the proposed biosensor. The morphologies of materials and the stepwise biosensor were characterized by scanning electron microscopy (SEM), transmission electron microscopy (TEM) and cyclic voltammetry (CV). Differential pulse voltammetry (DPV) signals of MB provided quantitative measures of the concentrations of target DNA, with a linear calibration range of 1.0×10 −15 –1.0×10 −9 M and a detection limit of 3.0×10 −16 M. Moreover, the resulting biosensor also exhibited good specificity, acceptable reproducibility and stability, indicating that the present strategy was promising for broad potential application in clinic assay.
研究领域:
生物化学
·
医学检测
·
纳米材料科学
✓ 已验证
DOI
PubMed
高影响因子
BRAIN RESEARCH BULLETIN
·
2025
·
IF 3.7
Qiyu Yang,Chunyan Wang,Jingwei Cao,Zhanbin Tang,Shurong Duan
Intracerebral hemorrhage (ICH) is associated with the highest rates of mortality and residual disability. To date, effective treatments to delay or prevent ICH are still lacking. Multiple forms of neuronal cell death have been discovered following ICH, including apoptosis, necrosis, autophagy, and ferroptosis. Aldo-keto reductase family 1 member C1 (AKR1C1) has been identified to act as a protective factor in ferroptosis. However, whether AKR1C1 was involved in the development of ICH was unknown. In this study, the left cerebral striatum of the Sprague-Dawley rat was injected with collagenase type IV to induce an in vivo model. Primary rat cortical neurons treated with oxygen hemoglobin (OxyHb) were applied to as an in vitro model. AKR1C1 was found to be downregulated and immunoreactivity colocalized with NeuN-positive neurons in the perihematomal region. Rats injected with lentiviral particles overexpressing AKR1C1 showed the reduction of cerebral hematoma and the remission of blood-brain barrier disruption. Moreover, AKR1C1 upregulation repressed cell apoptosis and ferroptosis induced by ICH through downregulating the expression of pro-apoptotic factors, inhibiting iron accumulation and lipid peroxidation, along with increasing the expression of solute carrier family 7 member 11 (SLC7A11) and glutathione peroxidase 4 (GPX4). The results of in vitro assays were consistent with results from the in vivo . Mechanistically, P53 overexpression augmented the cellular damage in OxyHb-stimulated neurons when AKR1C1 was overexpressed. Taken together, AKR1C1 improves ICH injury by inhibiting neuronal cell death via negatively regulating P53 expression and affecting the SLC7A11/GPX4 pathway.
研究领域:
神经科学
·
分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
NANOTECHNOLOGY
·
2019
·Vol. 30
·期 14
·145601
·
IF 3.399
Yuan Zhong,Yi Wang,Li Luo,Deti Nurhidayah,Ali Maruf,Hans Gregersen,Wei Wu,Gui-Xue Wang
The development of the tumor-targeting ability of nanocarriers is of paramount importance for gene delivery into tumor lesions as well as to avoid biotoxicity. Here we report the synthesis of the polyethyleneimine-fluorescein isothiocyanate-folic acid (PEI-FITC-FA) polymer, which could condense the tumor suppressor pp53 to form nanocomplexes. These targeted nanocomplexes exhibited favorable physical properties including a small size of <100 nm, exploiting the enhanced permeability and retention effect and tumor-targeting ability by binding to the overexpressed FA receptors on tumor cell surfaces. In addition, once the nanocomplexes are accumulating in the tumor tissue, the target functional ligand, FA, can selectively recognize the over-expressed FA receptor and subsequently remain on the tumor cell surface, which can significantly promote the tumor cell uptake because of the time- and concentration-dependent internalization caused by the enhanced interaction between nanocomplex and tumor cell. Our results indicated that PEI-FITC-FA/pp53 nanocomplexes could be efficiently delivered into tumor cells, and subsequently induce tumor cell apoptosis. Thus, the targeted cationic polymer PEI-FITC-FA could be used as an advanced nanocarrier for gene delivery.
研究领域:
药学
·
生物技术
·
纳米技术
·
肿瘤学
✓ 已验证
DOI
PubMed
高影响因子
ENVIRONMENTAL POLLUTION
·
2021
·
IF 8.071
Rili Hao,Xinyu Song,Dongxiao Sun-Waterhouse,Xintong Tan,Feng Li,Dapeng Li
Cadmium (Cd), as an environmental pollutant, can lead to nephrotoxicity. However, its nephrotoxicological mechanisms have not been fully elucidated. In this study, Cd (1.5 mg/kg body weight, gavaged for 4 weeks) was found to induce the renal damage in mice, based on indicators including Cd concentration, kidney index, serum creatinine and blood urea nitrogen levels, pro-inflammatory cytokines and their mRNA expressions, levels of Bcl-2, Bax and caspase9, and histopathological changes of the kidneys. Furthermore, Cd-caused detrimental changes through inducing inflammation and apoptosis via the miR-34a/Sirt1/p53 axis. This is the first report on the role of miR-34a/Sirt1/p53 axis in regulating Cd-caused apoptosis and nephrotoxicity in mice. The findings obtained in this study provide new insights into miRNA-based regulation of heavy metal induced-nephrotoxicity.
研究领域:
毒理学
·
分子生物学
✓ 已验证
DOI
PubMed
高影响因子
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