Frontiers in Pharmacology
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2020
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IF 4.225
Chen Qian,Zhu Min,Xie Jingwen,Dong Zhaojun,Khushafah Fatehi,Yun Di,Fu Weitao,Wang Ledan,Wei Tao,Liu Zhiguo,Qiu Peihong,Wu Jianzhang,Li Wulan
Aberrant fibroblast growth factor receptor-1 (FGFR1), a key driver promoting gastric cancer (GC) progression and chemo-resistance, has been increasingly recognized as a potential therapeutic target in GC. Hereon, we designed and synthesized a series of asymmetric analogues using Af23 and NDGA as lead compounds by retaining the basic structural framework (bisaryl-1,4-dien-3-one) and the unilateral active functional groups (3,4-dihydroxyl). Thereinto, Y14 showed considerable inhibitory activity against FGFR1. Next, pharmacological experiments showed that Y14 could significantly inhibit the phosphorylation of FGFR1 and its downstream kinase AKT and ERK, thus inhibiting the growth, survival, and migration of gastric cancer cells. Furthermore, compared with 5-FU treatment alone, the combination of Y14 and 5-FU significantly reduced the phosphorylation level of FGFR1, and enhanced the anti-cancer effect by inhibiting the viability and colony formation in two gastric cancer cell lines. These results confirmed that Y14 exerted anti-gastric activity and chemosensitizing effect by inhibiting FGFR1 phosphorylation and its downstream signaling pathway in vitro. This work also provides evidence that Y14, an effective FGFR1 inhibitor, could be used alone or in combination with chemotherapy to treat gastric cancer in the future.
研究领域:
肿瘤学
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药物化学
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分子生物学
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癌症研究
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PubMed
高影响因子
Molecular Medicine Reports
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2021
·Vol. 25
·期 2
·1-13
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IF 2.952
Hongbin Peng,Pingjiang Ge
It has been reported that long non‑coding RNA HLA complex group 18 (HCG18) is involved in the progression of cancer, acting as an oncogenic gene. The aim of the present study was to investigate the mechanism underlying the action of HCG18 in laryngeal and hypopharyngeal squamous cell carcinoma (LHSCC). The expression levels of HCG18, microRNA (miR)‑133b and fibroblast growth factor receptor 1 (FGFR1) in LHSCC tissues and transfected LHSCC cells were evaluated by reverse transcription‑quantitative PCR or immunohistochemistry. The viability, migration and invasion of transfected LHSCC cells were detected by Cell Counting Kit‑8, wound healing and Transwell assays, respectively. The targeting relationships of HCG18, miR‑133b and FGFR1 were predicted by bioinformatics analysis and confirmed using a dual‑luciferase reporter assay. Moreover, the expression levels of FGFR1, phosphorylated (p)‑PI3K, PI3K, p‑AKT, AKT, p53, Bax and Bcl‑2 in transfected LHSCC cells were measured by western blotting. It was found that the expression levels of HCG18 and FGFR1 were upregulated, but those of miR‑133b were downregulated in LHSCC tissues. Short hairpin RNA (sh) HCG18 and miR‑133b mimic inhibited LHSCC cell viability, while enhancing miR‑133b expression. HCG18 could competitively bind with miR‑133b. Moreover, the miR‑133b inhibitor promoted cell viability, migration, invasion and the expression levels of Bcl‑2, p‑PI3K and p‑AKT, but inhibited the expression levels of p53 and Bax, which were abrogated by shHCG18. miR‑133b could competitively bind with FGFR1, and the miR‑133b mimic decreased the expression level of FGFR1 in transfected LHSCC cells. shFGFR1 promoted the expression levels of p53 and Bax, while inhibiting viability, migration, invasion and Bcl‑2, p‑PI3K and p‑AKT expression in LHSCC cells. In conclusion, the current results indicated that HCG18 facilitated the progression of LHSCC by upregulating FGFR1 via miR‑133b. The present study evaluated the mechanism with regards to the action of HCG18 in LHSCC, and these experimental results may provide novel evidence for targeted therapy of LHSCC.
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高影响因子
Nature Chemical Biology
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2024
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IF 12.9
Yang Sihui,Wang Miao,Tian Dawei,Zhang Xiaoyu,Cui Kaiqing,Lü Shouqin,Wang Hong-hui,Long Mian,Nie Zhou
Synthetic signaling receptors enable programmable cellular responses coupling with customized inputs. However, engineering a designer force-sensing receptor to rewire mechanotransduction remains largely unexplored. Herein, we introduce nongenetically engineered artificial mechanoreceptors (AMRs) capable of reprogramming non-mechanoresponsive receptor tyrosine kinases (RTKs) to sense user-defined force cues, enabling de novo-designed mechanotransduction. AMR is a modular DNA–protein chimera comprising a mechanosensing-and-transmitting DNA nanodevice grafted on natural RTKs via aptameric anchors. AMR senses intercellular tensile force via an allosteric DNA mechano-switch with tunable piconewton-sensitive force tolerance, actuating a force-triggered dynamic DNA assembly to manipulate RTK dimerization and activate intracellular signaling. By swapping the force-reception ligands, we demonstrate the AMR-mediated activation of c-Met, a representative RTK, in response to the cellular tensile forces mediated by cell-adhesion proteins (integrin, E-cadherin) or membrane protein endocytosis (CI-M6PR). Moreover, AMR also allows the reprogramming of FGFR1, another RTK, to customize mechanobiological function, for example, adhesion-mediated neural stem cell maintenance.
研究领域:
生物技术
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细胞生物学
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分子生物学
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纳米技术
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高影响因子
Heliyon
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2024
·
IF 3.4
Min Cai,Yangchen Mao,Wenjing Gao,Zhenzhen Wang,Jianwei Mao,Ruyi Sha
Inflammatory bowel disease (IBD) is a growing global health problem. IBD is commonly prevalent in Europe and America and the incidence rate in Asia is on the rise due to altered dietary structure. Diosgenin is a natural steroidal saponin derived from Dioscorea plants. Diosgenin is the main active ingredient of some Chinese medicines which are mainly used to treat coronary heart disease, angina and hyperlipidemia. Recently, growing evidence has exhibited a crucial role of diosgenin and dioscin in alleviating IBD in multiple ways. However, the precise mechanism of diosgenin against IBD needs further exploration. In this study, network pharmacological and systematic bioinformatic analyses were performed to investigate the diosgenin's targets against IBD. 71 targets such as SRC, TNF and STAT3 were identified as overlapped genes between diosgenin and IBD. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis exhibited their involvement in the tyrosine kinase signaling pathway and its membrane receptors. Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor resistance and its downstream Ras-MAPK pathway and PI3K-Akt pathway might become the mechanism of diosgenin against IBD. In addition, molecular docking analysis showed that diosgenin has the massive potential of direct binding to tyrosine kinase and its receptors such as SRC, EGFR, FGFR1 and VEGFR. The results above collectively provided evidence that diosgenin is a promising nutraceutical food against IBD.
研究领域:
药理学
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分子生物学
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生物信息学
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功能性食品
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JOURNAL OF CHROMATOGRAPHY B-ANALYTICAL TECHNOLOGIES IN THE BIOMEDICAL AND LIFE SCIENCES
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2026
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IF 2.5
Sijie Li,Haiyu Wang,Pan Zhao,Qitao Zhao
Explored eleven potential ligands in the n-butanol fraction of Gualou-Xiebai-Banxia decoction against FGFR1, βKlotho and FRS2α. • Revealed the interactions between part ligands and three protein targets. • Constructed the first interaction network to unveil the empirical use of the n-butanol fraction of Gualou-Xiebai-Banxia decoction. • Integrating AlphaFold3 predictions with molecular dynamics simulations for the FGFR1, βKlotho, and FRS2α protein complex. • Timosaponin BII exerts effects via the FGF21/FGFR1/βKlotho-FRS2α axis. To systematically deconvolute bioactive components of the n-butanol fraction of Gualou-Xiebai-Banxia decoction (GXB-N) mitigating myocardial ischemia, an integrated drug discovery strategy combining affinity ultrafiltration with liquid chromatography-tandem mass spectrometry (LC-MS/MS) was employed. This approach was designed to screen specific ligands from the complex matrix that bind to key proteins of the fibroblast growth factor 21 (FGF21) signaling complex, including fibroblast growth factor receptor 1 (FGFR1), βKlotho, and fibroblast growth factor receptor substrate 2α (FRS2α). The thermodynamic stability of identified ligands was evaluated using molecular docking and molecular dynamics simulations, while pharmacological efficacy was validated in an isoproterenol-induced zebrafish model. The screening strategy successfully identified Timosaponin BII as a lead compound with notable binding for the FGFR1/βKlotho-FRS2α complex. In silico simulations demonstrated that Timosaponin BII stably occupies the active pockets of these targets. In vivo assays revealed that Timosaponin BII treatment significantly reversed myocardial ischemia phenotypes, characterized by improved cardiac function and reduced pathological lesions, through the activation of the FGF21 signaling pathway. This study demonstrates the efficacy of the affinity ultrafiltration LC-MS/MS method for clarifying the molecular mechanisms of complex herbal matrices and supports the potential of Timosaponin BII as a therapeutic agent for coronary artery disease. Download: Download high-res image (314KB) Download: Download full-size image
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高影响因子
ACS Nano
·
2024
·
IF 15.8
Jiayin Fu,Ning Zhang,Changfu Xu,Meng Zhao,Shaofei Wu,Shihui Xu,Xulin Hong,Meihui Wang,Guosheng Fu
Synthetic vascular grafts are promising conduits for small caliber arteries. However, due to restenosis caused by intimal hyperplasia, they cannot keep long patency in vivo. In this work, through single cell RNA sequencing, we found that thrombospondin-1 (THBS1) was highly expressed in the regenerated smooth muscle cells (SMCs) in electrospun polycaprolactone (PCL) vascular grafts. The expression of THBS1 by injured SMCs was confirmed in a balloon-induced vascular injury model. Downregulation of Thbs1 expression maintained contractile phenotypes of SMCs and reduced neointimal hyperplasia after vascular injury via inhibition of FGFR1/EGR1 signaling by decreasing THBS1 expression. THBS1 small interfering RNA (THBS1-siRNA) was then loaded into macrophage membrane (MM) hybrid lipid nanoparticles (Lipid NP@MM), which were used to modify PCL vascular grafts via polydopamine (PDA) coatings. Lipid NP@MM not only protected THBS1-siRNA from degradation but also improved its internalization by SMCs to decrease the level of THBS1 expression. PCL vascular grafts modified with PDA coatings and Thbs1-siRNA-loaded Lipid NP@MM showed significantly reduced intimal hyperplasia. Thus, the downregulation of THBS1 expression in regenerated SMCs in vascular grafts is a promising strategy to inhibit intimal hyperplasia during vascular graft regeneration in vivo.
研究领域:
生物材料
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组织工程
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血管生物学
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分子生物学
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纳米技术
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PubMed
高影响因子
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