CHINESE JOURNAL OF POLYMER SCIENCE
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2014
·Vol. 32
·期 10
·1329-1337
·
IF 1.42
Zhang Yan,Wang Xiao-ju,Guo Miao,Yan Hu-sheng,Wang Chen-hong,Liu Ke-liang
Multifunctional nanocarriers with multilayer core-shell architecture were prepared by coating superparamagnetic Fe 3 O 4 nanoparticles with diblock copolymer folate-poly(ethylene glycol)- b -poly(glycerol monomethacrylate) (FA-PEG- b -PGMA), and triblock copolymer methoxy poly(ethylene glycol)- b -poly(2-(dimethylamino) ethyl methacrylate)- b -poly(glycerol monomethacrylate) (MPEG- b -PDMA- b -PGMA). The PGMA segment was attached to the surfaces of Fe 3 O 4 nanoparticles, and the outer PEG shell imparted biocompatibility. In addition, folate was conjugated onto the surfaces of the nanocarriers. Cisplatin was then loaded into the nanocarrier by coordination between the Pt atom in cisplatin and the amine groups in the inner shell of the multilayer architecture. The loaded cisplatin showed pH-responsive release: slower release at pH 7.4 ( i.e. mimicking the blood environment) and faster release at more acidic pH ( i.e. mimicking endosome/lysosome conditions). All of the cisplatin-loaded nanoparticles showed concentration-dependent cytotoxicity in HeLa cells. However, the folate-conjugated cisplatin-loaded carriers exhibited higher cytotoxicity in HeLa cells than non-folate conjugated cisplatin-loaded carriers.
研究领域:
药学
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纳米医学
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肿瘤学
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DOI
高影响因子
Toxicological Research
·
2023
·
IF 2.3
Tian Jie,Mu Ying,Ma Lili
This study investigated whether chemerin/chemokine-like receptor 1 (CMKLR1) pathway participate in cisplatin‐induced spiral ganglion neuron (SGN) damage. Middle cochlear turn was collected from C57BL/6 mice and the SGNs were cultured. Cisplatin, 2-(anaphthoyl) ethyltrimethylammonium iodide (α-NETA), or recombinant mouse chemerin was added into the medium for the treatment. Relative mRNA and protein expression was determined by RT-PCR, ELISA and Western blot, respectively. In cultured mouse cochlear SGNs, the treatment of cisplatin enhanced the secretion of chemerin and CMKLR1. Recombinant chemerin promoted but α-NETA inhibited chemerin/CMKLR1 pathway in cisplatin stimulated SGNs. Cisplatin-induced apoptosis and inflammation response in SGNs were enhanced by recombinant chemerin while inhibited by α-NETA. Recombinant chemerin promoted but α-NETA inhibited NF-κB signal in cisplatin stimulated SGNs. In conclusion, chemerin/CMKLR1 pathway regulated apoptosis and inflammation response in cisplatin-induced SGN injury through NF-κB signaling pathway.
研究领域:
神经科学
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药理学
·
耳鼻喉科
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DOI
PubMed
高影响因子
Journal of Biomaterials and Tissue Engineering
·
2018
·Vol. 8
·期 3
·426-432
·
IF 0.781
Hu Jinghui,Wang Li,Shen Heping,Huang Yujie,Zhao Wei
The elevated expression of mammalian target of rapamycin (mTOR) is associated with the occurrence, progression, and drug resistance of various tumors. Studies have shown overexpression of mTOR and reduced expression of miR-101 in cervical cancer tissues. Bioinformatic analysis has revealed
that a targeting binding site exists between miR-101 and the 3'-UTR of mTOR mRNA. In this study we determined whether miR-101 played a role in regulating mTOR expression and influencing the proliferation, apoptosis, and drug resistance to cisplatin (DDP) of CC cells. The regulatory relationship
between miR-101 and mTOR was validated by dual-luciferase reporter gene assay. The DDP resistance cell line, CaSki/DDP, was established, and the expressions of miR-101, mTOR, p-mTOR, and p-4EBP1 in the CaSki/DDP cell line and parental CaSki cells. The effect of DDP treatment on the proliferation
and apoptosis of the two cell lines were detected by flow cytometry. CaSki/DDP cells were divided into the following four transfection groups: miR-NC group; miR-101 mimic group; si-NC group; and si-mTOR group. The expression of miR-101, MTOR, p-mTOR, and p-4EBP1 was determined, and the effect
of DDP treatment on the proliferation and apoptosis of the two cell lines we detected by flow cytometry. There was a targeted regulatory relationship between miR-101 and mTOR. The expression and apoptosis rate of miR-101 in CaSki/DDP cells were significantly lower than CaSki cells, while the
expression and proliferation of mTOR, p-mTOR, and p-4EBP1 in CaSki/DDP cells were significantly higher than CaSki cells. The transfection of miR-101 mimic or si-mTOR significantly reduced the expression of mTOR, p-mTOR, and p-4EBP1 in CaSki/DDP cells and weakened the cell proliferation ability.
DDP treatment significantly increased the apoptosis rate. The decreased expression of miR-101 is associated with CaSki/DD cell resistance to DDP. Overexpression of miR-101 can reduce the resistance of cervical cancer CaSki/DDP cells to DDP by targeted inhibition of the expression of mTOR.
研究领域:
肿瘤学
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分子生物学
·
癌症研究
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DOI
高影响因子
International Journal of Nanomedicine
·
2023
·
IF 8
Yuming Chen,Jiayi Gu,Jian Liu,Ling Tong,Fuxin Shi,Xiaoqin Wang,Xueling Wang,Dehong Yu,Hao Wu
Background: Cisplatin is an extensively used anti-neoplastic agent for the treatment of various solid tumors. However, a high incidence of severe ototoxicity is accompanied by its use in the clinic. Currently, no drugs or therapeutic strategies have been approved for the treatment of cisplatin-induced ototoxicity by the FDA.Purpose: The purpose of this study was to investigate the otoprotective effects of dexamethasone (DEX)-loaded silk-polyethylene hydrogel (DEX-SILK) following round window membrane administration in the cisplatin-induced ototoxicity mouse model.Methods: The morphology, gelation kinetics, viscosity and secondary structure of the DEX-SILK hydrogel were analyzed. DEX concentration in the perilymph was tested at different time points following hydrogel injection on the RWM niche. Cultured cells (HEI-OC1), organ of Corti explants (C57/BL6, P0-2), and cisplatin-induced hearing loss mice model (C57/BL6) were used as in vitro and in vivo models for investigating the otoprotective effects of DEX-SILK hydrogel against cisplatin.Results: Encapsulation of DEX with a loading of 8% (w/v) did not significantly change the silk gelation time, and DEX was evenly distributed in the Silk-PEG hydrogel as visualized by scanning electron microscopy (SEM). The concentration of Silk majorly influenced DEX distribution, morphological characteristics, viscosity, and gelation time. The optimized DEX-SILK hydrogel (8% w/v loading, 15% silk concentration, 10 μl) was administered directly onto the RWM of the guinea pigs. The DEX concentration in the perilymph was maintained above 1 μg/ml for at least 21 days for the DEX-SILK, while it was maintained for less than 6 h in the control sample of free DEX. DEX-SILK (5-60 ng/ml) exhibited significant protective effects against cisplatin-induced cellular ototoxicity and notably reduced the production of reactive oxygen species (ROS). Eventually, pretreatment with DEX-SILK effectively preserved outer hair cells in the cultured organ of Corti explants and demonstrated significant hearing protection at 4, 8, and 16 kHz in the cisplatin-induced hearing loss mice as compared to the effects noted following pretreatment with DEX.Conclusion: These results demonstrated the clinical value of DEX-SILK for the therapy of cisplatin-induced ototoxicity.
研究领域:
药理学
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耳鼻喉科学
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材料科学
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DOI
PubMed
高影响因子
Frontiers in Pharmacology
·
2026
·
IF 5.4
Nan Guo,Yahui Zhang,Guiyan Yuan,Xiaoran Zhang,Wen Zhang,Qing Wen
Ethnopharmacological Relevance Quassinoid brusatol, isolated from the traditional Chinese medicine Brucea javanica (L.) Merr. , significantly increases the intracellular concentration of cisplatin and reduces tumor size by inhibiting the Nrf2 pathway. However, the underlying mechanism remains unclear. Objective This study focuses on the effects of brusatol on plasma pharmacokinetics, tissue distribution, and nephrotoxicity of cisplatin. Materials and Methods For the pharmacokinetic study, 120 Kunming mice were randomly assigned to receive cisplatin (10 mg/kg) alone or in combination with brusatol (2 mg/kg). Blood and tissue samples were collected to evaluate the in vivo pharmacokinetic interaction. In the nephrotoxicity study, 30 Kunming mice were randomly divided into groups to receive cisplatin (10 mg/kg) alone or brusatol pretreatment (1 mg/kg or 2 mg/kg). Two control groups received brusatol (1 mg/kg) or solvent. Blood samples and kidney tissues were collected to investigate the underlying mechanisms of toxicity. Results The developed HPLC-MS method demonstrated high precision and accuracy, meeting the requirements for biological sample analysis. Brusatol reduced the plasma concentration of cisplatin, increased the apparent volume of distribution (Vd), and significantly increased cisplatin concentrations in the kidney and lung, particularly in the kidney. Combined with brusatol, serum levels of blood urea nitrogen and creatinine increased, antioxidant indices in kidney tissue decreased, and inflammatory factors increased. Pathological findings revealed increased tubular congestion. Discussion and Conclusion Brusatol increases renal cisplatin concentrations by altering its pharmacokinetics, intensifying dose-dependent nephrotoxicity. Further development as a chemotherapy sensitizer requires understanding the mechanisms of this effect and optimizing the combined dose.
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PubMed
高影响因子
Frontiers in Pharmacology
·
2026
·
IF 5.4
Liang Zhang,Huan Liu,Si Jiang,Desheng Li,Xin Li,Maolei Xu,Jianwen Fei,Ling Zhou
Background The natural compound morusin (Mor) acts as a potent tumor suppressor in non-small cell lung cancer (NSCLC), but its potential to sensitize DDP and its direct targets are less understood. This work aims to investigate the DDP-sensitizing effects of Mor and the underlying mechanisms. Methods Cell viability and drug synergy were assessed in NSCLC cells. Ferroptosis was evaluated by measuring lipid reactive oxygen species (ROS), iron accumulation, and the expression of ferroptosis markers. GDF15 was identified as a target via transcriptome sequencing. Its direct binding with Mor was confirmed by molecular docking. The ubiquitin-mediated degradation mechanism and its functional role in ferroptosis were validated using the proteasome inhibitor MG132, alongside GDF15 overexpression and knockdown models. Clinical relevance was assessed using TCGA database analysis. Results Mor induces ferroptosis and significantly augments DDP sensitivity in both NSCLC and cisplatin-resistant A549 cells (A549/DDP). Mechanistically, Mor directly binds to GDF15 and promotes its ubiquitin-mediated degradation. Consequently, GDF15 overexpression reversed Mor-induced cytotoxicity and DDP sensitization. Furthermore, DDP exposure impairs intracellular GDF15 protein levels, and the Mor/DDP combination synergistically suppresses GDF15 in A549 cells. Notably, GDF15 expression is elevated in NSCLC cells compared to normal lung epithelial cells. However, A549/DDP cells exhibit diminished intracellular GDF15 protein relative to parental cells, while GDF15 transcription is upregulated. Knockdown of GDF15 augmented DDP sensitivity in resistant cells. Conclusion Mor reverses DDP resistance by inducing GDF15 degradation and ferroptosis, suggesting that Mor-based combination therapy holds promise in treating NSCLC.
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DOI
PubMed
高影响因子
BIOCHEMICAL PHARMACOLOGY
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2026
·
IF 6.5
Xiaodan Zhu,Hongmin Li,Yang Wang,Yuan Zhang,Fanglei Ye
Cisplatin (DDP) is a potent chemotherapeutic agent with ototoxicity. It elicits oxidative stress (OS) and cell apoptosis in cochlear hair cells (HCs), leading to irreversible hearing loss. Taraxasterol (TAR) is a pentacyclic triterpene compound with anti-oxidative and anti-apoptotic properties. Here we identified that TAR inhibited DDP-induced cell apoptosis and OS in a mouse cochlear hair cell line (HEI-OC1). Besides, the beneficial effect of TAR on cochlear HC loss was validated in DDP-induced mice. Proteomics analysis identified the upregulation of G protein subunit alpha q (GNAQ) in TAR-treated HEI-OC1 cells, and it is predicted to bind with TAR via molecular docking. GNAQ inhibited cell apoptosis and OS injury in DDP-induced HEI-OC1 cells, accounting for TAR-mediated protection against DDP-induced cochlear HC injury. Collectively, this study validates the protective effect of TAR on DDP-induced cochlear HC loss, and highlights the potential role of TAR in preventing against DDP-induced hearing loss.
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DOI
PubMed
高影响因子
BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR BASIS OF DISEASE
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2025
·
IF 4.2
Huan Wu,Yichun Ning,Zhaoxing Sun,Ji Ji,Min Lu,Xiaoyan Jiao,Xiaoliang Xu,Xiaoqiang Ding,Xin Cheng,Xiaofang Yu
Background Cisplatin is a common chemotherapy agent for solid tumors but severe nephrotoxicity limits its application, with no effective pharmacological treatments. Organic cation transporter 2 (OCT2) is involved in cisplatin uptake in kidneys. This study aimed to find drugs with promising clinical applications that could prevent cisplatin-induced acute kidney injury (Cis-AKI) by inhibiting OCT2. Methods The mRNA level of OCT2 was examined in human induced pluripotent stem cells (iPSCs) from Cis-AKI patients and paired non-AKI patients. The association between OCT2 and Cis-AKI was investigated by HEK293FT cells and kidney organoids. We screened potential compounds exhibiting protective effects against Cis-AKI in US Food and Drug Administration-approved drugs through virtual screening and activity screening. Subsequently, we determined the effects of these compounds on OCT2 expression, cisplatin uptake, and apoptosis in cells, kidney organoids and mice. A549 and HeLa cells were adopted to observe the influence of drugs on the anti-tumor function of cisplatin. Results Compared to non-AKI patients, the OCT2 mRNA levels of iPSCs from Cis-AKI patients were elevated. OCT2 exhibits similar expression patterns in kidney organoids and human kidney tissues. Furthermore, the overexpression of OCT2 in kidney organoids and HEK293FT cells exacerbated the injury caused by cisplatin. Carvedilol and cimetidine were identified as potent OCT2 inhibitors by drug screening. Further analysis revealed that the pretreatment of carvedilol or cimetidine downregulated OCT2, reduced cisplatin uptake, and alleviated cisplatin-induced apoptosis, but the combination of the two drugs didn't further improve these outcomes. Additionally, carvedilol and cimetidine didn't compromise the cisplatin-induced cell death in A549 and HeLa cells. Conclusion Our study confirmed that carvedilol and cimetidine exert protective effects against Cis-AKI by inhibiting OCT2, without altering the anti-tumor effects of cisplatin.
研究领域:
药理学
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肾脏病学
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肿瘤学
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产品关联
DOI
PubMed
高影响因子
ACS Applied Materials & Interfaces
·
2018
·
IF 8.097
Yazhou Chen,Li Zhang,Yingjie Liu,Shiming Tan,Ruidan Qu,Zirong Wu,Yue Zhou,Jing Huang
Poly-γ-l-glutamic acid (PGA) is an outstanding drug carrier candidate owning to its excellent biodegradability and biocompatibility. The PGA carrier may shield toxic drugs from the body and enable the delivery of poorly soluble or unstable drugs and thereby minimize the side effects and improve drug efficacy. However, the limitation of PGA as a drug carrier is low drug loading efficiency (DLE), which is usually below 30%. In this study, we reported a chemical modification method using l-phenylalanine ethyl ester (PAE). PGA–PAE construct was amphiphilic, which could form micelles in aqueous solution. Cisplatin (CDDP), a commonly used chemotherapy drug whose side effect is well-known, was used as a model molecule to test the drug-loading efficiency of PGA–PAE. In this paper, two sizes of CDDP-loaded PGA–PAE micelles (M(Pt)-1 and M(Pt)-2) were prepared, the average diameter of M(Pt)-1 was 106 ± 6 nm and M(Pt)-2 was 210 ± 9 nm. The DLE of M(Pt)-1 and M(Pt)-2 was 52.8 ± 2.2 and 55.8 ± 1.2%, respectively. Both exhibited excellent biocompatibility, stability, and drug-retaining capability in physiological condition. The in vitro accumulative drug-releasing profile, IC50 for different tumor cell lines HeLa, A549, and HCCC9810, and in vivo pharmacokinetics were similar between these two micelles; however, M(Pt)-1 showed higher tumor tissue retention and longer efficient cancer cell internalization time (up to 20 d). Our results suggested PGA–PAE micelle carriers reduced the toxicity of CDDP and its size at around 100 nm was the better for CDDP high-efficacy.
研究领域:
药理学
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肿瘤学
·
纳米技术
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DOI
PubMed
高影响因子
Antioxidants
·
2022
·Vol. 11
·期 6
·1141
·
IF 7.675
Shuang Liu,Xing Wen,Qihan Huang,Minghui Zhu,Jun Lu
Cisplatin is one of the most active chemotherapy drugs to treat solid tumors. However, it also causes various side effects, especially nephrotoxicity, in which oxidative stress plays critical roles. Our previous studies found that cisplatin selectively inhibited selenoenzyme thioredoxin reductase1 (TrxR1) in the kidney at an early stage and, subsequently, induced the activation of Nrf2. However, the effects of selenium on cisplatin-induced nephrotoxicity are still unclear. In this study, we established mice models with different selenium intake levels to explore the effects of selenoenzyme activity changes on cisplatin-induced nephrotoxicity. Results showed that feeding with a selenium-deficient diet sensitize the mice to cisplatin-induced damage, whereas selenium supplementation increased the activities of selenoenzymes TrxR and glutathione peroxidase (GPx), changed the renal cellular redox environment to a reduced state, and exhibited protective effects. These results demonstrated the correlation of selenoenzymes with cisplatin-induced side effects and provided a basis for the potential approach to alleviate cisplatin-induced renal injury.Keywords:cisplatin;nephrotoxicity;oxidative stress;thioredoxin;selenium;selenoprotein
研究领域:
肿瘤学
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药理学
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毒理学
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DOI
PubMed
高影响因子
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS
·
2019
·
IF 2.705
Jianfa Wu,Li Zhang,Huixin Li,Suqin Wu,Zhou Liu
Cisplatin resistance is a vital obstacle for the prognosis of ovarian cancer. However, the mechanism of cisplatin resistance is still unknown. This research was performed to explore the role of Nrf2 (nuclear factor, erythroid 2 like 2) and CD99 (CD99 molecule) in cisplatin resistance in ovarian cancer. QRT-PCR and Western blot were used to detect the expression of CD99 in ovarian cancer cells and tissues with different cisplatin sensitivities. Cell viability was analyzed by the Cell Counting Kit-8 (CCK8). The relationship of Nrf2 and CD99 was assessed by dual-luciferase reporter gene assay and chromatin immunoprecipitation (ChIP). Bioinformatics analysis was performed to search for the downstream gene of CD99. In this study, it was revealed that CD99 was highly expressed in cisplatin-resistant ovarian cancer cells and tissues, while lower CD99 expression was found in cisplatin-sensitive ovarian cancer cells and tissues. In addition, the overexpression of CD99 resulted in cisplatin resistance; on the other hand, knockdown of CD99 sensitized ovarian cancer to cisplatin. Furthermore, survival analysis indicated that overall survival (OS) and progression-free survival (PFS) of patients with higher CD99 expression were shorter than those with lower CD99 expression. It was also found that when Nrf2 was upregulated in cisplatin-sensitive ovarian cells, CD99 expression and cell viability increased after cisplatin treatment. Knockdown of CD99 could reverse cisplatin resistance induced by Nrf2. Conversely, when Nrf2 was knocked down in cisplatin-resistant ovarian cancer cells, CD99 expression and cell viability with cisplatin treatment decreased, while simultaneously upregulating CD99 reactivated cisplatin resistance in ovarian cancer cells. The dual-luciferase reporter gene assay and ChIP analysis suggested CD99 was a downstream gene of Nrf2, and Nrf2 positively regulated the expression of CD99 at the transcriptional level. In conclusion, Nrf2 induced cisplatin resistance in ovarian cancer cells by promoting CD99 expression. Targeted CD99 might be an effective way to reverse cisplatin resistance in ovarian cancer.
研究领域:
肿瘤学
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分子生物学
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药理学
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DOI
PubMed
高影响因子
RSC Advances
·
2019
·Vol. 9
·期 4
·1982-1989
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IF 3.049
Chao Zhang,HongLei Zhang,MengNan Han,XueLi Yang,ChaoHong Pei,ZhiDong Xu,Jie Du,Wei Li,Shengxi Chen
Cisplatin is the most widely used anticancer drug, but its side effects limit the maximum systemic dose. To circumvent the side effects, a DNA tetrahedron–affibody nanoparticle was prepared by combination of a DNA chain with cisplatin via interstrand crosslinks or adducts. Each nanocarrier can bind ∼68 molecules of cisplatin. This cisplatin nanoparticle exhibited high selectivity and inhibition for breast cancer HER2 overexpressing cells BT474 and lower toxicity in MCF-7 cells with low HER2 expression. The nano-drug inhibited the growth of BT474 cells by 94.57% at 512 nM (containing 33.3 μM cisplatin), which was higher than that of cisplatin (82.9%, 33.3 μM).
研究领域:
肿瘤学
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分子生物学
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纳米医学
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产品关联
DOI
PubMed
高影响因子
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