FASEB JOURNAL
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2019
·Vol. 33
·期 5
·6311-6326
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IF 5.391
Yifan Wang,Xiaolong Zhang,Jilai Tian,Jinjun Shan,Yunfeng Hu,Yiqian Zhai,Jun Guo
Neuronal polarization depends on the interaction of intracellular chemical and mechanical activities in which the cytoplasmic protein, talin, plays a pivotal role during neurite growth. To better understand the mechanism underlying talin function in neuronal polarization, we overexpressed several truncated forms of talin and found that the presence of the rod domain within the overexpressed talin is required for its positive effect on neurite elongation because the neurite number only increased when the talin head region was overexpressed. The tension in the talin rod was recognized using a Förster resonance energy transfer-based tension probe. Nerve growth factor treatment resulted in inward tension of talin elicited by microfilament force and outward osmotic pressure. By contrast, the glial scar-inhibitor aggrecan weakened these forces, suggesting that interactions between inward pull forces in the talin rod and outward osmotic pressure participate in neuronal polarization. Integrin activation is also involved in up-regulation of talin tension and osmotic pressure. Aggrecan stimuli resulted in up-regulation of docking protein 1 (DOK1), leading to the down-regulation of integrin activity and attenuation of the intracellular mechanical force. Our study suggests interactions between the intracellular inward tension in talin and the outward osmotic pressure as the effective channel for promoting neurite outgrowth, which can be up-regulated by integrin activation and down-regulated by DOK1.—Wang, Y., Zhang, X., Tian, J., Shan, J., Hu, Y., Zhai, Y., Guo, J. Talin promotes integrin activation accompanied by generation of tension in talin and an increase in osmotic pressure in neurite outgrowth. FASEB J. 33, 6311–6326 (2019). www.fasebj.org
研究领域:
神经科学
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细胞生物学
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分子生物学
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DOI
PubMed
高影响因子
Nature Communications
·
2023
·Vol. 14
·期 1
·1-19
·
IF 16.6
Da Xingwen,Li Ziyan,Huang Xiaofan,He Zuhan,Yu Yubing,Tian Tongtong,Xu Chengqi,Yao Yufeng,Wang Qing K.
Thoracic aortic aneurysm (TAA) is a localized or diffuse dilatation of the thoracic aortas, and causes many sudden deaths each year worldwide. However, there is no effective pharmacologic therapy. Here, we show that AGGF1 effectively blocks TAA-associated arterial inflammation and remodeling in three different mouse models (mice with transverse aortic constriction, Fbn1 C1041G/+ mice, and β-aminopropionitrile-treated mice). AGGF1 expression is reduced in the ascending aortas from the three models and human TAA patients. Aggf1 +/- mice and vascular smooth muscle cell (VSMC)-specific Aggf1 smcKO knockout mice show aggravated TAA phenotypes. Mechanistically, AGGF1 enhances the interaction between its receptor integrin α7 and latency-associated peptide (LAP)-TGF-β1, blocks the cleavage of LAP-TGF-β1 to form mature TGF-β1, and inhibits Smad2/3 and ERK1/2 phosphorylation in VSMCs. Pirfenidone, a treatment agent for idiopathic pulmonary fibrosis, inhibits TAA-associated vascular inflammation and remodeling in wild type mice, but not in Aggf1 +/- mice. In conclusion, we identify an innovative AGGF1 protein therapeutic strategy to block TAA-associated vascular inflammation and remodeling, and show that efficacy of TGF-β inhibition therapies require AGGF1.
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
JOURNAL OF ETHNOPHARMACOLOGY
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2025
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IF 5.4
Yijie Chen,Liang Hong,Qifang Wu,Meiyan Sun,Menglai Ling,Haibin Tong,Zhengshuang Liu
Ethnopharmacological relevance Chimonanthus salicifolius S. Y. Hu (Salicaceae), known as "Liu Ye La Mei," is traditionally used by the She ethnic minority in China to treat respiratory ailments including cough, asthma, and bronchitis. This ethnobotanical background provides a strong rationale for investigating its potential therapeutic value in acute lung injury (ALI). Aim of the study : This study aimed to evaluate the protective effects of the essential oil from Chimonanthus salicifolius (CSEO) against lipopolysaccharide (LPS)-induced ALI in mice and to elucidate the underlying mechanisms. Methods ALI was induced in C57BL/6 mice by intratracheal LPS instillation, with separate cohorts pretreated intraperitoneally with CSEO or its component eucalyptol. In vivo therapeutic efficacy was evaluated by assessing lung histopathology, pulmonary edema, BALF inflammatory markers, and neutrophil activation status. In vitro , the effects of CSEO and eucalyptol on key neutrophil functions were assessed, including adhesion to ICAM-1 and chemotaxis (Transwell, Zigmond assays). The mechanism was investigated by evaluating interference with the β2 integrin/ICAM-1 interaction using competitive ELISA and co-immunoprecipitation. Following the identification of eucalyptol as a lead candidate via molecular docking, direct eucalyptol-β2 integrin binding was confirmed using multiple biophysical methods (CETSA, DARTS, MST). Results CSEO administration significantly ameliorated LPS-induced lung pathology, pulmonary edema, inflammatory cell infiltration, and suppressed MPO/NE activity and ROS levels in lung tissues. CSEO also reduced the production of pro-inflammatory cytokines and inhibited NF-κB pathway activation in the lungs. In vitro , CSEO dose-dependently inhibited neutrophil adhesion to ICAM-1 and chemotaxis towards CXCL1. Mechanistically, CSEO directly disrupted the binding between β2 integrin and ICAM-1 in both competitive ELISA and protein binding assays. Molecular docking identified eucalyptol as the CSEO constituent with the highest predicted binding affinity for β2 integrin. Subsequent experiments confirmed that eucalyptol significantly inhibited β2 integrin/ICAM-1 binding and suppressed neutrophil adhesion and chemotaxis in vitro . Biophysical assays provided strong evidence for a direct interaction between eucalyptol and β2 integrin, with MST determining a dissociation constant (Kd) of approximately 19.5 μM. Importantly, in vivo administration of eucalyptol replicated the protective effects of CSEO, significantly mitigating ALI severity, reducing inflammation, and inhibiting neutrophil recruitment and activation markers. Conclusions CSEO demonstrates significant therapeutic potential against ALI by inhibiting neutrophil trafficking. Its key component, eucalyptol, directly antagonizes the β2 integrin/ICAM-1 interaction, leading to reduced neutrophil adhesion and chemotaxis. This work provides scientific evidence for the traditional use of C. salicifolius and identifies eucalyptol as a promising β2 integrin-targeting agent for treating ALI.
研究领域:
药理学
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免疫学
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民族药理学
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肺病学
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生物化学
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分子生物学
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DOI
PubMed
高影响因子
Advanced Biosystems
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2018
·Vol. 3
·期 2
·1800253
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IF 0
Xiaobin Guo,Yu Liu,Jiaxiang Bai,Binqing Yu,Menglei Xu,Houyi Sun,Jining Shen,Jiayi Lin,Hongbo Zhang,Dongqing Wang,Dechun Geng,Guoqing Pan
Wear-debris-induced osteolysis and subsequent aseptic loosening of the prosthesis are the main reasons for failed arthroplasty. Inhibition of wear-debris-induced osteoclastogenesis is thus a promising method to prolong the lifetime of prostheses. In this work, a mussel-derived peptide, capped with an integrin-targeting RGD tripeptide and a titanium (Ti)-affinity tetrapeptide with catechol groups at each end is biomimetically designed. The RGD peptide can interfere with integrin α v β 3 to affect the cytoskeletal organization and functions of osteoclasts and subsequently inhibit osteoclast hyperactivation and osteoclastogenesis in vitro and in vivo, while the catechol groups could easily adhere to the TiO 2 layer of the Ti implant via Ti–catechol coordination. This design thus enables the stable immobilization of the RGD peptide on Ti implants to inhibit osteoclast formation and reduce osteolysis in vivo, even with the existence of Ti wear particles. Further study reveals that the suppression of osteoclastogenesis and osteoclast polarization on the peptide coating is regulated by blocking the PI3K/AKT and NF-κB signal pathways. Considering the simplicity in the surface engineering, the highly biomimetic nature of the bioactive peptide, and efficient inhibition of wear-debris-caused osteolysis, this work thus presents a simple and efficient strategy to improve clinical outcome of prosthesis implantation in challenging conditions.
研究领域:
生物医学工程
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材料科学
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骨科
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DOI
PubMed
Advanced Healthcare Materials
·
2021
·Vol. 10
·期 16
·2100536
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IF 9.933
Honglan Wang,Jiyuan Zhou,Ying Fu,Yuzhao Zheng,Weiyang Shen,Jianping Zhou,Tingjie Yin
A limited infiltration and the subsequent low effective drug concentration result in poor chemotherapeutic outcomes against tumors, and even further promote tumor resistance and metastatic. Herein, iRGD-modified graphene oxide (GO) nanosheets (IPHG) are developed for the intensive treatment of metastatic tumors using focus-specific penetrated delivery together with photothermal therapy-mediated chemosensitization and photothermal therapy-strengthened integrin targeting-based antimigration. In vitro and in vivo data verified the mechanism of the tumor-selective infiltration of IPHG is based on a rigid 2D structure-associated advantage regarding hemodynamics and endothelial contact, followed by iRGD-endowed transendothelial and intratumoral transport. Once IPHG-DOX-penetrated 4T1 tumors are exposed to near-infrared irradiation, hyperthermia stress and photothermal therapy-elevated effective drug concentrations result in chemosensitization and prominent tumor suppression. Meanwhile, the specific binding of iRGD to integrins and photothermal therapy leads to the synergistic perturbation of cytoskeleton remodeling and subsequent impairment of cell motility and metastasis. The tailored design of IPHG validates a promising paradigm for drug delivery to combat tumor resistance and metastasis resulting from poor target access for single chemotherapy.
研究领域:
肿瘤学
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纳米技术
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治疗学
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药物递送系统
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DOI
PubMed
高影响因子
BIOCHEMICAL ENGINEERING JOURNAL
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2025
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IF 3.8
Chuanfu Huo,Yuanyuan Zhao,Meng Song,Yuzhe Guo,Shihao Li,Wensong Tan,Yan Zhou
Exosomes are nanoscale vesicles containing a variety of bioactive factors, showing significant potential as cell-free therapeutic agents. However, the large clinical doses required for exosome administration highlight the need for a scalable serum-free production system to increase exosome yield. In this study, human umbilical cord-derived mesenchymal stem cells (hUCMSCs) were cultured in three-dimensional (3D) environments using polyethylene terephthalate (PET) fiber membranes. Two key pathways promoting exosome secretion and biogenesis through 3D culture were identified. Specifically, 3D culture reduced the expression of Integrin β1, leading to the decondensation of cortical actin, and increased the expression of RAC1, which promoted actin aggregation on the membranes of multivesicular bodies (MVBs). Building on this mechanistic understanding, we simulated the depolymerization/aggregation of the cytoskeleton in 3D culture and designed a serum-free medium optimized for exosome production. For large-scale exosome production, hUCMSCs were cultured in a fixed-bed bioreactor using PET fiber rolls as the fixed-bed layer with the developed serum-free medium. This setup increased exosome production per cell by 16-fold compared to 2D culture, yielding 2.6 × 10^14 exosome particles. The exosome products demonstrated enhanced in vitro angiogenesis, immunomodulation, and in vivo wound healing capabilities. This study provides valuable insights and strategic guidance for the serum-free, large-scale production of exosomes using bioreactors, with significant implications for therapeutic applications.
研究领域:
细胞生物学
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再生医学
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生物工程
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DOI
高影响因子
Chinese Medicine
·
2024
·Vol. 19
·期 1
·1-17
·
IF 5.3
Gao Jiaming,Guo Hao,Li Junmei,Zhan Min,You Yue,Xin Gaojie,Liu Zixin,Fan Xiaodi,Gao Qinghe,Liu Jianxun,Zhang Yehao,Fu Jianhua
Background Buyang Huanwu Decoction (BYHWD) is a traditional Chinese medicine to treat the syndrome of qi deficiency and blood stasis. Platelets play an important role in regulating thrombus and inflammation after ischemic injury, studies have shown that BYHWD regulate myocardial fibrosis and exert anti-inflammatory effects through IL-17 and TLR4 pathways, but the mechanism of platelet activation by BYHWD in stable coronary heart disease is still unknown. In the present study, model of left anterior descending coronary artery ligation was applied to investigate the mechanisms of BYHWD on modulating platelets hyperreactivity and heart function after fibrosis of ischemic myocardial infarction (MI). Methods Myocardial infarction model was constructed by ligation of the left anterior descending coronary artery. The rats were randomly divided into five groups: sham, model, MI with aspirin (positive), MI with a low dosage of BYHWD (BYHWD-ld) and MI with a high dosage of BYHWD (BYHWD-hd) for 28 days. Results Coronary artery ligation prominently induced left ventricle dysfunction, increased cardiomyocyte fibrosis, which was accompanied by platelets with hyperreactivity, and high levels of inflammatory factors. BYHWD obviously reversed cardiac dysfunction and fibrosis, increased the thickness of the left ventricular wall, and inhibited aggregation ratio and CD62p expression. BYHWD restored the mitochondrial respiration of platelets after MI, concomitant with an increased telomere expression and decreased inflammation. According to the result of transcriptome sequencing, we found that 106 differentially expressed genes compared model with BYHWD treatment. Enrichment analysis screened out the Ras-related protein Rap-1 (Rap1) signaling pathway and platelet activation biological function. Quantitative real-time PCR and Western blotting were applied to found that BYHWD reduced the expression of Rap1/PI3K-Akt/Src-CDC42 genes and attenuated the overactivity of PI3 kinase/Rap1/integrin α(IIb)β(3) pathway. Conclusion BYHWD reduced inflammation and platelet activation via the PI3 kinase/Rap1/integrin α(IIb)β(3) pathway and improved heart function after MI. Graphical Abstract
研究领域:
中医
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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
MOLECULAR PHARMACEUTICS
·
2018
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IF 4.556
Shihong Shao,Yun Zhu,Tingting Meng,Yupeng Liu,Yun Hong,Ming Yuan,Hong Yuan,Fuqiang Hu
Liver metastasis is a leading death cause in colorectal cancer. The pathological differences between orthotopic tumors and metastatic lesions increased the therapeutic difficulty of metastasis. Herein, the α5β1 integrin receptor expression on metastatic cells was first measured, the result showed that metastatic cells expressed the α5β1 integrin higher than that of the original cells from orthotopic tumors. Afterward, RPM peptide-modified chitosan-stearic (RPM-CSOSA) was designed based on α5β1 integrin expression. The cytotoxicity and resistance to migration and the invasion ability of the targeting drug delivery system loading doxorubicin (DOX) and curcumin (CUR) were evaluated in vitro. The metastatic inhibition of the targeting drug delivery system was also investigated in HT29 liver metastatic models. The modified RPM peptide could increase the cellular internalization of CSOSA micelles in metastatic tumor cells and endothelial cells mediated by α5β1 integrin. The synergistic effects of RPM-CSOSA/DOX and RPM-CSOSA/CUR could obviously inhibit migratory and invasive abilities of HT29 cells and endothelial cells. Moreover, the RPM-CSOSA/DOX&RPM-CSOSA/CUR could obviously decrease the number of metastatic sites by 86.96%, while CSOSA/DOX&CSOSA/CUR decreased liver metastasis by 66.58% compared with that in the saline group. In conclusion, the RPM peptide-modified drug delivery system may provide insights into targeting the metastatic cells overexpressing the α5β1 integrin, and it has the potential to inhibit liver metastasis of colorectal cancer.
研究领域:
肿瘤学
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药剂学
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分子生物学
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DOI
PubMed
高影响因子
Frontiers in Oncology
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2022
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IF 5.738
Long Yu,Shao Fuqiang,Ji Hao,Song Xiangming,Lv Xiaoying,Xia Xiaotian,Liu Qingyao,Zhang Yongxue,Zeng Dexing,Lan Xiaoli,Gai Yongkang
Ovarian cancer has the highest mortality rate of gynecologic malignancy. 18F-FDG positron emission tomography (PET) adds an important superiority over traditional anatomic imaging modalities in oncological imaging but has drawbacks including false negative results at the early stage of ovarian cancer, and false positives when inflammatory comorbidities are present. Aminopeptidase N (APN, also known as CD13) and integrin αvβ3 are two important targets overexpressed on tumor neo-vessels and frequently on ovarian cancerous cells. In this study, we used subcutaneous and metastatic models of ovarian cancer and muscular inflammation models to identify 68Ga-NGR-RGD, a heterodimeric tracer consisting of NGR and RGD peptides targeting CD13 and integrin αvβ3, respectively, and compared it with 18F-FDG. We found that 68Ga-NGR-RGD showed greater contrast in SKOV3 and ES-2 tumors than 18F-FDG. Low accumulation of 68Ga-NGR-RGD but avid uptake of 18F-FDG were observed in inflammatory muscle. In abdominal metastasis models, PET imaging with 68Ga-NGR-RGD allowed for rapid and clear delineation of both peritoneal and liver metastases (3-6 mm), whereas, 18F-FDG could not distinguish the metastasis lesions due to the relatively low metabolic activity in tumors and the interference of intestinal physiological 18F-FDG uptake. Due to the high tumor-targeting efficacy, low inflammatory uptake, and higher tumor-to-background ratios compared to that of 18F-FDG, 68Ga-NGR-RGD presents a promising imaging agent for diagnosis, staging, and follow-up of ovarian tumors.
研究领域:
肿瘤学
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医学影像学
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分子生物学
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癌症研究
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产品关联
DOI
PubMed
高影响因子
JOURNAL OF MEDICINAL CHEMISTRY
·
2025
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IF 6.8
Chaoming Wang,Jing Zhang,Dongping Wang,Shengle Chen,Qi Yuan,Ruijuan Yin,Guiyang Yao,Xin Qi,Jing Li,Tao Jiang
Peptide–drug conjugates (PDCs) targeting integrin αvβ3 represent a promising strategy for tumor-targeted therapies. We designed and synthesized a series of integrin αvβ3-selective PDCs (PDC-1 to PDC-5) using a 1,3,5-triazine-based linker to conjugate the camptothecin derivative with the c(RGDfC) peptide. Among these, PDC-2 exhibited high stability in plasma, selective internalization via integrin αvβ3, efficient cell binding, and potent cytotoxicity. Additionally, it induced apoptosis of A549 and AsPC-1 cells and inhibited their adhesion, migration, and invasion in a concentration-dependent manner. Mechanistically, PDC-2 dually inhibits Survivin protein expression and the PI3K/AKT/mTOR signaling pathway. In A549 and AsPC-1 xenograft models, PDC-2 demonstrated superior tumor growth inhibition, reduced systemic toxicity, and enhanced tumor specificity compared to FL118. Pharmacokinetically, it enabled a sustained release of FL118, extending its half-life by 3.4-fold and promoting targeted tumor accumulation, positioning it as a promising therapeutic for lung and pancreatic cancers.
研究领域:
肿瘤学
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药学
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分子靶向治疗
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药物递送
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癌症生物学
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药物化学
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产品关联
DOI
PubMed
高影响因子
Journal of Cancer
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2020
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IF 3.565
Ying Song,Chen Li,Yahan Fu,Qiu Xie,Jun Guo,Guangming Li,Huiwen Wu
The integrin receptor protein talin plays vital roles in intracellular chemical and mechanical activities, and it is implicated in the high invasion and poor prognosis of non-small cell lung cancer (NSCLC). To better understand the mechanism underlying the function of talin in NSCLC invasion and metastasis, a few newly designed tension probe based on Förster resonance energy transfer was used for real-time observation of tension changes in A549 cells. High NSCLC cell aggressiveness was found to be accompanied with inward talin and outward glial fibrillary acidic protein (GFAP) tensions, which are closely associated with microfilament (MF) force and intracellular osmotic potential. The increased osmotic pressure resulted from the production of intracellular protein nanoparticles and the related ion influx. Furthermore, integrin activation was found to adjust the talin and GFAP tensions. Disruption of the interaction between talin and MFs blocked the mechanical source of talin, reducing both talin tension and osmotic pressure and thus inhibiting NSCLC cell invasion and migration. Consequently, our study demonstrates that talin is involved in NSCLC invasion and migration via its inward tension and that the integrin pathway is correlated closely with protein-nanoparticle-induced outward osmotic pressure.
研究领域:
癌症生物学
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细胞生物学
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分子生物学
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生物物理学
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产品关联
DOI
PubMed
高影响因子
EXPERIMENTAL CELL RESEARCH
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2022
·
IF 4.145
Runze Zhao,Li Yang,Shuangjian He,Tingting Xia
Intervertebral disc degeneration (IVDD) is a main contributor to induce low back pain, and the pathogenic mechanism of IVDD remains unclear. The nucleus pulposus (NP) is a component of the intervertebral disc (IVD) that provides protection from mechanical stimuli. The matrix stiffness of NP tissue increases during the process of disc degeneration. Although several studies have found that pathological mechanical stimuli induce NP cell senescence, which is relevant for NP degeneration, however, the effect of matrix stiffness on NP cell senescence is not clear. Therefore, in the present study, we used polyvinyl alcohol (PVA) hydrogel with controllable stiffness to mimic the matrix stiffness of normal (4 kPa) and severely degenerated (20 kPa) NP tissue. Rat NP cells were isolated and cultured on substrates with different stiffness, and the cell proliferation , SA-β-gal activity, cell cycle, telomerase activity and the phenotype markers of NP cells were analyzed. Moreover, cytoskeleton staining and NP cellular Young's modulus on different substrates were also measured. To further investigate how substrate stiffness affects NP cell senescence, lysyl oxidase (LOX) was used to restore the extracellular matrix (ECM) synthesis of NP cells. The expression levels of integrin β1 and p38 MAPK were then measured. Our results showed that the 20 kPa substrate significantly induced NP cell senescence compared to the 4 kPa substrate. NP cells cultured on the 20 kPa substrate failed to maintain the expression of their phenotype markers. Furthermore, the 20 kPa substrate induced an increase of Young's modulus of NP cells, which possibly through up regulating the expressions of integrin β1 and p38 MAPK. These results indicated that the integrin β1-p38 MAPK signaling pathway may participated in substrate stiffness induced senescence of NP cells. LOX significantly increased ECM synthesis and inhibited substrate stiffness induced NP cell senescence, which indicated that matrix mechanics may be essential for maintaining the function of NP cell. Our results may provide a new perspective on the mechanism of IVDD by pathological matrix mechanics.
研究领域:
骨科
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细胞生物学
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生物力学
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产品关联
DOI
PubMed
高影响因子
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