DRUG DELIVERY
·
2017
·
IF 6.402
Chen-Lin Feng,Yan-Xing Han,Hui-Hui Guo,Xiao-Lei Ma,Zhi-Qiang Wang,Lu-Lu Wang,Wen-Sheng Zheng,Jian-Dong Jiang
Our previous work proved that sequence specific double strand RNA (dsRNA-p21) effectively activated p21 gene expression of colorectal cancer (CRC) cells and consequently suppressed CRC growth. However, efficient delivery system is a significant challenge to achieve sufficient therapy. In this study, a self-assembled HA/PEI/dsRNA-p21 ternary complex (TC-dsRNA-p21) was developed for the tumor-target delivery of dsRNA-p21 into CRC cells. Hyaluronic acid (HA) was introduced to shield the PEI/dsRNA-p21 binary complexes (BC-dsRNA-p21) for reducing the cytotoxicity of PEI and for increasing the tumor-targeted intracellular uptake by cancer cells through HA-CD44 mediated endocytosis. Comparing to the BC-dsRNA-p21, the TC-dsRNA-p21 showed increase in size, decrease in zeta potential, low cytotoxicity as well as high stability in physiological conditions due to the anionic shielding. Confocal microscopy analysis and flow cytometry confirmed that TC-dsRNA-p21 had high transfection efficiency in the CD44-abundant Lovo cells, as compared with binary complex. In vitro physiological experiment showed that, comparing to the control group, the TC-dsRNA-p21 effectively activated the expression of p21 mRNA and P21 protein, causing blockage of cell cycle at G0/G1 phase and suppression of cancer cell proliferation as well as colony formation. Furthermore, in vivo distribution experiment demonstrated that the TC-dsRNA-p21 could effectively accumulate at rectal wall for up to 10 h, following in situ application. These findings indicated that TC-dsRNA-p21 might hold great potential for delivering dsRNA-p21 to treat CRC.
研究领域:
生物医学工程
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肿瘤学
·
分子生物学
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DOI
PubMed
高影响因子
ACS Nano
·
2025
·
IF 16
Tiandi Xiong,Xiaofang Xiao,Haitao Zhao,Wen Yang,Xu Gao,Keni Yang,Kexin Zheng,Yuxuan Ji,Duoduo Xu,Ruoyao Fu,Longwei Li,Lulu Zhang,Yan Zhuang,Yanyan Chen,Jianwu Dai
Spinal cord injury (SCI) is a devastating traumatic condition of the central nervous system (CNS), usually resulting in irreversible motor and sensory deficits that severely compromise patients’ quality of life. Harnessing the untapped potential of endogenous neural stem/progenitor cells (NSPCs) may yield revolutionary therapeutic techniques for overcoming the limited NSPC proliferative capacity following SCI in adults. Single-cell sequencing results demonstrated that the limited proliferative capacity of NSPCs after SCI is associated with the upregulation of the p21. Herein, we developed a cationic liposome-based delivery system encapsulating p21 small interfering RNA (P21siRNA@LP) to enhance NSPC proliferation following SCI. P21siRNA@LP significantly increased the primary NSPC proliferation rate (145.4% on day 1 and 144.7% on day 3, respectively) while maintaining differentiation capacity in vitro. Transcriptomic and functional characterization showed that P21siRNA@LP modulated the expression of cyclin-dependent kinases in NSPCs, enhancing cell cycle pathways (enrichment score: 0.6691) and proliferation, with extracellular matrix reorganization (col1a1, col5a1) and gliogenesis (olig1/2) identified as key regulation pathways. Gelatin hydrogels incorporating P21siRNA@LP promoted dense tissue cable formation in T9 SCI rats, facilitating NSPC migration and proliferation at lesion sites, which accelerated locomotor function recovery. These findings emphasize cell cycle manipulation as a promising method to spinal cord regeneration, providing a basis for future therapeutic advances in CNS disorders.
研究领域:
神经生物学
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再生医学
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分子生物学
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生物材料学
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转化医学
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DOI
PubMed
高影响因子
Frontiers in Cardiovascular Medicine
·
2022
·
IF 5.846
Hongge Fa,Dandan Xiao,Wenguang Chang,Lin Ding,Lanting Yang,Yu Wang,Mengyu Wang,Jianxun Wang
Objective Many studies have reported that microRNAs (miRs) are involved in the regulation of doxorubicin (DOX)-induced cardiotoxicity. MiR-194-5p has been reported significantly upregulated in patients with myocardial infarction; however, its role in myocardial diseases is still unclear. Various stimuluses can trigger the endoplasmic reticulum (ER) stress and it may activate the apoptosis signals eventually. This study aims to explore the regulatory role of miR-194-5p in DOX-induced ER stress and cardiomyocyte apoptosis. Methods H9c2 was treated with 2 μM DOX to induce apoptosis, which is to stimulate the DOX-induced cardiotoxicity model. The expression of miR-194-5p was detected by quantitative real-time PCR (qRT-PCR); the interaction between miR-194-5p and P21-activated kinase 2 (PAK2) was tested by dual luciferase reporter assay; terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL) assay and caspase-3/7 activity were used to assess apoptosis; trypan blue staining was applied to measure cell death; Western blotting was performed to detect protein expressions; and ER-related factors splicing X-box binding protein 1 (XBP1s) was detected by polyacrylamide gel electrophoresis and immunofluorescence to verify the activation of ER stress. Results MiR-194-5p was upregulated in cardiomyocytes and mouse heart tissue with DOX treatment, while the protein level of PAK2 was downregulated. PAK2 was predicted as the target of miR-194-5p; hence, dual luciferase reporter assay indicated that miR-194-5p directly interacted with PAK2 and inhibited its expression. TUNEL assay, caspase-3/7 activity test, and trypan blue stain results showed that either inhibition of miR-194-5p or overexpression of PAK2 reduced DOX-induced cardiomyocyte apoptosis. Silencing of miR-194-5p also improved DOX-induced cardiac dysfunction. In addition, DOX could induce ER stress in H9c2, which led to XBP1 and caspase-12 activation. The expression level of XBP1s with DOX treatment increased first then decreased. Overexpression of XBP1s suppressed DOX-induced caspase-3/7 activity elevation as well as the expression of cleaved caspase-12, which protected cardiomyocyte from apoptosis. Additionally, the activation of XBP1s was regulated by miR-194-5p and PAK2. Conclusion Our findings revealed that silencing miR-194-5p could alleviate DOX-induced cardiotoxicity via PAK2 and XBP1s in vitro and in vivo . Thus, the novel miR-194-5p/PAK2/XBP1s axis might be the potential prevention/treatment targets for cancer patients receiving DOX treatment.
研究领域:
心脏病学
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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
CHEMICO-BIOLOGICAL INTERACTIONS
·
2025
·
IF 5.4
Xiangyun Tan,Yuan Yang,Junjie Hu,Yan Meng,Liang Chen,Guohua Zheng,Han Xiao,Zhenpeng Qiu
Intrahepatic cholangiocarcinoma (iCCA) is a malignant liver tumor with insidious onset, limited treatments, and poor prognosis. Recent studies show celecoxib exerts marked cytotoxic effects on cholangiocarcinoma cell lines, suggesting its potential as an iCCA therapy. However, the potential molecular and cellular mechanisms that link celecoxib treatment to its toxicological outcomes remain unclear. In this study, we induced iCCA in mice by overexpressing AKT and YapS127A (hereafter referred to as AKT/YapS127A) and administered celecoxib continuously to evaluate its antitumor effects in vivo . The results demonstrate that celecoxib effectively inhibited tumor growth in AKT/YapS127A-driven iCCA mice. Mechanistically, celecoxib boosted levels of cell cycle inhibitors p21 Waf1/Cip1 and p27 Kip1 , leading to cell cycle arrest. It also promoted apoptosis by downregulating the expression of anti-apoptotic proteins Mcl-1 and Bcl-2. These effects were associated with the modulation of the AKT/mTORC1 signaling pathway. Consistently, celecoxib recapitulated AKT/mTORC1 inhibition and subsequent cell cycle/apoptotic regulator alterations in iCCA cell lines. Collectively, our study elucidates the molecular mechanisms through which celecoxib exerts its anti-tumor effects in iCCA, demonstrating its capacity to induce cytotoxic outcomes via the precise regulation of the AKT/mTORC1 pathway. These findings deepen understanding of the toxicological actions of celecoxib and provide critical insights for developing targeted iCCA therapies.
研究领域:
肿瘤学
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药理学
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分子生物学
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肝病学
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细胞信号传导
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产品关联
DOI
PubMed
高影响因子
ANALYST
·
2013
·Vol. 138
·期 12
·3450-3456
·
IF 3.969
Lei Wu,Zhuyuan Wang,Shenfei Zong,Hui Chen,Chunlei Wang,Shuhong Xu,Yiping Cui
Simultaneous detection of tumor suppressor p53 and cyclin-dependent kinase inhibitor p21 has been achieved for the first time with a high sensitivity using surface enhanced Raman scattering (SERS) technique. In this immunoassay, gold@silver core–shell nanorods (Au@Ag NRs) with a high SERS activity and chemical stability were chosen to fabricate immuno-probes, which were conjugated with different antibodies to specifically target each analyte. Qualitative and quantitative analysis of p53 and p21 were achieved by characterizing SERS signals of two different Raman reporters (4MBA and DTNB), which were labeled on the corresponding optical probes. In addition, we investigated the detection of these biomarkers in the medium of blood serum. Our experimental results indicate the excellent specificity, high sensitivity (1 pg mL−1), as well as the great reproducibility of this immunoassay. More importantly, this assay presents a powerful ability to detect multiple analytes due to the great multiplexing capacity of SERS spectroscopy. Since the combined evaluation of p53 and p21 expression level acts as an indicator for early cancer prediction, our demonstrated immunoassay will potentially promote the application of SERS technique to practical clinical diagnoses.
研究领域:
生物医学工程
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癌症生物学
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分析化学
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纳米技术
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产品关联
DOI
PubMed
高影响因子
TOXICOLOGY
·
2023
·
IF 4.5
Miao Zhang,Xiaowen Bi,Shuai Liu,Yu Liu,Qiyu Wang
Sodium p -perfluorous nonenoxybenzene sulfonate (OBS), an economical alternative to perfluorooctane sulfonate (PFOS) in multiple industrial fields, is widely detected in the environment. The toxicity of OBS has received increasing attention. Pituitary cells are components of the endocrine system and act as vital regulators of homeostatic endocrine balance. However, the effects of OBS on pituitary cells remain unknown. The present study explores the effects of OBS (0.5, 5, and 50 μM) on GH3 rat pituitary cells after treatment for 24, 48, and 72 h. We found that OBS significantly inhibited cell proliferation in GH3 cells with remarkable senescent phenotypes, including enhanced SA-β-gal activity and expression of senescence-associated secretory phenotype (SASP)-related genes, cell cycle arrest, and upregulation of the senescence-related proteins γ-H2A.X and Bcl-2. OBS caused significant cell cycle arrest of GH3 cells at the G1-phase and concomitantly downregulated the expression of some key proteins for the G1/S transition, including cyclin D1 and cyclin E1. Consistently, the phosphorylation of retinoblastoma (RB), which plays a central role in regulating the cell cycle, was prominently reduced after OBS exposure. Furthermore, OBS notably activated the p53-p21 signalling pathway in GH3 cells, as evidenced by increased p53 and p21 expressions, enhanced p53 phosphorylation, and augmented p53 nuclear import. To our knowledge, this study is the first to reveal that OBS triggers senescence in pituitary cells via the p53-p21-RB signalling pathway. Our study demonstrates a novel toxic effect of OBS in vitro, and provides new perspectives for understanding the potential toxicity of OBS.
研究领域:
毒理学
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细胞生物学
·
内分泌学
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产品关联
DOI
PubMed
高影响因子
Translational Research
·
2024
·
IF 6.4
Aoran Huang,Jianyun Rao,Xin Feng,Xingru Li,Tianhua Xu,Li Yao
Vascular calcification (VC) poses significant challenges in cardiovascular health. This study employs single-cell transcriptome sequencing to dissect cellular dynamics in this process. We identify distinct cell subgroups, notably in vascular smooth muscle cells (VSMCs), and observe differences between calcified atherosclerotic cores and adjacent regions. Further exploration reveals ID3 as a key gene regulating VSMC function. In vitro experiments demonstrate ID3′s interaction with USP1 and E12, modulating cell proliferation and osteogenic differentiation. Animal models confirm the critical role of the USP1/ID3/E12/P21 axis in VC. This study sheds light on a novel regulatory mechanism, offering potential therapeutic targets. 1. This study uses single-cell transcriptome to investigate vascular calcification in depth. 2. This study successfully identifies cellular heterogeneity related to vascular calcification. 3. This study reveals the crucial role of ID3 in vascular smooth muscle cell osteogenic differentiation. 4. In vivo and in vitro experiments of this study demonstrate the regulatory role of the USP1/ID3/E12/P21 axis in calcification. 5. This study provides potential molecular targets for the treatment of calcification-related diseases.
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产品关联
DOI
PubMed
高影响因子
ENVIRONMENTAL SCIENCE & TECHNOLOGY
·
2025
·
IF 11.3
Jinxiu Lou,Feilong Dong,Huijie Lu,Shuangxi Fang,Xiangliang Pan
Disinfection byproducts (DBPs), such as haloacetamides (HAMs), have been associated with adverse health outcomes, including bladder cancer. The potential for DBPs to exacerbate cellular senescence, thereby linking exposure to health impacts, remains underexplored. In this study, MRC-5 cells were exposed to HAMs at concentrations of 2, 5, and 8 μg/L for 30 days to simulate long-term exposure to levels found in drinking water. All six tested HAMs significantly increased the cellular senescence degree and enriched the cellular senescence pathway at the proteomic-wide level. Specifically, HAMs upregulated microRNA-24 expression, which increased p16 mRNA levels and decreased p16 protein levels, thereby activating oncogene-induced senescence pathways. Additionally, HAMs were found to covalently bind to TNRC6A, activating the p53/p21 pathway. Principal component analysis highlighted the critical role of functional groups in activating senescence, and the interaction between HAMs and TNRC6A could extend to at least 27 other amide-containing DBPs. Prolonged exposure to HAMs at environmentally relevant levels notably exacerbates cellular senescence, shedding light on a commonly overlooked phenomenon. Given the widespread presence of DBPs in drinking water and their continuous exposure in humans, their role in cellular senescence represents an ongoing public health concern.
研究领域:
环境科学
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毒理学
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分子生物学
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产品关联
DOI
PubMed
高影响因子
TOXICOLOGY AND APPLIED PHARMACOLOGY
·
2026
·
IF 3.6
Haoguo Wang,Yiying Wang,Siyuan Huang,Jiahui Wang,Erxi Xu,Yufei Pang,Jiqing Shen,Changtai Luo,Jiyong Tan
This study investigates how environmental arsenic exposure induces cardiotoxicity via myocardial senescence by in vivo/in vitro models and evaluates the protective effects of quercetin. In vivo, 3-week-old male C57BL/6 mice were exposed to sodium arsenite (NaAsO 2 ) in drinking water at 10 or 20 mg/L for 6 weeks, with 22-month-old mice serving as a natural aging reference. In vitro, H9C2 rat cardiomyoblasts were treated with 6 μM NaAsO 2 for 24 h to establish a sub-lethal senescence model, followed by PBS or 60 μM quercetin for a further 24 h. Arsenic-exposed mice exhibited dose-dependent aging-like behavioral impairment, left ventricular systolic and diastolic dysfunction, and myocardial fibrosis, driven by P53/P21 upregulation. Network toxicology and in vitro assays revealed that arsenic directly binds a p53 cysteine residue, initiating senescence through the p53/p21 axis and altering pathways including PI3K-Akt and HIF-1. At 6 μM, NaAsO 2 increased the proportion of SA-β-gal-positive H9C2 cells and upregulated P53, P21, and IL-6 at both mRNA and protein levels. Network pharmacology identified TP53, AKT1, and EGFR as quercetin's core targets, with molecular docking and 100 ns dynamics simulations confirming stable, spontaneous binding. Co-treatment with 60 μM quercetin for 24 h reversed arsenic-induced senescence and downregulated these overactivated targets. Ultimately, this study provides evidence that arsenic drives myocardial senescence and associated with upregulation of the p53/p21 axis, highlighting quercetin as a promising multi-target botanical countermeasure for cardiovascular protection in arsenic-exposed populations.
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DOI
高影响因子
FOOD AND CHEMICAL TOXICOLOGY
·
2025
·
IF 3.5
Min Li,Shuaijun Peng,Jingjing Bu,Siqi Quan,Liming Liu,Zhouli Yue,Linlin Wang,Yucheng Li
Gefitinib, a first-line tyrosine kinase inhibitor (TKI) target to non-small cell lung cancer (NSCLC) treatment, is known to cause hepatotoxicity, which seriously limiting its therapeutic application. This study investigated the underlying mechanisms of gefitinib-induced liver injury and the protective effects of glycyrrhizic acid (GL) in mice and AML12 cells. Sixty mice were randomly divided into six groups: control, gefitinib, glutathione (200 mg/kg), and three doses of GL (50, 100, and 200 mg/kg). Liver injury was induced in mice through daily oral administration of gefitinib (400 mg/kg) for 16 days, with hepatotoxicity was assessed through serum alanine transaminase (ALT) and aspartate transaminase (AST) levels, and hepatic histopathology. Hepatic mRNA profiles were analyzed using RNA sequencing, with differentially expressed genes (DEGs) confirmed by reverse transcription quantitative polymerase chain reaction (RT-qPCR) and Western blot. Finally, the effect of GL on the anticancer efficacy of gefitinib was assessed in A549 and Lewis lung carcinoma (LLC) lung cancer cells, as well as in a urethane-induced lung cancer mouse model. GL treatment significantly reduced liver index and serum ALT and AST levels, while also improving hepatic histopathology. Transcriptomic analysis identified 114 DEGs linked to the p53 pathway and cell cycle regulation. Further study indicated that GL inhibited the expression of p53 and p21, thereby upregulated Cyclin D1 expression, thereby alleviating gefitinib-induced cell cycle arrest without impairing its anticancer activity in vivo and in vitro . These findings highlight the potential of GL as a safe adjunct therapy, effectively mitigating gefitinib-induced hepatotoxicity while preserving its anticancer efficacy.
研究领域:
药理学
·
肿瘤学
·
分子生物学
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产品关联
DOI
PubMed
高影响因子
RSC Advances
·
2019
·Vol. 9
·期 67
·39082-39089
·
IF 3.049
Jingwen Li,Rong Ding,Hao Gao,Liangdong Guo,Xinsheng Yao,Youwei Zhang,Jinshan Tang
Natural products from fungi have remained a rich resource for drug discovery. Here we report the isolation of three new spirobisnaphthalenes, namely sacrosomycin A-C (1–3), and three known analogues (4–6), from the ethyl acetate extract of a nonsporulating endolichenic fungus derived from Peltigera elisabethae var. mauritzii. The structures of these compounds were elucidated by IR, UV, MS, and NMR. Biological functions of these compounds were evaluated using cultured human cancer cell lines. Short-term cell growth and long-term cell survival assays show that compound 5 demonstrated the strongest cancer cell growth inhibition effect. We reveal that compound 5 induced both cell cycle arrest at the G2/M phase and cell death. Using western blotting, luciferase reporter assay and quantitative PCR (qPCR), we show that compound 5 induced up-regulation of the P53–P21 pathway, supporting the cell cycle arrest and growth inhibition effect of this compound. In contrast, these compounds did not induce cell death in a normal cell line. These results demonstrate a potential anticancer effect of this rare family of spirobisnaphthalene compounds isolated from endolichenic fungi.
研究领域:
药理学
·
肿瘤学
·
天然产物化学
·
细胞生物学
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DOI
PubMed
高影响因子
INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES
·
2025
·
IF 8.5
Kang wei,Lu He,Xuan Li,Meng Wu,Haijie Wang,Liangcong Hu,Huanhuan Xu,Yixuan Zhang,Ling Zhou,Xiaojuan Xu,Liang Guo
Excessive exposure to ultraviolet (UV) radiation results in premature aging of the skin. Lentinan polysaccharide (LNT), has been reported in the literature to exhibit a variety of biological functions, such as anti-inflammatory, antioxidant, and anticancer activities. In this research, the function and underlying mechanisms of LNT in UVB-induced photoaging were evaluated in vivo and in vitro . Initially, we developed a UVB-induced photoaging model in HDFs. The results indicated that following UVB irradiation, the positive rate of β-galactosidase, the proportion of dead cells, the generation of ROS, the expression of the senescence-associated secretory phenotype (SASP), the mRNA levels of inflammatory factors, as well as the activity of matrix metalloproteinases (MMPs) were upregulated in HDFs. In contrast, the components of the extracellular matrix (ECM), were decreased. Simultaneously, the impact of UVB exposure on the dorsal skin of mice exhibited a similar pattern. LNT was demonstrated to effectively mitigate the aforementioned changes and inhibit UVB-induced skin photoaging and damage in mice. Mechanistically, our findings revealed that LNT inhibited UVB-activated nuclear factor kappa B (NF-κB), the mitogen-activated protein kinase (MAPK) pathways and the P21/P16 axis. This property of LNT presents considerable potential for the development of therapeutic strategies aimed at delaying skin photoaging.
研究领域:
皮肤生物学
·
分子生物学
·
药理学
·
光老化研究
·
天然产物药理
·
细胞衰老机制
·
信号转导
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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）