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Poly-L-ornithine blocks the inhibitory effects of fibronectin on oligodendrocyte differentiation and promotes myelin repair

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Neural Regeneration Research 2023年第4期18卷 832-839页

作者： Ya-Jie Xiong Shahid Hussain Soomro Zhong-Hai Huang Pan-Pan Yu Jie Ping Hui Fu Department of Anatomy School of Basic Medical SciencesWuhan UniversityWuhanHubei ProvinceChina Guangdong-Hongkong-Macao Institute of CNS Regeneration Ministry of Education Joint International Research Laboratory of CNS RegenerationJinan UniversityGuangzhouGuangdong ProvinceChina Department of Pharmacology School of Basic Medical SciencesWuhan UniversityWuhanHubei ProvinceChina

The extracellular matrix surrounding oligodendrocytes plays an important role during myelination and remyelination in the brain.In many cases,the microenvironment surrounding demyelination lesions contains inhibitory molecules,which lead to repair failure.Accordingly,blocking the activity of these inhibitory factors in the extracellular matrix should lead to more successful remyelination.In the central nervous system,oligodendrocytes form the myelin sheath.We performed primary cell culture and found that a natural increase in fibronectin promoted the proliferation of oligodendrocyte progenitors during the initial stage of remyelination while inhibiting oligodendrocyte differentiation.Poly-L-ornithine blocked these inhibitory effects without compromising fibronectin’s pro-proliferation function.Experiments showed that poly-L-ornithine activated the Erk1/2 signaling pathway that is necessary in the early stages of differentiation,as well as PI3K signaling pathways that are needed in the mid-late stages.When poly-L-ornithine was tested in a lysolecithin-induced animal model of focal demyelination,it enhanced myelin regeneration and promoted motor function recovery.These findings suggest that poly-L-ornithine has the potential to be a treatment option for clinical myelin sheath injury.

关键词： differentiation Erk1/2 extracellular matrix fibronectin lysolecithin-induced demyelination oligodendrocyte PI3K poly-L-ornithine proliferation remyelination

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The role of fibronectin in multiple sclerosis and the effect of drug delivery across the blood-brain barrier

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Neural Regeneration Research 2023年第10期18卷 2147-2155页

作者： Shuang-Shuang Wei Le Chen Feng-Yuan Yang Si-Qi Wang Peng Wang Ningxia Key Laboratory of Craniocerebral Diseases School of Clinical MedicineNingxia Medical UniversityYinchuanNingxia Hui Autonomous RegionChina Ningxia Key Laboratory of Craniocerebral Diseases Ningxia Medical UniversityYinchuanNingxia Hui Autonomous RegionChina

Remyelination failure is one of the main characteristics of multiple sclerosis and is potentially correlated with disease progression.Previous research has shown that the extracellular matrix is associated with remyelination failure because remodeling of the matrix often fails in both chronic and progressive multiple sclerosis.fibronectin aggregates are assembled and persistently exist in chronic multiple sclerosis,thus inhibiting remyelination.Although many advances have been made in the mechanisms and treatment of multiple sclerosis,it remains very difficult for drugs to reach pathological brain tissues;this is due to the complexity of brain structure and function,especially the existence of the blood-brain barrier.Therefore,herein,we review the effects of fibronectin aggregates on multiple sclerosis and the efficacy of different forms of drug delivery across the blood-brain barrier in the treatment of this disease.

关键词： blood-brain barrier brain delivery exosomes extracellular matrix fibronectin aggregates fibronectin intestinal flora multiple sclerosis remyelination failure remyelination

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Neuroprotective role of fibronectin in neuron-glial extrasynaptic transmission

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Neural Regeneration Research 2013年第4期8卷 376-382页

作者： Jintang Wang Ling Yin Zheng Chen Institute for Geriatric Clinic and Rehabilitation Beijing Geriatric Hospital Institute of Medical Informatics General Hospital of PLA

Most hypotheses concerning the mechanisms underlying Parkinson＇s disease are based on altered synaptic transmission of the nigrostriatal system. However, extrasynaptic transmission was recently found to affect dopamine neurotransmitter delivery by anisotropic diffusion in the extracellular matrix which is modulated by various extracellular matrix components such as flbronectin. The present study reviewed the neuroprotective effect of fibronectin in extrasynaptic transmission. fibronectin can regulate neuroactive substance diffusion and receptor activation, and exert anti- neuroinflammatory, adhesive and neuroprotective roles. fibronectin can bind to integrin and growth factor receptors to transactivate intracellular signaling events such as the phosphatidylinositol 3-kinase/protein kinase B pathway to regulate or amplify growth factor-like neuroprotective actions. fibronectin is assembled into a fibrillar network around cells to facilitate cell migration, molecule and ion diffusion, and even drug delivery and treatment. In addition, the present study analyzed the neuroprotective mechanism of fibronectin in the pathogenesis of Parkinson＇s disease, involving integrin and growth factor receptor interactions, and discussed the possible therapeutic and diagnostic significance of fibronectin in Parkinson＇s disease.

关键词： neural regeneration neurodegenerative diseases Parkinson＇s disease fibronectin integrin extrasynaptic transmission neuroglia neuroprotection grants-supported paper photographs-containing paper neuroregeneration

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Activated vascular endothelia regulate invasion of glioma cells through expression of fibronectin

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Chinese Medical Journal 2010年第13期123卷 1754-1761页

作者： LIN Zhi-xiong YANG Li-juan HUANG Qiang FU Jin Department of Neurosurgery the First Affiliated Hospital Fujian Medical University Fuzhou Fujian 350005 China Department of Pharmacology Fujian Medical University Fuzhou Fujian 350004 China Department of Neurosurgery the Second Hospital Suzhou University Suzhou Jiangsu 215004 China Department of Pharmacology the School of Medicine Xiamen University Xiamen 361005 China Department of Pharmacology University of California Irvine USA

Background Previous researches have indicated that glioma invasion may occur within a tumor-host microecology, and that fibronectin may be involved in glioma invasion as an important component of the extracellular matrix. However, how the interaction between tumor cells and vascular endothelial cells affects glioma invasion is poorly understood. The aim of this study was to investigate the effects of the interaction between tumor cells and vascular endothelial cells on glioma invasion, and the relationship of this interaction to fibronectin. Methods The localization of fibronectin in different brain astrocytoma tissues was determined by immunohistochemistry Then, vascular endothelial cells and glioma cells were co-cultured in a Transwell co-culturing system. fibronectin expression was detected by reverse transcriptase-polymerase chain reaction, immunocytochemistry, and enzyme-linked immunosorbent assay. Additionally, the influence of the interaction between tumor cells and vascular endothelial cells on glioma cell invasion was determined by an in vitro rapid invasion test. Results In brain astrocytoma tissues, fibronectin was present on the endothelial cells, in the extracellular matrix. fibronectin expression was greater in higher grade tumors than in lower grade tumors. The interaction of glioma cells and vascular endothelial cells in vitro induced fibronectin release from vascular endothelial cells, which in turn stimulated glioma cell migration. This effect was inhibited by fibronectin blocking antibody. Conclusion Glioma cells may induce vascular epithelial cells to express fibronectin, and in turn fibronectin could promote glioma cell invasion.

关键词： glioma fibronectin neoplasm invasiveness tumor-host microecology cell-to-cell communication

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Role of connective growth factor in plasminogen activator inhibitor-1 and fibronectin expression induced by transforming growth factor β1 in renal tubular cells

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Chinese Medical Journal 2004年第7期117卷 990-996页

作者：张春孟宪芳朱忠华杨晓邓安国 Department of Nephrology Department of Neuroscience

Background Connective tissue growth factor (CTGF) contributes greatly to renal tubulointerstitial fibrosis, which is the final event leading to end-stage renal failure. This study was designed to investigate the effects of CTGF antisense oligodeoxynucleotides (ODNs) on the expressions of plasminogen activator inhibitor-1 (PAI-1) and fibronectin in renal tubular cells induced by transforming growth factor β1 (TGF-β1) in addition to the role of CTGF in the accumulation and degradation of renal extracellular matrix (ECM).Methods A human proximal tubular epithelial cell line (HKC) was cultured in vitro. Cationic lipid-mediated CTGF antisense ODNs were transfected into HKC cells. After HKC cells were stimulated with TGF-β1 (5 μg/L), the mRNA levels of PAI-1 and fibronectin were measured by RT-PCR. Intracellular PAI-1 protein synthesis was assessed by flow cytometry. The secreted PAI-1 and fibronectin in the medium were determined by Western blot and ELISA, respectively.Results TGF-β1 was found to induce tubular CTGF, PAI-1, and fibronectin mRNA expression. PAI-1 and fibronectin mRNA expression induced by TGF-β1 was significantly inhibited by CTGF antisense ODNs. CTGF antisense ODNs also inhibited intracellular PAI-1 protein synthesis and lowered the levels of PAI-1 and fibronectin protein secreted into the medium.Conclusions CTGF may play a crucial role in the accumulation and degradation of excessive ECM during tubulointerstitial fibrosis, and transfecting CTGF antisense ODNs may be an effective way to prevent renal fibrosis.

关键词： connective tissue growth factor antisense oligodeoxynucleotide plasminogen activator inhibitor-1 fibronectin renal tubular epithelial cells

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Dexamethasone enhances invasiveness ofAspergillusfumigatus conidia and fibronectin expression in A549 cells

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Chinese Medical Journal 2013年第17期126卷 3289-3294页

作者： LI Tao LI Jing-chao QI Qian LI Yu Department of Respiratory Medicine Qilu Hospital of Shandong University Jinan Shandong 250012 China

Background The efficacies of current treatments for invasive aspergillus （IA） are unsatisfactory and new therapeutic targets or regimens to treat IA are urgently needed. Previous studies have indicated that the ability of conidia to invade host cells is critical in IA development and fibronectin has a hand in the conidia adherence process. In the clinical setting, many patients who receive glucocorticoid for extended periods are susceptible to Aspergillus fumigatus （A. fumigatus） infection, for this reason we investigated the effect of glucocorticoid on conidia invasiveness by comparing the invasiveness of A. fumigatus conidia in the type II human alveolar cell line （A549） cultured with different concentrations of dexamethasone. We also explored the relationships between dexamethasone and fibronectin expression. Methods Following culture with anti-fibronectin antibodies and/or dexamethasone, type II human alveolar A549 cells were infected with conidia of A. fumigatus. After 4 hours, the extracellular free conidia were washed away and the remaining immobilized conidia were released using Triton-X 100 and quantified by counting the colony-forming units. The invasiveness of conidia was measured by calculating the invasion rate （%）. The transcription of the fibronectin gene in cells cultured with different concentrations of dexamethasone for 24 hours was tested by fluorogenic quantitative RT-PCR while the expression of fibronectinin cells cultured for 48 hours was tested by Western blotting and immunocytochemistry. Results A significant reduction in the invasiveness of conidia was seen in the cells cultured with anti-fibronectin antibody （（14.42±1.68）% vs. （19.17±2.53）%, P 〈0.05）, but no significant difference was observed in cells cultured with a combination of anti-fibronectin antibody and dexamethasone （6.37×10^-5 mol/L）. There was no correlation between the dexamethasone concentration and the invasiveness of conidia after dexamethasone pretreatment of cells for 4 hours. In contrast, after pretreated for 24 hours,

关键词： Aspergillus fumigatus conidia invasiveness dexamethasone fibronectin

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MYC retards cancer cell migration through suppressing fibronectin expression

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Science Bulletin 2019年第11期64卷 715-717页

作者： Mengjia Zhao Peng Jiang Wenjing Du School of Life Sciences Tsinghua UniversityCollaborative Innovation Center for Cancer MedicineBeijing 100084China State Key Laboratory of Medical Molecular Biology Key Laboratory of RNA Regulation and HematopoiesisDepartment of Cell BiologyInstitute of Basic Medical SciencesChinese Academy of Medical SciencesSchool of Basic MedicinePeking Union Medical CollegeBeijing 100005China

The oncoprotein MYC is a transcription factor that regulates arange of genes involved in various biological processes includingcell cycle arrest, cell proliferation, metabolism, protein synthesisand genomic instability. Recently, MYC has been shown playing arole in regulating cancer cell metastasis, while outcomes of thisregulation remain controversial. In some breast tumors, MYCaccelerates metastasis by elevating miR-9 miRNA expression [1].However, under certain circumstance, MYC activation may havean opposite function in suppressing cell motility and impairingcancer invasion [2-4]. Intriguingly, through direct suppressingexpressions of av and p3 integrin subunits, MYC impedes breastcancer cell metastasis [3]. Moreover, MYC blocks JNK signalingand consequently causes reduced tumor cell migration [5]. Therefore,the role of MYC in cell migration is largely unknown andneeds further investigation.

关键词： MYC retards cancer cell suppressing fibronectin expression

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Mechanistic insights into the adsorption and bioactivity of fibronectin on surfaces with varying chemistries by a combination of experimental strategies and molecular simulations

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Bioactive Materials 2021年第10期6卷 3125-3135页

作者： Lijing Hao Tianjie Li Lin Wang Xuetao Shi Yan Fan Chang Du Yingjun Wang School of Materials Science and Engineering South China University of TechnologyGuangzhou510640China Department of Physics The Chinese University of Hong KongShatinN.T.Hong Kong National Engineering Research Center for Tissue Restoration and Reconstruction Guangzhou510006China Key Laboratory of Biomedical Engineering of Guangdong Province Guangzhou510006China Key Laboratory of Biomedical Materials and Engineering of the Ministry of Education Guangzhou510006China Innovation Center for Tissue Restoration and Reconstruction Guangzhou510006China Bioland Laboratory(Guangzhou Regenerative Medicine and Health Guangdong Laboratory) Guangzhou510005China

fibronectin(Fn)is significant to the performance of biomaterials,and the chemistry of biomaterial surface play important roles in Fn adsorption and subsequent cell behavior.However,the“molecular scale”mechanism is still unclear.Herein,we combined experimental strategies with molecular simulations to solve this problem.We prepared self-assembled monolayers with varying chemistries,i.e.,SAMs-CH3,SAMs-NH2,SAMs-COOH and SAMs-OH,and characterized Fn adsorption and cell behaviors on them.Next,Monte Carlo method and all-atom molecular dynamics simulations were employed to reveal the orientation/conformation of Fn on surfaces.We found that SAMs-CH3 strongly adsorbed Fn via hydrophobic interactions,but show poor bioactivity as the low exposure of RGD/PHSRN motifs and the deformation of Fn.SAMs-NH2 and SAMs-COOH could adsorb Fn efficiently via vdW interactions,electrostatic interactions,hydrogen bonds and salt bridges.Fn exhibited excellent bioactivity for cell adhesion,proliferation and osteogenic differentiation as high exposure of bioactive motifs on SAMs-NH2,or as the activation of other inferior cell-binding motifs on SAMs-COOH.SAMs-OH showed poor Fn adsorption as the water film.However,the adsorbed Fn displayed non-negligible bioactivity due to high exposure of PHSRN motif and large degree of protein flexibility.We believe that the revealed mechanism presents great potential to rationally design Fn-activating biomaterials.

关键词： fibronectin Self-assembled hBMSCs Molecular dynamics simulation Orientation

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Triptolide inhibits TGF-β-induced matrix contraction and fibronectin production mediated by human Tenon fibroblasts

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International Journal of Ophthalmology(English edition) 2018年第7期11卷 1108-1113页

作者： Yang Liu Ping-Ping Liu Lei Liu Xiao-Shuo Zheng Hui Zheng Cheng-Cheng Yang Ci-Ren Luobu Ye Liu Department of Ophthalmology the Fifth Affiliated Hospital Sun Yat-sen University Department of Ophthalmology the First Hospital of Jilin University Department of Pathology the Fifth Affiliated Hospital Sun Yat-sen University

AIM： To determine if triptolide influences the contractility and fibronectin production in human Tenon fibroblasts（HTFs）. METHODS： HTFs were cultured in type I collagen gels with or without transforming growth factor beta（TGF-β） and/or triptolide. The diameter of the collagen gel was used to measure contraction. Immunoblot analysis was used to quantify myosin light chain（MLC） phosphorylation and integrin expression. Laser confocal fluorescence microscopy was used to monitor the formation of actin stress fibers. fibronectin production was measured with an enzyme immunoassay. RESULTS： Triptolide inhibition of contraction in TGF-β-induced collagen gel mediated by HTFs was dosedependent and statistically significant at 3 nmol/L（P〈0.05） and maximal at 30 nmol/L and significantly time dependent at 2 d（P〈0.05）. Triptolide reduced TGF-β-induced expression of integrins α5 and β1, phosphorylation of MLC, and formation of stress fibers in HTFs. Furthermore, the inhibition of triptolide on the attenuated TGF-β-induced production of fibronectin by HTFs was concentration-dependent and significant at 1 nmol/L（P〈0.05） and maximal at 30 nmol/L. CONCLUSION： Triptolide suppress the contractility of HTFs induced by TGF-β and the production of fibronectin by these cells. It is promising that triptolide treatment may possibly inhibit scar formation after glaucoma filtration surgery.

关键词： Tenon fibroblast triptolide transforming growth factor β wound healing fibronectin

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Novel fibronectin-targeted nanodisk drug delivery system displayed superior efficacy against prostate cancer compared with nanospheres

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Nano Research 2019年第10期12卷 2451-2459页

作者： Luyao Wang Bingjie Zhou Shiqi Huang Mengke Qu Qing Lin Tao Gong Yuan Huang Xun Sun Qin He Zhirong Zhang Ling Zhang Key Laboratory of Drug Targeting and Drug Delivery Systems Ministry of EducationWest China School of PharmacyCollege of Polymer Science and EngineeringSichuan UniversityChengdu 610041China

Currently,prostate cancer is the most frequently diagnosed cancer in males and chemotherapy is often essential for treating advaneed prostate cancer.However,common chemotherapies for prostate cancer suffer from serious adverse effects due to poor drug targeting ability and tissue penetration,even with the help of conventional drug delivery systems.Here,encouraged by recent studies showing possible drug retention and tissue pen etration advan tages of unconventional non-spherical nan oparticles over conventional spherical nan oparticles,we design and construct a novel non-spherical nano disk drug delivery system for treating prostate cancer.norder to enhance tumor-targeting capability,these nanodisks are further modified with targeting peptide,Cys-Arg-Glu丄ys?Ala peptide with N-methylated Glu(CR(NMe)EKA),which recognizes extracellular matrix fibronectin and its complexes specifically expressed on the walls of tumor vessels and in tumor stroma.Compared with conventional nano spheres,the nano disks achieve much higher drug accumulati on at prostate tumor sites.When loaded with paclitaxel,the CR(NMe)EKA-modified nan odisks display superior an titumor efficacy to free paclitaxel,unmodified nan odisks and nano spheres.In summary,our study provides an attractive therapeutic strategy for targeted therapy against prostate cancer with simple preparation,high efficiency and low toxicity,and supplements a theoretical support for treatments realized by different shaped nano platforms.Our study also offers valuable data for understa nding biological effects of non-spherical nano disks and highlights the great pote ntial of unconventional nan oparticles in biomedical applicati ons.

关键词： Cys-Arg-Glu-Lys-Ala peptide with N-methylated Glu(CR(NMe)EKA) fibronectin nanodisks prostate cancer tumor-targeting

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