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1.
The role of integrin glycosylation in galectin-8-mediated trabecular meshwork cell adhesion and spreading 总被引:2,自引:0,他引:2
Primary open angle glaucoma (POAG) is a major blindness-causingdisease, characterized by elevated intraocular pressure dueto an insufficient outflow of aqueous humor. The trabecularmeshwork (TM) lining the aqueous outflow pathway modulates theaqueous outflow facility. TM cell adhesion, cell–matrixinteractions, and factors that influence Rho signaling in TMcells are thought to play a pivotal role in the regulation ofaqueous outflow. In a recent study, we demonstrated that galectin-8(Gal8) modulates the adhesion and cytoskeletal arrangement ofTM cells and that it does so through binding to β1 integrinsand inducing Rho signaling. The current study is aimed at thecharacterization of the mechanism by which Gal8 mediates TMcell adhesion and spreading. We demonstrate here that TM cellsadhere to and spread on Gal8-coated wells but not on galectin-1(Gal1)- or galectin-3 (Gal3)-coated wells. The adhesion of TMcells to Gal8-coated wells was abolished by a competing sugar,β-lactose, but not by a noncompeting sugar, sucrose. Also,a trisaccharide, NeuAc2-3Galβ1-4GlcNAc, which binds specificallyto the N-CRD of Gal8, inhibited the spreading of TM cells toGal8-coated wells. In contrast, NeuAc2-6Galβ1-4GlcNAc whichlacks affinity for Gal8 had no effect. Affinity chromatographyof cell extracts on a Gal8-affinity column and binding experimentswith plant lectins, Maakia Amurensis and Sambucus Nigra, revealedthat 3β1, 5β1, and vβ1 integrins are major counterreceptorsof Gal8 in TM cells and that TM cell β1 integrins carrypredominantly 2-3-sialylated glycans, which are high-affinityligands for Gal8 but not for Gal1 or Gal3. These data lead usto propose that Gal8 modulates TM cell adhesion and spreading,at least in part, by interacting with 2-3-sialylated glycanson β1 integrins. 相似文献
2.
Background
Cellular processes occur within dynamic and multi-molecular compartments whose characterization requires analysis at high spatio-temporal resolution. Notable examples for such complexes are cell-matrix adhesion sites, consisting of numerous cytoskeletal and signaling proteins. These adhesions are highly variable in their morphology, dynamics, and apparent function, yet their molecular diversity is poorly defined.Methodology/Principal Findings
We present here a compositional imaging approach for the analysis and display of multi-component compositions. This methodology is based on microscopy-acquired multicolor data, multi-dimensional clustering of pixels according to their composition similarity and display of the cellular distribution of these composition clusters. We apply this approach for resolving the molecular complexes associated with focal-adhesions, and the time-dependent effects of Rho-kinase inhibition. We show here compositional variations between adhesion sites, as well as ordered variations along the axis of individual focal-adhesions. The multicolor clustering approach also reveals distinct sensitivities of different focal-adhesion-associated complexes to Rho-kinase inhibition.Conclusions/Significance
Multicolor compositional imaging resolves “molecular signatures” characteristic to focal-adhesions and related structures, as well as sub-domains within these adhesion sites. This analysis enhances the spatial information with additional “contents-resolved” dimensions. We propose that compositional imaging can serve as a powerful tool for studying complex multi-molecular assemblies in cells and for mapping their distribution at sub-micron resolution. 相似文献3.
Background
Adhesion dependent mechanisms are increasingly recognized to be important for a wide range of biological processes, diseases and therapeutics. This has led to a rising demand of pharmaceutical modulators. However, most currently available adhesion assays are time consuming and/or lack sensitivity and reproducibility or depend on specialized and expensive equipment often only available at screening facilities. Thus, rapid and economical high-content screening approaches are urgently needed.Results
We established a fully open source high-content screening method for identifying modulators of adhesion. We successfully used this method to detect small molecules that are able to influence cell adhesion and cell spreading of Swiss-3T3 fibroblasts in general and/or specifically counteract Nogo-A-Δ20-induced inhibition of adhesion and cell spreading. The tricyclic anti-depressant clomipramine hydrochloride was shown to not only inhibit Nogo-A-Δ20-induced cell spreading inhibition in 3T3 fibroblasts but also to promote growth and counteract neurite outgrowth inhibition in highly purified primary neurons isolated from rat cerebellum.Conclusions
We have developed and validated a high content screening approach that can be used in any ordinarily equipped cell biology laboratory employing exclusively freely available open-source software in order to find novel modulators of adhesion and cell spreading. The versatility and adjustability of the whole screening method will enable not only centers specialized in high-throughput screens but most importantly also labs not routinely employing screens in their daily work routine to investigate the effects of a wide range of different compounds or siRNAs on adhesion and adhesion-modulating molecules. 相似文献4.
Julie A. Cakebread Hans Michael Haitchi Yunhe Xu Stephen T. Holgate Graham Roberts Donna E. Davies 《PloS one》2014,9(4)
Background
In response to viral infection, bronchial epithelial cells increase inflammatory cytokine release to activate the immune response and curtail viral replication. In atopic asthma, enhanced expression of Th2 cytokines is observed and we postulated that Th2 cytokines may augment the effects of rhinovirus-induced inflammation.Methods
Primary bronchial epithelial cell cultures from pediatric subjects were treated with Th2 cytokines for 24 h before infection with RV16. Release of IL-8, IP-10 and GM-CSF was measured by ELISA. Infection was quantified using RTqPCR and TCID50. Phosphatidyl inositol 3-kinase (PI3K) and P38 mitogen activated protein kinase (MAPK) inhibitors and dexamethasone were used to investigate differences in signaling pathways.Results
The presence of Th2 cytokines did not affect RV replication or viral titre, yet there was a synergistic increase in IP-10 release from virally infected cells in the presence of Th2 cytokines. Release of IL-8 and GM-CSF was also augmented. IP-10 release was blocked by a PI3K inhibitor and IL-8 by dexamethasone.Conclusion
Th2 cytokines increase release of inflammatory cytokines in the presence of rhinovirus infection. This increase is independent of effects of virus replication. Inhibition of the PI3K pathway inhibits IP-10 expression. 相似文献5.
Caio Cesar de Souza Alves Adam Collison Luke Hatchwell Maximilian Plank Matthew Morten Paul S. Foster Sebastian L. Johnston Cristiane Fran?a da Costa Mauro Vieira de Almeida Henrique Couto Teixeira Ana Paula Ferreira Joerg Mattes 《PloS one》2013,8(11)
Background
Severe asthma is associated with T helper (TH) 2 and 17 cell activation, airway neutrophilia and phosphoinositide-3-kinase (PI3K) activation. Asthma exacerbations are commonly caused by rhinovirus (RV) and also associated with PI3K-driven inflammation. Anthraquinone derivatives have been shown to reduce PI3K-mediated AKT phosphorylation in-vitro.Objective
To determine the anti-inflammatory potential of anthraquinones in-vivo.Methods
BALB/c mice were sensitized and challenged with crude house dust mite extract to induce allergic airways disease and treated with mitoxantrone and a novel non-cytotoxic anthraquinone derivative. Allergic mice were also infected with RV1B to induce an exacerbation.Results
Anthraquinone treatment reduced AKT phosphorylation, hypoxia-inducible factor-1α and vascular endothelial growth factor expression, and ameliorated allergen- and RV-induced airways hyprereactivity, neutrophilic and eosinophilic inflammation, cytokine/chemokine expression, mucus hypersecretion, and expression of TH2 proteins in the airways. Anthraquinones also boosted type 1 interferon responses and limited RV replication in the lung.Conclusion
Non-cytotoxic anthraquinone derivatives may be of therapeutic benefit for the treatment of severe and RV-induced asthma by blocking pro-inflammatory pathways regulated by PI3K/AKT. 相似文献6.
Background
The Drosophila pupal eye has become a popular paradigm for understanding morphogenesis and tissue patterning. Correct rearrangement of cells between ommatidia is required to organize the ommatidial array across the eye field. This requires cell movement, cell death, changes to cell-cell adhesion, signaling and fate specification.Methodology
We describe a method to quantitatively assess mis-patterning of the Drosophila pupal eye and objectively calculate a ‘mis-patterning score’ characteristic of a specific genotype. This entails step-by-step scoring of specific traits observed in pupal eyes dissected 40–42 hours after puparium formation and subsequent statistical analysis of this data.Significance
This method provides an unbiased quantitative score of mis-patterning severity that can be used to compare the impact of different genetic mutations on tissue patterning. 相似文献7.
Willian F. Zambuzzi Estevam A. Bonfante Ryo Jimbo Mariko Hayashi Martin Andersson Gutemberg Alves Esther R. Takamori Paulo J. Beltr?o Paulo G. Coelho José M. Granjeiro 《PloS one》2014,9(7)
Background
It is known that physico/chemical alterations on biomaterial surfaces have the capability to modulate cellular behavior, affecting early tissue repair. Such surface modifications are aimed to improve early healing response and, clinically, offer the possibility to shorten the time from implant placement to functional loading. Since FAK and Src are intracellular proteins able to predict the quality of osteoblast adhesion, this study evaluated the osteoblast behavior in response to nanometer scale titanium surface texturing by monitoring FAK and Src phosphorylations.Methodology
Four engineered titanium surfaces were used for the study: machined (M), dual acid-etched (DAA), resorbable media microblasted and acid-etched (MBAA), and acid-etch microblasted (AAMB). Surfaces were characterized by scanning electron microscopy, interferometry, atomic force microscopy, x-ray photoelectron spectroscopy and energy dispersive X-ray spectroscopy. Thereafter, those 4 samples were used to evaluate their cytotoxicity and interference on FAK and Src phosphorylations. Both Src and FAK were investigated by using specific antibody against specific phosphorylation sites.Principal Findings
The results showed that both FAK and Src activations were differently modulated as a function of titanium surfaces physico/chemical configuration and protein adsorption.Conclusions
It can be suggested that signaling pathways involving both FAK and Src could provide biomarkers to predict osteoblast adhesion onto different surfaces. 相似文献8.
Alexander H. Benz Christoph Renné Erik Maronde Marco Koch Urszula Grabiec Sonja Kallendrusch Benjamin Rengstl Sebastian Newrzela Sylvia Hartmann Martin-Leo Hansmann Faramarz Dehghani 《PloS one》2013,8(12)
Background
Cannabinoid receptor 1 (CB1) is expressed in certain types of malignancies. An analysis of CB1 expression and function in Hodgkin lymphoma (HL), one of the most frequent lymphomas, was not performed to date.Design and Methods
We examined the distribution of CB1 protein in primary cases of HL. Using lymphoma derived cell lines, the role of CB1 signaling on cell survival was investigated.Results
A predominant expression of CB1 was found in Hodgkin-Reed-Sternberg cells in a vast majority of classical HL cases. The HL cell lines L428, L540 and KM-H2 showed strong CB1-abundance and displayed a dose-dependent decline of viability under CB1 inhibition with AM251. Further, application of AM251 led to decrease of constitutively active NFκB/p65, a crucial survival factor of HRS-cells, and was followed by elevation of apoptotic markers in HL cells.Conclusions
The present study identifies CB1 as a feature of HL, which might serve as a potential selective target in the treatment of Hodgkin lymphoma. 相似文献9.
Dong Ling Tong David J. Boocock Gopal Krishna R. Dhondalay Christophe Lemetre Graham R. Ball 《PloS one》2014,9(7)
Objective
To model the potential interaction between previously identified biomarkers in children sarcomas using artificial neural network inference (ANNI).Method
To concisely demonstrate the biological interactions between correlated genes in an interaction network map, only 2 types of sarcomas in the children small round blue cell tumors (SRBCTs) dataset are discussed in this paper. A backpropagation neural network was used to model the potential interaction between genes. The prediction weights and signal directions were used to model the strengths of the interaction signals and the direction of the interaction link between genes. The ANN model was validated using Monte Carlo cross-validation to minimize the risk of over-fitting and to optimize generalization ability of the model.Results
Strong connection links on certain genes (TNNT1 and FNDC5 in rhabdomyosarcoma (RMS); FCGRT and OLFM1 in Ewing’s sarcoma (EWS)) suggested their potency as central hubs in the interconnection of genes with different functionalities. The results showed that the RMS patients in this dataset are likely to be congenital and at low risk of cardiomyopathy development. The EWS patients are likely to be complicated by EWS-FLI fusion and deficiency in various signaling pathways, including Wnt, Fas/Rho and intracellular oxygen.Conclusions
The ANN network inference approach and the examination of identified genes in the published literature within the context of the disease highlights the substantial influence of certain genes in sarcomas. 相似文献10.
11.
Background
Previous research has yielded evidence for enhanced semantic priming in formal thought-disordered schizophrenia patients, a result that fits well with the hypothesis of disinhibited processes of spreading activation in this population.Objective
The current study examined whether hyper priming among schizophrenia patients is an outcome of further spreading of activation of a node or a result of farther activation of nodes in the semantic network. We also try to shed light on the fate of this activation.Methods
The present study tested this hypothesis by using semantic and identical priming in two different experiments. SOA (stimulus onset asynchrony) was manipulated (240 ms vs. 740 ms) within block. It is assumed that among healthy individuals, performance relies on a balance between activation and inhibition processes, contrary to in schizophrenic individuals. In order to examine this hypothesis, we compared formal thought-disordered schizophrenia patients, non thought-disordered schizophrenia patients, and healthy controls.Results
For thought-disordered schizophrenia patients, we found a large positive semantic effect and identical priming effect (129 ms and 154 ms, respectively) only with short SOA. SOA and type of priming did not modulate priming effects in the control groups.Conclusions
This result supports the claim that there is a lack of inhibitory processes among thought-disordered patients. Hyper priming in the thought-disorder group may be an outcome of hyper activation followed by rapid decay below baseline threshold. 相似文献12.
Christian Wolf Jagdev Sidhu Christian Otoul Dexter L. Morris Jennifer Cnops Jorg Taubel Barbara Bennett 《PloS one》2013,8(3)
Background
Lymphocyte inhibition by antagonism of α4 integrins is a validated therapeutic approach for relapsing multiple sclerosis (RMS).Objective
Investigate the effect of CDP323, an oral α4-integrin inhibitor, on lymphocyte biomarkers in RMS.Methods
Seventy-one RMS subjects aged 18–65 years with Expanded Disability Status Scale scores ≤6.5 were randomized to 28-day treatment with CDP323 100 mg twice daily (bid), 500 mg bid, 1000 mg once daily (qd), 1000 mg bid, or placebo.Results
Relative to placebo, all dosages of CDP323 significantly decreased the capacity of lymphocytes to bind vascular adhesion molecule-1 (VCAM-1) and the expression of α4-integrin on VCAM-1–binding cells. All but the 100-mg bid dosage significantly increased total lymphocytes and naive B cells, memory B cells, and T cells in peripheral blood compared with placebo, and the dose-response relationship was shown to be linear. Marked increases were also observed in natural killer cells and hematopoietic progenitor cells, but only with the 500-mg bid and 1000-mg bid dosages. There were no significant changes in monocytes. The number of samples for regulator and inflammatory T cells was too small to draw any definitive conclusions.Conclusions
CDP323 at daily doses of 1000 or 2000 mg induced significant increases in total lymphocyte count and suppressed VCAM-1 binding by reducing unbound very late antigen-4 expression on lymphocytes.Trial Registration
ClinicalTrials.gov NCT00726648. 相似文献13.
Background
It is difficult to experimentally infect volunteers with RV strains to which the subject demonstrates serological immunity. However, in RV challenges, viral clearance begins before de novo adaptive immune responses would develop. We speculated that adaptive immunity to RV reflects heterologous immunity by effector memory cells.Methods
DCs were generated from monocytes using GM-CSF and IL-4 and RV39 loading accomplished with a dose of ∼350 TCID50/105 cells. RV-induced maturation was established as modulation of MHC class II, CD80, CD83, and CD86. Circulating RV targeting CD4 and CD8 T cells were investigated as induction of RV-specific proliferation (CFSE-dilution).Results
Maturation of DC by RV was confirmed as upregulation of MHC Class II (83.3±5.0% to 87.8±4.1%), CD80 (39.4±7.2% to 47.6±7.7%) and CD86 (78.4±4.7% to 84.1±3.4%). Both CD4 and CD8 memory T cells were recognized in the circulation of healthy subjects.Conclusions
RV drives DC maturation and results in their ability to present RV antigens to both T helper and cytotoxic lymphocytes. Both CD4 and CD8 cells capable of recognizing RV-associated antigens are present in the circulation of healthy subjects where they are presumably involved in immune surveillance and explain the rapid recruitment of an adaptive immune response during RV infection. 相似文献14.
Gilbert G. G. Donders Christophe E. Depuydt John-Paul Bogers Annie J. Vereecken 《PloS one》2013,8(12)
Objective
Is Trichomonas vaginalis (TV) an inducing factor for the development of (pre-)cancerous lesions of the cervix?Design
Cross sectional study.Setting
Screening healthy Belgian women with low infection risk.Sample
63,251 consecutive liquid based cervical samples.Methods
Real time quantitative PCR for presence of TV, 18 HPV types and Pap smear analysis of cytologic abnormalities.Main Outcome Measures
Association of TV and HPV with cervix dysplasiaResults
The overall prevalence of TV DNA was 0.37%, of low risk HPV 2%, of high risk HPV 13.2%, and 8.8 % had cytological abnormalities. Both LR-HPV and HR-HPV were significantly associated with all cytological abnormalities. Presence of TV was associated with LR- and HR-HPV, ASC-US and HSIL, but not with other abnormalities. All women with TV and HSIL also had HR-HPV, while the latter was present in only 59% of women with TV and ASC-US. Amongst HPV negative women, TV was found in 1.3% of women with ASC-US, but only in 0.03% of women with normal cytology (OR 4.2, CL95% 2.1-8.6). In HR-HPV positive women, presence of TV increased the likelihood of cytological abnormalities somewhat (P=0.05), mainly due to an increase in ASC-US and LSIL, but not HSIL.Conclusions
We conclude that TV infection is associated with both LR and HR-HPV infection of the cervix, as well as with ASC-US and HSIL. TV is a concomitant STI, but is not thought to be a co-factor in the causation of HSIL and cervical cancer. However, TV may cause false positive diagnoses of ASC-US. 相似文献15.
Objectives
To examine the association of individual income and end of life (EOL) care in older cancer decedents in Taiwan.Design
Retrospective cohort study.Setting
National Health Insurance Research Database (NHIRD) in Taiwan.Participants
28,978 decedents >65 years were diagnosed with cancer and died during 2009-2011 in Taiwan. Of these decedents, 10941, 16535, and 1502 were categorized by individual income as having low, moderate, and high SES, respectively.Main outcome measures
Indicators of aggressiveness of EOL care: chemotherapy use before EOL, more than one emergency department (ER) visit, more than one hospital admission, hospital length of stay >14 days, intensive care unit (ICU) admission, and dying in a hospital.Results
Low individual income was associated with more aggressive EOL treatment (estimate -0.30 for moderate income, -0.27 for high income, both p<0.01). The major source of aggressiveness was the tendency for older decedents with low income to die in the acute care hospital. The indicators had an increasing trend from 2009 to 2011, except for hospital stay >14 days.Conclusions
Low individual income is associated with more aggressive EOL treatment in older cancer decedents. Public health providers should make available appropriate education and hospice resources to these decedents and their families, to reduce the amount of aggressive terminal care such decedents receive. 相似文献16.
Jaeuk Hwang Jieun E. Kim Marc J. Kaufman Perry F. Renshaw Sujung Yoon Deborah A. Yurgelun-Todd Yera Choi Chansoo Jun In Kyoon Lyoo 《PloS one》2013,8(10)
Objective
Adolescent-onset exposure to highly addictive substances such as opiates may induce far-reaching deleterious effects on later mental and physical health. However, little is known about the neurodevelopmental basis for adolescent-onset opiate dependence. Here we examined whether having an abnormally large cavum septum pellucidum (CSP), a putative marker of limbic structural maldevelopment, is associated with opiate dependence particularly beginning in adolescence.Method
The overall length of the CSP and the prevalence of abnormal enlargement of the CSP were assessed and compared in 65 opiate-dependent subjects (41 adolescent-onset opiate users and 24 adult-onset opiate users) and 67 healthy subjects.Results
Opiate-dependent subjects showed a greater prevalence of abnormal CSP enlargement relative to healthy subjects (odds ratio [OR]=3.64, p=0.034). The overall CSP length of adolescent-onset opiate-dependent subjects was greater, as compared not only with healthy subjects (F1,104=11.03, p=0.001) but also with those who began opiate use during adulthood (F1,61=4.43, p=0.039).Conclusions
The current findings provide the first evidence that abnormal CSP enlargement, which reflects limbic system dysgenesis of neurodevelopmental origin, may be linked to later development of opiate dependence. In addition, a greater CSP length, which indicates more severe limbic abnormalities, appears to confer higher risk for earlier onset of opiate use. 相似文献17.
Katy Morgan Roach Stephen Mark Duffy William Coward Carol Feghali-Bostwick Heike Wulff Peter Bradding 《PloS one》2013,8(12)
Background
Idiopathic pulmonary fibrosis (IPF) is a common, progressive and invariably lethal interstitial lung disease with no effective therapy. We hypothesised that KCa3.1 K+ channel-dependent cell processes contribute to IPF pathophysiology.Methods
KCa3.1 expression in primary human lung myofibroblasts was examined using RT-PCR, western blot, immunofluorescence and patch-clamp electrophysiology. The role of KCa3.1 channels in myofibroblast proliferation, wound healing, collagen secretion and contraction was examined using two specific and distinct KCa3.1 blockers (TRAM-34 and ICA-17043 [Senicapoc]).Results
Both healthy non fibrotic control and IPF-derived human lung myofibroblasts expressed KCa3.1 channel mRNA and protein. KCa3.1 ion currents were elicited more frequently and were larger in IPF-derived myofibroblasts compared to controls. KCa3.1 currents were increased in myofibroblasts by TGFβ1 and basic FGF. KCa3.1 was expressed strongly in IPF tissue. KCa3.1 pharmacological blockade attenuated human myofibroblast proliferation, wound healing, collagen secretion and contractility in vitro, and this was associated with inhibition of TGFβ1-dependent increases in intracellular free Ca2+.Conclusions
KCa3.1 activity promotes pro-fibrotic human lung myofibroblast function. Blocking KCa3.1 may offer a novel approach to treating IPF with the potential for rapid translation to the clinic. 相似文献18.
Mincai Li Suqin Li Liangzhu Yu Jiliang Wu Tonghui She Yaping Gan Zhenwu Hu Wenli Liao Hongli Xia 《PloS one》2013,8(12)
Objectives
Recent findings suggest that in response to repair-to-injury bone marrow mesenchymal stem cells (BMSCs) participate in the process of angiogenesis. It is unclear what role BMSCs play in the structure of the vessel wall. In present study, we aimed to determine whether BMSCs had the capacity of endothelial cells (ECs).Methods
BMSCs were separated and cultured. FACS and RT-PCR analysis confirmed the gene expression phenotype. The capacity of migration and adhesion and the ultrastructure of BMSCs were examined. The effect of BMSCs transplantation on the vascular repair was investigated in a murine carotid artery-injured model.Results
BMSCs could express some markers and form the tube-like structure. The migration and adhesion capacity of BMSCs increased significantly after stimulated. In addition, BMSCs had the intact cell junction. In vivo the local transfer of BMSCs differentiated into neo-endothelial cells in the injury model for carotid artery and contributed to the vascular remodeling.Conclusion
These results showed that BMSCs could contribute to neointimal formation for vascular lesion and might be associated with the differentiation into ECs, which indicated the important therapeutic implications for vascular diseases. 相似文献19.
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