CHEMISTRY OF MATERIALS
·
2019
·
IF 10.159
Siming Yu,Rong Wen,Haiyang Wang,Yongchao Zha,Lin Qiu,Bo Li,Wei Xue,Dong Ma
Au nanoclusters (Au NCs) are materials that hold great promise in biomedical applications due to their improved photophysical properties. However, the current nonthiolate polymer-based self-assembly methods for preparing Au NCs face drawbacks of usage of environmentally unfriendly reducing reagents or nonbiocompatible polymers, which largely hamper their more extensive biomedical use. In this work, biocompatible chitosan-graft-poly(l-lysine) (CPL) dendrons are designed and synthesized based on a simple azide–alkyne cyclization reaction for facile preparation of Au@CPL NCs in one step. The obtained Au@CPL NCs exhibited enhanced computer tomography imaging property as compared with clinically used iohexol (Omnipaque) and displayed high delivery efficiency for matrix metalloproteinase-9 plasmid shRNA (pMMP-9). After surface functionalization by cyclic arginine-glycine-aspartic (Arg-Gly-Asp, RGD), a peptide that specifically targets αvβ3 integrin overexpressed by cancer cells, the resultant Au@CPL-RGD/pMMP-9 complex can precisely and efficiently inhibit tumor growth both in vitro and in vivo. Our work provides a novel strategy to fabricate Au NCs with enhanced biorelevant properties for more efficient cancer diagnosis and therapy.
研究领域:
生物医学工程
·
分子生物学
✓ 已验证
产品关联
DOI
高影响因子
Acta Biomaterialia
·
2017
·
IF 6.319
Yanan Kang,Lu Lu,Jinshuai Lan,Yue Ding,Jing Yang,Yong Zhang,Yuan Zhao,Tong Zhang,Rodney J.Y. Ho
A novel redox-sensitive system for co-delivering hydrophobic drugs and hydrophilic siRNA or shRNA was developed by conjugating gambogic acid (GA) with poly(amido amine)s (PAAs) through amide bonds, which is called GA-conjugated PAAs (PAG). PAG can self-assemble into micelles as amphiphilic block copolymers , which exhibits an excellent loading ability for the co-delivery of docetaxel (DTX) and MMP-9 shRNA with adjustable dosing ratios. In addition, confocal microscopy , flow cytometry and in vitro transfection analyses demonstrated more efficient cellular internalization of DTX and MMP-9 shRNA after incubation with PAG/DTX- MMP-9 shRNA micelles (PAG/DTX-shRNA) than with free drugs. Unlike traditional amphiphilic copolymer micelles, GA conjugated in PAG possesses an intrinsic anticancer efficacy. The presence of disulfide bonds in PAAs enables rapid disassembly of PAG micelles in response to reducing agents, inducing the release of loaded drugs (DTX, GA and MMP-9 shRNA). In vitro cellular assays revealed that PAG/DTX-shRNA micelles inhibited MCF-7 cell proliferation more efficiently than the single drug or single drug-loaded micelles. In vivo biodistribution and anti-tumor effect studies using an MCF-7 breast cancer xenograft mouse model have indicated that PAG/DTX-shRNA micelles can enhance drug accumulation compared with the free drug, thereby sustaining the therapeutic effect on tumors. Additionally, PAG/DTX-shRNA micelles displayed a greater anti-tumor efficacy than Taxotere® and PAG-shRNA micelles. These results suggest that the redox-sensitive PAG platform is a promising co-delivery system for combining drugs and gene therapy for the treatment of cancer. Statement of Significance The PAG micelles were designed by conjugating gambogic acid (GA) with poly(amido amine)s (PAAs), which would serve dual purposes as both gene and drugs co-delivery carrier and an anti-tumor prodrug. Unlike traditional amphiphilic micelles, GA conjugated in PAG could exert its intrinsic efficacy and provide synergistic antiproliferative effects with docetaxel (DTX) on MCF-7 cells. Disulfide bonds in PAG enables a rapid disassembly of PAG micelles in response to reducing agents and to release all loaded drugs (DTX, GA and MMP-9 shRNA) at tumor sites. PAG/DTX-shRNA micelles displayed greater anti-tumor efficacy than that of Taxotere®, indicating the design concept for PAG works well. And the strategy for PAG could be used to develop a series of similar co-delivery systems through conjugations of other small-molecule drugs with PAAs, such as doxorubicin , methotrexate and other drugs with carboxy groups in their structure.
研究领域:
药学
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纳米技术
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癌症研究
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药物递送系统
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生物医学工程
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Acta Biomaterialia
·
2018
·
IF 6.383
Tingting Lv,Ziying Li,Liang Xu,Yingying Zhang,Haijun Chen,Yu Gao
Although novel molecular targeted drugs have been recognized as an effective therapy for non-small cell lung cancer (NSCLC) harboring epidermal growth factor receptor (EGFR) activating mutations, their efficacy fails to meet the expectation due to the acquired resistance in tumors. Up-regulation of the anti-apoptotic protein Survivin was shown to contribute to the resistance to EGFR tyrosine kinase inhibitors (TKI) in EGFR mutation–positive NSCLC. However, the unorganized tumor blood vessels impeded drug penetration into tumor tissue. The resulting insufficient intracellular drug/gene delivery in drug-resistant cancer cells remarkably weakened the drug efficacy in NSCLC. In this work, a multi-functional drug delivery system AP/ES was developed by using anti-EGFR aptamer (Apt)-modified polyamidoamine to co-deliver erlotinib and Survivin-shRNA. Chloroquine (CQ) was used in combination with AP/ES to normalize tumor vessels for sufficient drug/gene delivery to overcome drug resistance in NSCLC cells. The obtained AP/ES possessed desired physicochemical properties, good biostability , controlled drug release profiles, and strong selectivity to EGFR-mutated NSCLC mediated by Apt. CQ not only enhanced endosomal escape ability of AP/ES for efficient gene transfection to inhibit Survivin, but also showed strong vessel-normalization ability to improve tumor microcirculation , which further promoted drug delivery and enhanced drug efficacy in erlotinib-resistant NSCLC cells. Our innovative gene/drug co-delivery system in combination with CQ showed a promising outcome in fighting against erlotinib resistance both in vitro and in vivo . This work indicates that normalization of tumor vessels could help intracellular erlotinib/Survivin-shRNA delivery and the down-regulation of Survivin could act synergistically with erlotinib for reversal of erlotinib resistance in EGFR mutation-positive NSCLC. Statement of Significance NSCLC patients who benefited from EGFR-TKIs inevitably developed acquired resistance. Previous research focused on synthesis of new generation of molecular targeted drugs that could irreversibly inhibit EGFR with a particular gene mutation to overcome drug resistance. However, they failed to inhibit EGFR with other gene mutations. Activation of bypass signaling pathway and the changes of tumor microenvironment are identified as two of the mechanisms of acquired resistance to EGFR-TKIs. We therefore constructed multifunctional gene/drug co-delivery nanocomplexes AP/ES co-formulated with chloroquine that could target the both two mechanisms. We found that chloroquine not only enhanced endosomal escape ability of AP/ES for efficient gene transfection to inhibit Survivin, but also showed strong vessel-normalization ability to improve tumor microcirculation, which further promoted drug delivery into tumor tissue and enhanced drug efficacy in erlotinib-resistant NSCLC.
研究领域:
肿瘤学
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药学
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分子生物学
✓ 已验证
DOI
PubMed
高影响因子
RSC Advances
·
2025
·Vol. 15
·期 29
·23966
·
IF 4.6
Yi Liu,Zheng Zhang,Huyang Du,Xiangjun Chen,Nan Hu,Tingting Yu,Meili Hou,Xiaolin Yu
Chemoresistance poses a critical challenge in cancer therapy across diverse tumor types, including non-small cell lung cancer (NSCLC), where chemotherapy-induced neuroendocrine differentiation (NED) of tumor cells plays a pivotal role in acquiring treatment resistance. This process significantly reduces chemotherapy efficacy, accelerates tumor progression, and ultimately worsens patient survival outcomes. The complex mechanisms underlying chemoresistance involve multiple factors, including enhanced DNA repair pathways, increased drug efflux capacity, and alterations in gene expression. Additionally, the tumor microenvironment, a dynamic ecosystem surrounding cancer cells, fosters a protective niche that exacerbates chemotherapy resistance. To address this challenge, we propose an innovative nanocomposite hydrogel system for the co-delivery of cisplatin and short hairpin RNA (shRNA) targeting protein arginine methyltransferase 5 (PRMT5), a key gene implicated in drug resistance. This system utilizes polyethyleneimine-modified mesoporous silica nanoparticles, which serve as nanocarriers, encapsulating cisplatin within the mesopores and coating the surface with methacryloylated hyaluronic acid (HA-MA). The design enables tumor microenvironment-responsive drug release, triggered by hyaluronidase enzymes abundant within the tumor, resulting in nanoparticle disassembly and the release of cisplatin. Simultaneously, the delivery of shRNA silences PRMT5 expression, enhancing chemosensitivity. By integrating targeted gene therapy with chemotherapy, this system offers a promising strategy for overcoming chemoresistance in NSCLC. Targeting both cancer cells and their microenvironment, this approach holds potential to transform the treatment of chemotherapy-resistant cancers, advancing more effective and personalized oncological therapies. An enzyme-responsive hydrogel to co-deliver cisplatin and shRNA, targeting NED-driven chemoresistance in NSCLC.
研究领域:
肿瘤学
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纳米医学
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药物递送
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分子生物学
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癌症治疗
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生物材料
✓ 已验证
DOI
PubMed
高影响因子
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS
·
2018
·
IF 2.559
Zhigang Nie,Sen Chen,Shuang Deng,Linsheng Long,Puji Peng,Mingyong Gao,Shile Cheng,Jiarui Cao,Hao Peng
Objective Glucocorticoids (GCs)-induced osteoblast apoptosis has been identified as an important cause of GCs related osteonecrosis of the femoral head (ONFH). Glycogen synthase kinase 3β (GSK3β) has been proved to mediate dexamethasone (Dex)-induced osteoblast apoptosis. This study aimed to investigate the underlying mechanism of GSK3β in Dex-induced osteoblast apoptosis. Methods Osteoblast cells were transfected with lentivirus expressing GSK3β-shRNA, and a DNA microarray was performed to analyze gene expression after Dex treatment with or without GSK3β-shRNA. Some differentially expressed genes were further validated by quantitative real-time-PCR (qRT-PCR). Results 460 genes were up-regulated (at least 2-fold) with Dex treatment but down-regulated (at least 2-fold) with GSK3β-shRNA treatment. In addition, 315 genes were down-regulated (at least 2-fold) with Dex treatment but up-regulated (at least 2-fold) with GSK3β-shRNA treatment. Among these genes, the apoptosis-related genes Hoxb8 , Kif18a , Dock8, Dlk1, Tnfsf14 , Casq2 , Bcl2l14 and mechanosensation-related gene Piezo2 were selected for further qRT-PCR analysis. 7 of 8 genes (Piezo2, Hoxb8, Kif18a, Dlk1, Tnfsf14, Casq2, Bcl2l14) showed the same tendency between gene chip results and qRT-PCR results. The microarray data also showed that apoptotic pathway, MAPK pathway, TGFβ pathway and Wnt pathway might be related to the mechanism of GSK3β in Dex-induced osteoblast apoptosis. Conclusion Our findings indicate that GSK3β-shRNA treatment can alter various genes expression levels and change diverse signaling pathways involved in Dex-induced osteoblast apoptosis. Furthermore, Piezo2, Hoxb8, Kif18a, Dlk1, Tnfsf14, Casq2 and Bcl2l14 genes may play an important role in the GSK3β-mediated osteoblast apoptosis process.
研究领域:
药理学
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细胞生物学
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分子生物学
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基因组学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Translational Cancer Research
·
2025
·Vol. 14
·期 10
·6454
·
IF 1.7
Jiaxuan Zhao,Han Wu,Zhe Sun,Yeting Cui,Nan Liu,Yixuan Wang,Youyong Wang,Jiangzhou Shi,Tongcun Zhang
Background Chimeric antigen receptor T cell (CAR-T) therapy targeting cluster of differentiation 19 (CD19) has shown promise in treating B-cell acute lymphoblastic leukemia (B-ALL), but the long-term efficacy of CD19-targeted CAR-T therapy remains limited. Programmed cell death protein 1 (PD-1), an inhibitory receptor on activated T cells, engages programmed death ligand 1 (PD-L1) in the tumor microenvironment, suppressing CAR-T cell function by impairing key signaling pathways. To address this limitation, we investigated the effect of short hairpin RNA (shRNA)-mediated PD-1 knockdown on alleviating CAR-T cell exhaustion, preserving memory phenotype, and enhancing the long-term efficacy of CD19-targeted CAR-T cells. Methods To overcome this limitation, we employed shRNA to achieve PD-1 knockdown in CD19-targeting CAR-T cells. Following screening multiple shRNA candidates, we assessed the cytotoxicity, cytokine secretion, and proliferation of PD-1 knockdown CAR-T cells. Their memory phenotype, exhaustion marker, and cytolytic function were further evaluated after repeated antigen stimulation. Therapeutic efficacy and safety were validated in NOD.Cg-PrkdC scid Il2rg tm1 /Vst (NPG) mice. Results PD-1 knockdown significantly enhanced CAR-T cell cytotoxicity and persistence against PD-L1+ RAJI (human Burkitt’s lymphoma cell line) cells. After three rounds of antigen stimulation, PD-1 knockdown CAR-T cells sustained cytotoxic activity, retained a memory-like phenotype, and displayed attenuated exhaustion markers. In vivo , they prolonged survival without inducing cytokine release syndrome (CRS), indicating improved efficacy and safety. Conclusions PD-1 knockdown mitigates tumor-induced T-cell exhaustion and represents a promising strategy to enhance the durability and potency of CAR-T cell therapy in cancer treatment.
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Metabolites
·
2021
·Vol. 11
·期 12
·873
·
IF 4.932
Fengjiao Chen,Ying Yang,Jianling Chen,Zihua Tang,Qian Peng,Jinfu Wang,Jie Ding
The Notch signaling pathway plays an important role in otic neurogenesis by regulating the differentiation of inner ear hair cells and supporting cells. Notch-regulated differentiation is required for the regeneration of hair cells in the inner ear. The temporal expression pattern of Notch ligands and receptors during in vitro hair cell-like cell differentiation from human embryonic stem cells (hESCs) was detected by quantitative reverse transcription-polymerase chain reaction (qRT-PCR). Subsequently, pAJ-U6-shRNA-CMV-Puro/GFP recombinant lentiviral vectors encoding short hairpin RNAs were used to silence JAG-1, JAG-2, and DLL-1, according to the temporal expression pattern of Notch ligands. Then, the effect of each ligand on the in vitro differentiation of hair cells was examined by RT-PCR, immunofluorescence, and scanning electron microscopy (SEM). The results showed that the individual deletion of JAG-2 or DLL-1 had no significant effect on the differentiation of hair cell-like cells. However, the simultaneous inhibition of both DLL-1 and JAG-2 increased the number of hair cell-like cells and decreased the number of supporting cells. JAG-2 and DLL-1 may have a synergistic role in in vitro hair cell differentiation.Keywords:human embryonic stem cells;progenitor cells;hair cell-like cells;Notch signaling pathway;shRNA
研究领域:
干细胞生物学
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分子生物学
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发育生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
FASEB JOURNAL
·
2023
·Vol. 37
·期 4
·e22866
·
IF 4.8
Shan-Yan Gao,Yong-Ping Liu,Ri Wen,Xin-Mei Huang,Ping Li,Yu-Hang Yang,Ni Yang,Tie-Ning Zhang
Uncontrolled diabetes causes a catabolic state with multi-organic complications, of which impairment on skeletal muscle contributes to the damaged mobility. Kcnma1 gene encodes the pore-forming α-subunit of Ca 2+ - and voltage-gated K + channels of large conductance (BK channels), and loss-of-function mutations in Kcnma1 are in regards to impaired myogenesis. Herein, we observed a time-course reduction of Kcnma1 expression in the tibialis anterior muscles of leptin receptor-deficient (db/db) diabetic mice. To investigate the role of Kcnma1 in diabetic muscle atrophy, muscle-specific knockdown of Kcnma1 was achieved by mice receiving intravenous injection of adeno-associated virus-9 (AAV9)-encoding shRNA against Kcnma1 under the muscle creatine kinase (MCK) promoter. Impairment on muscle mass and myogenesis were observed in m/m mice with AAV9-sh Kcnma1 intervention, while this impairment was more obvious in diabetic db/db mice. Simultaneously, damaged mitochondrial dynamics and biogenesis showed much severer in db/db mice with AAV9-sh Kcnma1 intervention. RNA sequencing revealed the large transcriptomic changes resulted by Kcnma1 knockdown, and changes in mitochondrial homeostasis-related genes were validated. Besides, the artificial alteration of Kcnma1 in mouse C2C12 myoblasts was achieved with an adenovirus vector. Consistent results were demonstrated by Kcnma1 knockdown in palmitate-treated cells, whereas opposite results were exhibited by Kcnma1 overexpression. Collectively, we document Kcnma1 as a potential keeper of mitochondrial homeostasis, and the loss of Kcnma1 is a critical event in priming skeletal muscle loss in diabetes.
研究领域:
糖尿病
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肌肉生物学
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分子遗传学
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细胞生理学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
ACS Applied Materials & Interfaces
·
2016
·
IF 7.145
Yi Zhang,Junkun Duan,Lingguang Cai,Dong Ma,Wei Xue
For cancer gene therapy, a safe and high-efficient gene carrier is a must. To resolve the contradiction between gene transfection efficiency and cytotoxicity, many polymers with complex topological structures have been synthesized, although their synthesis processes and structure control are difficult as well as the high molecular weight also bring high cytotoxicity. We proposed an alternative strategy that uses supramolecular inclusion to construct the aggregate from the small molecules for gene delivery, and to further explore the relationship between the topological assembly structure and their ability to deliver gene. Herein, PEI-1.8k-conjugating β-CD through 6-hydroxyl (PEI-6-CD) and 2-hydroxyl (PEI-2-CD) have been synthesized respectively and then assembled with diferrocene (Fc)-ended polyethylene glycol (PEG-Fc). The obtained aggregates were then used to deliver MMP-9 shRNA plasmid for MCF-7 cancer therapy. It was found that the higher gene transfection efficiency can be obtained by selecting PEI-2-CD as the host and tuning the host/guest molar ratios. With the rational modulation of supramolecular architectures, the aggregate played the functions similar to macromolecules which exhibit higher transfection efficiency than PEI-25k, but show much lower cytotoxicity because of the nature of small/low molecules. In vitro and in vivo assays confirmed that the aggregate could deliver MMP-9 shRNA plasmid effectively into MCF-7 cells and then downregulate MMP-9 expression, which induced the significant MCF-7 cell apoptosis, as well inhibit MCF-7 tumor growth with low toxicity. The supramolecular aggregates maybe become a promising carrier for cancer gene therapy and also provided an alternative strategy for designing new gene carriers.
研究领域:
生物化学
·
分子生物学
·
药学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Journal of Materials Chemistry B
·
2014
·Vol. 2
·期 30
·4901-4910
·
IF 0
Wenjie Li,Jing Shi,Chun Zhang,Min Li,Lu Gan,Huibi Xu,Xiangliang Yang
The overexpression of thioredoxin (Trx) 1 is one of the mechanisms for drug resistance in hepatocellular carcinoma (HCC) treatment. The co-delivery of drugs and a short hairpin RNA (shRNA) against Trx1 to silence its expression might provide a promising approach to improve drug sensitivity to chemotherapeutic agents. In this paper, cationic liposomes containing gemini surfactants, soybean lecithin and DOPE were firstly constructed as gene transfection carriers. The length and symmetrical degree of aliphatic chains of gemini surfactants were found to affect gene transfection efficiency of cationic liposomes. Cationic liposome containing gemini surfactants with symmetrical C16 aliphatic chains (L16-2-16) showed the highest transfection efficiency in HCC Bel7402 cells and also displayed the strongest DNA condensation capacity and the highest cellular uptake. Folic acid (FA) targeting further enhanced the transfection efficiency of L16-2-16 by binding to the folate receptor (FR) in FR-overexpressing Bel7402 cells and lipid raft/caveolae-dependent endocytosis might be involved in FA-L16-2-16-mediated gene delivery. Then the multifunctional co-delivery system for doxorubicin (DOX) and Trx1 shRNA was developed via electrostatic interactions between the FA-L16-2-16 and Trx1 shRNA/DOX complex. Co-delivery of Trx1 shRNA and DOX by FA-L16-2-16 inhibited the cell viability and induced apoptosis of Bel7402 cells more efficiently than co-delivery of control shRNA and DOX. The system for co-delivering DOX and Trx1 shRNA could simultaneously achieve gene transfection and drug release in the same cell and increase the intracellular as well as intranuclear DOX concentrations. These results demonstrated that gemini surfactant-based cationic liposomes were promising carriers for the co-delivery of nucleic acids and chemotherapeutic agents to sensitize HCC chemotherapy.
研究领域:
药理学
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肿瘤学
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分子生物学
·
纳米技术
✓ 已验证
DOI
PubMed
Brazilian Journal of Otorhinolaryngology
·
2019
·Vol. 85
·期 6
·705-715
·
IF 1.603
Chen Jing,Li Hai Liang,Li Bo Bo,Li Wei,Ma Dong,Li Yong He,Liu Tao
Introduction: Serum- and glucocorticoid-inducible kinase 3, a serine/threonine kinase that functions downstream of the PI3K signaling pathway, plays a critical role in neoplastic processes. It is expressed by various tumors and contributes to carcinogenesis. Objective: The objective was to investigate serum- and glucocorticoid-inducible kinase 3 expression in nasopharyngeal carcinoma, to study the anti-tumor effects of serum- and glucocorticoid-inducible kinase 3 shRNA by inhibiting its expression in nasopharyngeal carcinoma cells and to discuss the potential implications of our findings. Methods: Serum- and glucocorticoid-inducible kinase 3 protein expression in nasopharyngeal carcinoma cell lines (CNE-1, CNE-2, HNE-1, HONE-1, and SUNE-1) and the human immortalized nasopharyngeal epithelium cell line NP69 were assayed by western blotting. Serum- and glucocorticoid-inducible kinase 3 expression in 42 paraffin-embedded nasopharyngeal carcinoma tissues were performed by immunohistochemistry. MTT assay, flow cytometry, and scratch tests were performed after CNE-2 cells were transfected with the best serum- and glucocorticoid-inducible kinase 3 shRNA plasmid selected by western blotting using lipofectamine to study its effect on cell proliferation, apoptosis, and migration. Results: Serum- and glucocorticoid-inducible kinase 3 was overexpressed in human nasopharyngeal carcinoma tissues and cells. Serum- and glucocorticoid-inducible kinase 3 expression decreased markedly after CNE-2 cells were transfected with the serum- and glucocorticoid-inducible kinase 3 shRNA, leading to strong inhibition of cell proliferation and migration. In addition, the apoptosis rate increased in CNE-2 cells after serum- and glucocorticoid-inducible kinase 3 knockdown. Conclusion: Serum- and glucocorticoid-inducible kinase 3 expression was more frequently observed as the nasopharyngeal epithelium progresses from normal tissue to carcinoma. This suggests that serum- and glucocorticoid-inducible kinase 3 contributes to the multistep process of NPC carcinogenesis. Serum- and glucocorticoid-inducible kinase 3 represents a target for nasopharyngeal carcinoma therapy, and a basis exists for the further investigation of this adjuvant treatment modality for nasopharyngeal carcinoma.
研究领域:
肿瘤学
·
分子生物学
·
细胞生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
EXPERIMENTAL CELL RESEARCH
·
2023
·
IF 3.7
Hai-Tao Yang,Guan Wang,Peng-Cheng Zhu,Zhao-Yang Xiao
Pulmonary vascular remodeling caused by the excessive proliferation of pulmonary arterial smooth muscle cells (PASMCs) is the hallmark feature of pulmonary arterial hypertension (PAH). Eukaryotic initiation factor 3 subunit A (EIF3A) exhibited proliferative activity in multiple cell types. The present study investigated the role of EIF3A in the progression of PAH. A monocrotaline (MCT)-induced PAH rat model was constructed, and adeno-associated virus type 1 (AAV1) carrying EIF3A shRNA was intratracheally delivered to PAH rats to block EIF3A expression. PASMCs were isolated from rats and treated with PDGF-BB to simulate PASMC proliferation , and shRNA for EIF3 was conducted to investigate the mechanism behind the role of EIF3A in PASMC function in vitro . EIF3A expression was upregulated in pulmonary arteries, and EIF3A inhibition effectively improved pulmonary hypertension and right ventricular hypertrophy and suppressed MCT-induced vascular remodeling in vivo . In addition, we found that genetic knockdown of EIF3A reduced PDGF-triggered proliferation and arrested cell cycle, accompanied by downregulated proliferation-related protein expression in PASMCs. Mechanistically, the histone deacetylase 1 (HDAC1)-mediated PTEN/PI3K/AKT pathway was recognized as a primary mechanism in PAH progression. Silencing EIF3A decreased HDAC1 expression, and further inhibited the excessive proliferation of PASMCs by increasing the phosphatase and tension homolog (PTEN) expression and suppressing the AKT phosphorylation. Notably, HDAC1 expression reversed the effect of silencing EIF3A on PAH and PTEN/PI3K/AKT pathway. Collectively, silencing EIF3A improved PAH by decreasing PASMC proliferation through the HDAC1-mediated PTEN/PI3K/AKT pathway. These findings suggest that targeting EIF3A may represent a potential approach for the treatment of PAH.
研究领域:
心血管疾病
·
分子生物学
·
药理学
·
细胞生物学
✓ 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）