EUROPEAN JOURNAL OF PHARMACOLOGY
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2023
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IF 5
Limin Chai,Qingting Wang,Yan Wang,Danyang Li,Qianqian Zhang,Yuqian Chen,Jin Liu,Huan Chen,Yuanjie Qiu,Nirui Shen,Jian Wang,Xinming Xie,Manxiang Li
To address the molecular mechanisms underlying macrophage migration inhibitory factor (MIF) induced pulmonary artery smooth muscle cells (PASMCs) proliferation, migration and vascular remodeling in pulmonary hypertension (PH), primary cultured rat PASMCs and monocrotaline (MCT)-induced rats with PH were applied in the present study. The results showed that MIF increased signal transducer and activator of transcription 3 (STAT3) phosphorylation, and then stimulated activating transcription factor 6 (ATF6) activation, subsequently triggered autophagy activation, which further led to programmed cell death factor 4 (PDCD4) lysosomal degradation, and eventually promoted PASMCs proliferation/migration. In lung tissues of MCT rats, MIF protein expression was elevated, phosphorylation of STAT3 and activation of ATF6 were increased, activation of autophagy was evident, and reduction of PDCD4 was observed. Intervention with MIF inhibitor 4-Iodo-6-phenylpyrimidine (4-IPP), ATF6 blocker melatonin or autophagy inhibitor chloroquine, confirmed the in vitro interaction among MIF, STAT3, ATF6, autophagy and PDCD4 in MCT induced rats with PH. Targeting MIF/STAT3/ATF6/autophagy/PDCD4 axis effectively prevented the development of PH by suppressing PASMCs proliferation and vascular remodeling. In conclusions, we demonstrate that MIF activates the STAT3/ATF6/autophagy cascade and then degrades PDCD4 leading to PASMCs proliferation/migration and pulmonary vascular remodeling, suggesting that intervention this axis might have potential value in management of PH.
研究领域:
心血管疾病
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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
Nanoscale
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2020
·Vol. 12
·期 47
·24100-24106
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IF 6.895
Xia Li,Fang Yang,Chunfang Gan,Ruo Yuan,Yun Xiang
The simultaneous imaging of the dynamic expression variations of regulatory RNAs in cells, which remains a major challenge, has important applications in precise disease diagnosis, treatment and prognosis. Here, we describe the establishment of a biodegradable ZnO nanoparticle (NP)-assisted asymmetric amplification approach for the simultaneous imaging of microRNA-21 (miRNA-21) and programmed cell death 4 (PDCD4) mRNA at distinct expression levels in live cells. The DNA signal probe complexes are immobilized on the ZnO NPs and readily delivered into the target cancer cells via the endocytosis pathway. The acidic microenvironment in cancer cells leads to the dissolution of the ZnO NPs to release Zn2+ ions and the intracellular miRNA-21 activates the Zn2+-dependent DNAzyme to cleave the substrate signal probes with the assistance of the Zn2+ cofactor to show green fluorescence for imaging miRNA-21. Meanwhile, the PDCD4 mRNA can displace the other quenched signal probes to generate red fluorescence. Importantly, the PDCD4 mRNA sequences can be recycled and reused by using the DNAzyme-cleaved sequences as the fuel strands through two strand displacement reactions to yield amplified red fluorescence for detecting low levels of PDCD4 mRNA. Moreover, our approach can be used to evaluate the varied expression levels of miRNA-21 and PDCD4 mRNA responsive to different drugs in cells, reflecting its usefulness for precise cancer diagnosis and prognosis upon anticancer drug treatment.
研究领域:
分子生物学
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癌症研究
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纳米医学
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DOI
PubMed
高影响因子
ADVANCES IN POLYMER TECHNOLOGY
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2020
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IF 1.539
Lei Li,Yan Li,Cheng Miao,Rui Liu
This study was to explore the therapeutic effect and mechanism of puerarin (PUE) combined with PEGylated nanoparticles on a rat cerebral infarction cell model. In this context, PEG-PLGA/PUE nanoparticles were prepared by the thin-film hydration method, and the toxicity of PEG-PLGA/PUE nanoparticles to brain capillary endothelial cell (BCEC) was detected by MTT. The BCEC/TF cell model was obtained by induction of BCEC cells with TNF-α. The BCEC/TF cell model was identified by immunofluorescence; the protein expression was detected by western blotting; the expression level of miR-424 in cells was measured by RT-qPCR; the targeting relationship between miR-424 and PDCD4 was confirmed by dual-luciferase reporter assay. We found that PEG-PLGA/PUE nanoparticles prepared by the thin-film hydration method had uniform particle size, regular shape, and good stability and were not toxic to cells. The vWF was widely expressed in the cytoplasm in BCECs. The BCEC/TF cell model was obtained after TNF-α treatment, and tissue factor (TF) was widely expressed on the cell membrane of BCEC/TF cells. Furthermore, it was observed that the PEG-PLGA/PUE nanoparticles showed better therapeutic effect on the BCEC/TF cell model than PUE. PEG-PLGA/PUE nanoparticles and PUE inhibited the expression of PDCD4 protein by increasing the expression of miR-424 in BCEC/TF cells. In summary, the therapeutic effect of PEG-PLGA/PUE nanoparticles on the in vitro cell model of cerebral infarction is better than that of PUE. Moreover, PEG-PLGA/PUE inhibits the expression of PDCD4 protein by lowering the expression level of miR-424 in cells, thereby reducing the hazard of cerebral infarction.
研究领域:
药理学
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神经科学
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分子生物学
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产品关联
DOI
高影响因子
Journal of Orthopaedic Surgery and Research
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2025
·Vol. 20
·期 1
·1079
·
IF 2.8
Li Ye,Huang Siyuan,Xing Yihan,Chen Zhuofan,Yu Dongsheng
Background Medication-related osteonecrosis of the jaw (MRONJ), caused by long-term anti-resorptive therapy, leads to bone necrosis and impaired healing. This study developed a miR-21-loaded mesoporous silica nanoparticles (MSN) hydrogel to promote local bone regeneration. Methods Transcriptome sequencing of zoledronic acid (ZOL)-treated osteoclasts (OCs) revealed PDCD4 upregulation and NF-κB (p65) phosphorylation inhibition. miR-21, identified as a regulator of PDCD4, was validated in vitro. Amino-modified mesoporous silica nanoparticles (MSN-NH₂) were synthesized to carry miR-21, and embedded in a dynamic Schiff base-crosslinked hydrogel. The hydrogel's biocompatibility, sustained release, and therapeutic effect were evaluated in a rat MRONJ model via micro-CT, histology, TRAP staining, and RNA in situ hybridization (RISH). Results miR-21 reversed ZOL-induced suppression of NF-κB/p65 phosphorylation by targeting PDCD4, thereby restoring osteoclast differentiation and resorption activity. The miR-21-loaded MSN hydrogel promoted bone regeneration, increased TRAP⁺ osteoclast numbers, and elevated local miR-21 expression, while maintaining systemic safety. These findings suggest that the miR-21-loaded MSN hydrogel system exerts its therapeutic effect primarily through the miR-21/PDCD4/NF-κB signaling pathway, facilitating coordinated regulation of osteoclast-mediated bone remodeling. Conclusions The miR-21-loaded MSN hydrogel effectively restored bone remodeling and healed MRONJ defects without systemic toxicity, offering a promising localized adjunct to anti-resorptive therapies.
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产品关联
DOI
PubMed
高影响因子
Polymer Chemistry
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2016
·Vol. 7
·期 26
·4352-4366
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IF 5.687
Changyu He,Zhen Zhang,Qinglai Yang,Qing Chang,Zhifeng Shao,Bing Gong,Yu-Mei Shen,Bingya Liu,Zhenggang Zhu
A reductive tri-block copolymer PEG-SS-PLA-SS-PEI with a double disulphide linkage in the backbone directed by H-bonding association was synthesized and self-assembled into cationic polymeric nanomicellar particles for in vivo antimiRNA delivery with an average diameter of 68 nm and a zeta potential of approximately 39 mV. The chemical structure of the copolymer was well characterized by 1H NMR and GPC. The cationic polymeric nanomicellar particles could be unpacked in an intracellular reductive environment (GSH) leading to the release of encapsulated antimiRNA. MTT assays in vitro showed no significant cytotoxicity of SGC7901 gastric cancer cells incubated with PEG-SS-PLA-SS-PEI micelles. The in vitro study indicated that the micelle-based antimiR-21 delivery system could effectively facilitate cellular uptake and greatly down-regulate the expression level of miR-21 in SGC7901 cell lines, which was comparable to Lipofectamine™ 2000. The down regulation of miR-21 remarkably induced apoptosis, suppressed the tumor cell migration and invasion, and increased the expression of target genes such as phosphatase and tensin homolog deleted on chromosome ten (PTEN) and Programmed Cell Death Protein 4 (PDCD4). More importantly, the in vivo systemic administration of the micelles/antimiR-21 complex in a gastric cancer model significantly inhibited tumor growth and increased the expression of target genes. The nanoparticle based on the PEG-SS-PLA-SS-PEI copolymer would be a safe and efficient carrier for delivery of therapeutic antimiRNA, which shows a prospective therapy method in gastric cancer.
研究领域:
纳米技术
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药学
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肿瘤学
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分子生物学
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产品关联
DOI
高影响因子
危险品化学品经营许可证（带存储）