MOLECULES
·
2020
·Vol. 25
·期 11
·2621
·
IF 3.267
Xinli Guo,Zhou Fang,Min Zhang,Deyu Yang,Shuyue Wang,Kehai Liu
In order to enhance the sensitivity of drug-resistant ovarian cancer cells to cisplatin (DDP), a co-delivery system was designed for simultaneous delivery of curcumin (CUR) and p53 DNA. Firstly, the bifunctional peptide K14 composed of tumor targeting peptide (tLyP-1) and nuclear localization signal (NLS) was synthesized. A nonviral carrier (PEI-K14) was synthesized by cross-linking low molecular weight polyethyleneimine (PEI) with K14. Then, CUR was coupled to PEI-K14 by matrix metalloproteinase 9 (MMP9)-cleavable peptide to prepare CUR-PEI-K14. A co-delivery system, named CUR-PEI-K14/p53, was obtained by CUR-PEI-K14 and p53 self-assembly. Furthermore, the physicochemical properties and gene transfection efficiency were evaluated. Finally, ovarian cancer cisplatin-resistant (SKOV3-DDP) cells were selected to evaluate the effect of CUR-PEI-K14/p53 on enhancing the sensitivity of drug-resistant cells to DDP. The CUR-PEI-K14/DNA complexes appeared uniformly dispersed and spherical. The particle size was around 20–150 nm and the zeta potential was around 18–37 mV. It had good stability, high transfection efficiency, and low cytotoxicity. CUR-PEI-K14/p53 could significantly increase the sensitivity of SKOV3-DDP cells to DDP, and this effect was better as combined with DDP. The sensitizing effect might be related to the upregulation of p53 messenger RNA (mRNA), the downregulation of P-glycoprotein (P-gp) mRNA, and the upregulation of BCL2-Associated X (bax) mRNA. CUR-PEI-K14/p53 can be used as an effective strategy to enhance the sensitivity of drug-resistant ovarian cancer cells to DDP.Keywords:ovarian cancer;drug resistance;polyethyleneimine;curcumin;p53;co-delivery system
研究领域:
药学
·
肿瘤学
·
生物技术
·
分子生物学
·
化疗
✓ 已验证
DOI
PubMed
高影响因子
NEUROCHEMISTRY INTERNATIONAL
·
2024
·
IF 4.4
Hong Guo,Yuanwei Dong,Danqing Luo,Meng Gong,Jianfeng Sun,Zhipeng Wu,Zhixiang Liu,Lei Zhong,Song Jin
Neuronal death is the key cause of ischemic stroke. Acupuncture (Acu) is a recognized method for the treatment and amelioration of cerebral ischemia. However, the molecular mechanism of Acu for treating ischemic stroke has not yet been detailedly elucidated. Based our microarray analysis results, mitochondrial ribosomal protein L41 (MRPL41), which is related to apoptosis, was identified as the target of Acu. MRPL41 expression was increased in middle cerebral artery occlusion/reperfusion (MCAO/R) model and reduced after Acu treatment. Following, MCAO/R model and oxygen and glucose deprivation/reoxygenation (OGD/R) model were established to explore the effect of MRPL41. Knockdown of MRPL41 increased cell viability and ani-apoptotic protein (Bcl-2) expression, and reduced apoptosis intensity and pro-apoptotic protein (Bax and Cleaved caspase-3) of OGD/R neurons. In vivo , MRPL41 silencing decreased neurological severity score, shrank infarct area, reduced encephaledema and neuron apoptosis. In addition, reduction of MRPL41 caused loss of p53. Our data uncover that Acu targets MRPL41, following with inhibiting neuron apoptosis via p53 pathway, thereby ameliorating ischemic stroke.
研究领域:
神经科学
·
分子生物学
·
针灸
·
中风研究
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Frontiers in Immunology
·
2022
·
IF 8.786
Liu Senyue,Luo Lin,Zuo Fengyuan,Geng Yi,Ou Yangping,Chen Defang,Yang Shiyong,Luo Wei,Wang Yan,Wang Jun,Huang Xiaoli
Myxobolus, a major harmful type of myxospora, is one of the main parasitic pathogens of freshwater fish. Once myxoboliosis occurs, treatment can be extremely difficult. Therefore, clear understandings of the etiology of myxoboliosis and its pathological mechanism are keys for prevention and control. Here, histology, transmission electron microscopy, transcriptome study, tunel assay, and immunohistochemistry were carried out, revealing the morphology, pathological effects as well as host response mechanism of goldfish gill to Myxobolus ampullicapsulatus. Histological studies showed that the mature spores of Myxobolus ampullicapsulatus were composed of three parts, the spore shell, sporoplasm and bottle shaped polar capsule containing double S-shaped polar filaments. Transcriptome analysis revealed that Myxobolus ampullicapsulatus -infected (Myx) goldfish gills were characterized by apoptosis activation mediated by “p53 signaling pathway” with significantly up-regulated apoptosis-related differential genes dominated by p53-Bcl2/Bax signaling pathway. In addition, tunel assay revealed severe gill apoptosis in the Myx group. Transcriptome analysis also revealed that Myx group showed changes in immune response and significantly down-regulated immune-related differential genes. Beyond that, immunohistochemistry showed that there was no significant increase in the number of gill lymphocyte after parasite infection. These results suggest that the pathological mechanism of Myxobolus ampullicapsulatus infection on gills of goldfish may be related to apoptosis and immunosuppression. Subsequent qRT-PCR showed that apoptosis-related genes (Caspase3,Bad, Bax) and anti-inflammatory gene IL-10 were significantly increased, while immune-related pro-inflammatory genes (IL-1β, IL-8) were markedly down-regulated, further verifying the transcriptome results. Based on the above results, we concluded that p53-Bcl2/Bax related networks that dominant the expression of apoptosis genes were activated while immunity was suppressed in the gills of Myxobolus ampullicapsulatus infected goldfish. Our study is not only of benefit to enrich the taxonomy of Myxobolus but also clarifies its pathogenic mechanism, thus providing targets for prevention and control of myxoboliosis.
研究领域:
鱼类病理学
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分子生物学
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寄生虫学
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免疫学
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转录组学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
CHEMOSPHERE
·
2019
·
IF 5.108
Caihong Wang,Wenhao Huang,Jiebo Lin,Fang Fang,Xuedong Wang,Huili Wang
Triclosan (TCS) is widely used in personal care products, and its chronic exposure leads to severely toxic effects in zebrafish ( Danio rerio ). PKCα, Nrf2 and p53 are three important signaling pathways concerned with cell development. Herein, we speculated on and verified a novel TCS regulatory pathway: (1) TCS acted on GPER (G-protein-coupled estrogen receptor) to activate MAPK/ERK pathway, further resulting in the expression changes of protein kinase C (PKC) family; (2) PKC participated in Nrf2 phosphorylation; (3) The expression of miR-125b was regulated by Nrf2; and (4) The expression changes of related genes in the PKCs-Nrf2-ARE pathway showed the specificity of zebrafish tissue and organ. TCS exposure led to down-regulation of the Nrf2 and phosphorylated Nrf2(Ser40) protein in diencephalon nucleus, stratum marginale and stratum centrale areas in adult zebrafish brain. The phosphorylated Nrf2(Ser40) was mainly expressed in PGz area, while it was not the case for Nrf2. Both Nrf2 and phosphorylated Nrf2 were activated by TCS exposure; however, the changing trend of PKCs was opposite to that of Nrf2 in the liver. Both DAPI staining and Merge images demonstrated that TCS induced oxidative phosphorylation, and phosphorylated Nrf2 is translocated into the nucleus as the transcription factor to regulate gene transcription in liver and brain. Nrf2 over-expression increased accumulation of lipid droplets in yolk, brain and liver, resulting from the upregulation of pri-miR-125b1, pri-miR-125b3, but not pri-miR-125b2. These findings reveal the upstream regulation mechanism of miR-125b for TCS-induced fat-metabolism disorder from the regulatory perspective of the pri-miR-125b promoter region.
研究领域:
毒理学
·
分子生物学
·
水生生物学
·
药理学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
JOURNAL OF INVESTIGATIVE DERMATOLOGY
·
2020
·
IF 7.143
Xiaoxuan Yu,Hui Li,Mengyuan Zhu,Po Hu,Xiao Liu,Yingjie Qing,Xiangyuan Wang,Hongzheng Wang,Zhanyu Wang,Jingyan Xu,Renxiang Tan,Qinglong Guo,Hui Hui
Cutaneous T-cell lymphomas (CTCLs) represent a rare form of non-Hodgkin lymphomas characterized by an accumulation of malignant CD4 + T cells in the skin. TP53 genetic alteration is one of the most prevalent genetic abnormalities in CTCLs. Therefore, it is a promising target for innovative therapeutic approaches. We found that p53 could physically interact with histone deacetylase (HDAC) 1 and HDAC8, and was subsequently deacetylated to lose its function in CTCL cells, and the p53 downstream apoptosis-associated genes were repressed. Thus, the anti-CTCL activity displayed by HDAC inhibitors depends on p53 status. However, recent studies have reported that HDAC inhibitors could induce a wide variety of drug-resistant characteristics in cancer cells by regulating ATP-binding cassette transporters. Moreover, we discovered that Baicalein, a natural product, exhibited an inhibitory effect on HDAC1 and HDAC8. Though the inhibition of HDAC1 was mild, Baicalein could induce the degradation of HDAC1 through the ubiquitin proteasome pathway, thereby markedly upregulating the acetylation of histone H3 without promoting ATP-binding cassette transporter gene expression. In terms of the mechanism, Baicalein showed better growth inhibition than traditional HDAC inhibitors in CTCLs. This study indicates a special mechanism of HDAC1 and HDAC8 and p53 in T-cell lymphoma cells and identifies a potential and safe natural HDAC inhibitor for the treatment of CTCLs.
研究领域:
肿瘤学
·
分子生物学
·
药理学
·
免疫学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
CHEMICAL ENGINEERING JOURNAL
·
2019
·
IF 8.355
Fan Wu,Ming Zhang,Xiaohong Chu,Qicheng Zhang,Yutian Su,Baohong Sun,Tingyu Lu,Ninglin Zhou,Jun Zhang,Jianxiu Wang,Xinyao Yi
Chemotherapy resistance hinders the successful clinical cancer therapy, because of the low sensitivity of drugs to resistant cancer cells. In resistant cancer cells, the mutant p53 possesses anti-apoptosis capability to tolerate chemotherapeutic drugs such as doxorubicin (DOX). Phenethyl isothiocyanate (PEITC) derived from cruciferous vegetables can deplete intracellular mutant p53. In this work, the black phosphorus nanosheets-based (BPNs-based) drug delivery system integrated with PEITC can effectively decrease mutant p53 level in resistant cancer cells and realize multiple drug resistance (MDR) reversal. The intrinsic properties of BPNs could achieve synergistic photothermal/photodynamic/chemo-therapy of resistant cancer. Magnetic resonance imaging (MRI) is used to investigate the biodistribution of nanoparticles which confirmed the efficient accumulations of nanoparticles at tumor sites. In vitro and in vivo anticancer experiments demonstrate the drug resistance tumor is effectively inhibited with minimal side effects by BPNs-based drug delivery system.
研究领域:
纳米技术
·
肿瘤学
·
药学
·
生物医学工程
✓ 已验证
产品关联
DOI
高影响因子
ANALYTICA CHIMICA ACTA
·
2023
·
IF 6.2
Zhen-Zhen Mi,Hao-Cheng Hu,Jian-Jun Sun,Shao-Hua Wu
An ultrasensitive electrochemical biosensor for detecting p53 gene was fabricated based on heated gold disk electrode coupling with endonuclease Nt.BstNBI-assisted target recycle amplification and alkaline phosphatase (ALP)-based electrocatalytic signal amplification. For biosensor assembling, biotinylated ssDNA capture probes were first immobilized on heated Au disk electrode (HAuDE), then combined with streptavidin-alkaline phosphatase (SA-ALP) by biotin-SA interaction. ALP could catalyze the hydrolysis of ascorbic acid 2-phosphate (AAP) to produce ascorbic acid (AA). While AA could induce the redox cycling to generate electrocatalytic oxidation current in the presence of ferrocene methanol (FcM). When capture probes hybridized with p53, Nt.BstNBI would recognize and cleave the duplexes and p53 was released for recycling. Meanwhile, the biotin group dropt from the electrode surface and subsequently SA-ALP could not adhere to the electrode. The signal difference before and after cleavage was proportional to the p53 gene concentration. Furthermore, with electrode temperature elevated, the Nt.BstNBI and ALP activities could be increased, greatly improving the sensitivity and efficiency for p53 detection. A detection limit of 9.5 × 10 −17 M could be obtained (S/N = 3) with an electrode temperature of 40 °C, ca. four magnitudes lower than that at 25 °C.
研究领域:
生物技术
·
生物化学
·
电化学
·
分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
JOURNAL OF HAZARDOUS MATERIALS
·
2020
·
IF 9.038
Junke Wang,Tianxin Zhao,Jiadong Chen,Lian Kang,Yuexin Wei,Yuhao Wu,Lindong Han,Lianju Shen,Chunlan Long,Shengde Wu,Guanghui Wei
Di(2-ethylhexyl) phthalate (DEHP) is a widely-used plasticizer and has long been recognized as an endocrine-disrupting chemical with male reproductive toxicities. DEHP exposure at the prepubertal stage may lead to extensive testicular injury. However, the underlying mechanisms remain to be elucidated. In the present study, we gavaged male C57BL/6 mice with different concentrations of DEHP (0, 250, and 500 mg/kg-bw·d) from postnatal day 22–35, and exposed TM3 Leydig cells with 0, 100, 200, 300, and 400 μM of MEHP (bioactive metabolite of DEHP) for 12–48 h. RNA sequencing was performed both in testicular tissue and TM3 cells. The results showed that DEHP disrupts testicular development and reduces serum testosterone levels in male prepubertal mice. Bioinformatic analysis and experimental verification have revealed that DEHP/MEHP induces cell cycle arrest in TM3 cells and increases apoptosis both in vivo and in vitro. Furthermore, the p53 signaling pathway was found to be activated upon DEHP/MEHP treatment. The inhibition of p53 by pifithrin-α significantly reduced MEHP-induced injuries in TM3 cells. Cumulatively, these findings revealed the involvement of the p53 signaling pathway in DEHP-induced prepubertal testicular injury by promoting cell apoptosis and inhibiting cell proliferation of Leydig cells.
研究领域:
毒理学
·
生殖生物学
·
分子生物学
·
生物信息学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
BIOCHEMICAL PHARMACOLOGY
·
2022
·
IF 6.1
Liangping Li,Pingping Li,Xuesong Ma,Shulan Zeng,Yan Peng,Guohai Zhang
p53 inactivation by disabling its function is a hallmark in lung carcinomas , emphasizing the significance of restoring p53 function as an attractive therapeutic strategy. However, the clinical efficacy of existing p53 activators is limited due to their inability to effectively activate p53 within the tumors. Here, we established a p53 activator screening assay in EGFR-driven lung cancer cells and identified a small molecular, MX-C4, as a promising candidate. Using high throughput compound screening and combination analyses, we found that MX-C4 effectively promoted the phosphorylation of p53 at serine-392 (s392). It exhibited potent antitumor activity in a variety of cancer cell lines, but only limited toxicity to NCI-H1299 (p53-null) and normal cell lines such as LX2 and HL-7702. Overexpression of p53 in NCI-H1299 cells by a p53 expressing virus vector sensitized cells to MX-C4 treatment, suggesting a p53-dependent anticancer activity. Furthermore, we demonstrated that MX-C4 bound to p53 and exerted its anticancer activity through cell cycle arrest at G2/M phase and apoptosis induction. Mechanistic study indicated that p53 activation regulated cell cycle and cell survival related targets at protein levels. Moreover, p53 activation raised phospho-p53 translocation to mitochondria and subsequently reorganized the Bcl-xl-Bak complex, thus conformationally activating Bak and inducing apoptosis. It is noteworthy that MX-C4 could effectively activate p53 within the tumors in EGFR-driven xenograft models, where tumor was significantly suppressed without obvious toxicity. Our study identified a promising candidate for lung cancer therapy by restoring p53 function.
研究领域:
肿瘤学
·
分子生物学
·
药理学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Acta Biomaterialia
·
2019
·
IF 6.638
Kang Chen,Xiu Xin,Lipeng Qiu,Wenpan Li,Guannan Guan,Gang Li,Mingxi Qiao,Xiuli Zhao,Haiyang Hu,Dawei Chen
P53 inactivation is often achieved through gene mutation and the excessive activity of its major negative regulator, murine double minute 2 protein (MDM2). In the present study we utilized a PAMAM-OH derivative (PAMSPF) to co-deliver p53 plasmid and MDM2 inhibitor (RG7388) to the tumor site and evaluated the synergistic anti-tumor effect of p53 plasmid and RG7388. PAMSPF was able to condense DNA and encapsulate RG7388 to form spherical nanoparticles (PAMSPF/p53/RG) with particle sizes of around 200 nm, and remain stable in the presence of heparin and nuclease . The drug loading capacity and encapsulation efficiency of RG7388 in PAMSPF/p53/RG were 0.5% and 92.5%, respectively. The p53 expressions in MDA-MB-435, p53-wild type MCF-7 cells (MCF-7/WT) and p53-silenced MCF-7 cells (MCF-7/S) treated with PAMSPF/p53/RG were promoted significantly. As a result, PAMSPF/p53/RG was able to inhibit cell proliferation , arrest cell cycle , and induce cell apoptosis of MDA-MB-435, MCF-7/WT and MCF-7/S cells. PAMSPF/p53/RG suppressed human umbilical vascular endothelial cells (HUVECs) migration, invasion and tube formation through decreasing the VEGF expression. And the biological activities described above of PAMSPF/p53/RG were significantly higher than those of PAMSPF/53 and PAMSPF/RG, exhibiting the synergistic actions of p53 plasmid and RG7388. In addition, intravenous administration of PAMPSF/p53/RG inhibited tumor growth of MDA-MB-435 and MCF-7/WT xenograft mice models, and induced no substantial weight loss. PAMSPF/p53/RG also reduced cell proliferation, and induced cell apoptosis in vivo based on the immunohistochemistry results. Collectively, PAMSPF/p53/RG is an excellent system for gene and drug co-delivery, and the combined treatment of p53 plasmid and RG7388 possesses a synergistic antitumor activity both in vitro and in vivo . Statement of significance In the present study we utilized a PAMAM-OH derivative (PAMSPF) to co-deliver p53 plasmid and RG7388 (MDM2 inhibitor) and evaluated their synergistic anti-tumor effect. PAMSPF could condense p53 plasmid and encapsulate RG7388 to form nanoparticles (PAMSPF/p53/RG). The p53 expressions in MDA-MB-435, p53-wild type MCF-7 cells (MCF-7/WT) and p53-silenced MCF-7 cells (MCF-7/S) treated with PAMSPF/p53/RG were promoted significantly. As a result, PAMSPF/p53/RG could inhibit cell proliferation, arrest cell cycle, and induce cell apoptosis of three kinds of cells. In addition, intravenous administration of PAMPSF/p53/RG inhibited tumor growth of MDA-MB-435 and MCF-7/WT xenograft mice models. Collectively, PAMSPF/p53/RG is an excellent system for gene and drug co-delivery, and the combined treatment of p53 plasmid and RG7388 possesses a synergistic antitumor activity.
研究领域:
癌症治疗
·
药学
·
纳米技术
·
分子生物学
·
细胞生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
ANALYST
·
2023
·Vol. 148
·期 5
·1005-1015
·
IF 4.2
Yali Wang,Shuai Liu,Dongyou Zhang,Qi Xiao,Shan Huang
As an important tumor suppressor gene, the p53 gene is considered to be a typical biomarker for the early diagnosis and prognosis evaluation of severe cancer. Herein, an electrochemical biosensor was proposed for the ultrasensitive detection of the p53 gene based on molecular beacon-mediated circular strand displacement polymerization combined with terminal deoxynucleotide transferase-mediated template-free DNA extension. Firstly, the p53 gene opened the hairpin structure of the molecular beacon, thereby exposing the binding sequence region of the primer DNA. The circular strand displacement polymerization occurred in the presence of the primer DNA and phi29 DNA polymerase, subsequently resulting in the circulation of the p53 gene. With the catalysis of the terminal deoxynucleotide transferase, the 3′-OH terminal sequence of the molecular beacon elongated to produce long single-stranded DNA under the template-free DNA extension. Methylene blue bound with such DNA strands generated a strong differential pulse voltammetry (DPV) signal with a peak potential of −0.28 V. Under the optimal detection conditions, the DPV signal of methylene blue showed good linear relationships with the logarithm value of the p53 gene in two concentration ranges of 0.05 fM to 3 pM and 5 fM to 100 fM, and the detection limit of the p53 gene was as low as 0.018 fM. This electrochemical biosensor possessed high recognition ability for the p53 gene in its analogues and was successfully applied for p53 gene analysis in human serum samples.
研究领域:
生物化学
·
分子生物学
·
癌症研究
·
分析化学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
BIOMATERIALS
·
2013
·
IF 7.604
Yiyan He,Yu Nie,Li Xie,Hongmei Song,Zhongwei Gu
Reduction-sensitive hyaluronic acid derivatives (HA–SS–COOH) were shielded on the DNA/polyethylenimine (PEI) to construct ternary complexes ( D NA/ P EI/HA– S S–COOH, DPS ternary complexes) with efficient gene transfection. Details studied were conducted to investigation of factors influencing transfection efficiency, including the gene compression by fluorescence resonance energy transfer (FRET) spectrum and the intracellular fate of fluorescent labeled complexes by the confocal laser scanning microscope (CLSM). In the FRET study, DPS complexes were found to enhance condensation of DNA in preparation, while timely loosen gene under exposure to reductive reagent. Similar cellular uptake levels were observed for the designed reduction sensitive complexes and the stable one ( D NA/ P EI/ H A, DPH ternary complexes), but the intracellular process was strikingly different for the two types of complexes. Only DPS showed obvious desired intracellular deshielding and endosomal escape, which contributed to highly efficient gene delivery. After loading with p53 plasmid, DPS complexes achieved significantly up-regulated p53 tumor suppressor gene expression at both mRNA and protein levels, as revealed by quantitative polymerase chain reaction (qPCR) and western blot investigations. Transgene induced apoptosis was evaluated by propidium iodide staining and flow cytometry analysis of cell cycle. Tumor cells transfected by DPS complexes containing p53 gene displayed almost 50% higher suppression in proliferation compared to those untreated cells, accompanied with a 46% elevation in the number of cells at sub-G1 phase and remarkable p53 dependent cell cycle perturbations prior to apoptosis. These results demonstrated that targeted delivery of p53 gene via reduction-sensitive DPS ternary complexes enabled up-regulated cellular p53 mRNA level through the exogenous p53 gene, inducing a significant p53-dependent anti-proliferative effect on tumor cells, which could be effective means of cancer treatment.
研究领域:
生物医学工程
·
分子生物学
·
癌症研究
·
基因治疗
✓ 已验证
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）