The differentiation of cells composing mature human hairs produces layers with different corneous characteristics that would tend to flake away one from another,as in the corneous layer of the epidermis,without anchor...The differentiation of cells composing mature human hairs produces layers with different corneous characteristics that would tend to flake away one from another,as in the corneous layer of the epidermis,without anchoring junctions.It is likely that cell junctions established in the forming cells of the hair bulb are not completely degraded like in the corneous layer of the epidermis but instead remain in the hair shaft to bind mature cuticle,cortex,and medulla cells into a compact hair shaft.During cell differentiation in hairs,cell junctions seem to disappear,and little is known about the fate of junctional proteins present in the mature human hair shaft.The present ultrastructural immunogold study has detected some marker proteins of adhesion junction(cadherin and beta-catenin)and tight junctions(occludin and cingulin)that are still present in cornified hairs where numerous isopeptide bonds are detected,especially in the medulla.This qualitative ultrastructural study indicates that aside from the cell membrane complex,a long corneo-desmosome bonding cortex and cuticle cells,also sparse adherens and tight junction remnants are present.It is suggested that the cornification of these junctions with the incorporation of their proteins within the mature corneous material of the hair shaft likely contributes to maintaining the integrity of the mature hair.This information will also allow us to evaluate the effects of different chemical components present in hair formulations and stains on these junctional proteins and the consequent integrity of the hair shaft.展开更多
Cell-cell and cell-matrix signaling and communication between adhesion sites involve mechanisms which are required for cellular functions during normal development and homeostasis; however these cellular functions and...Cell-cell and cell-matrix signaling and communication between adhesion sites involve mechanisms which are required for cellular functions during normal development and homeostasis; however these cellular functions and mechanisms are often deregulated in cancer. Aberrant signaling at cell-cell and cell-matrix adhesion sites often involves downstream mediators including Rho GTPases and tyrosine kinases. This review discusses these molecules as putative mediators of cellular crosstalk between cell-cell and cell-matrix adhesion sites, in addition to their attractiveness as therapeutic targets in cancer. Interestingly, inter-junctional crosstalk mechanisms are frequently typified by the way in which bacterial and viral pathogens opportunistically infect or intoxicate mammalian cells. This review therefore also discusses the concept of learning from pathogen-host interaction studies to better understand coordinated communication between cell-cell and cell-matrix adhesion sites, in addition to highlighting the potential therapeutic usefulness of exploiting pathogens or their products to tap into inter-junctional crosstalk. Taken together, we feel that increased knowledge around mechanisms of cell-cell and cell-matrix adhesion site crosstalk and consequently a greater understanding of their therapeutic targeting offers a unique opportunity to contribute to the emerging molecular revolution in cancer biology.展开更多
Objective:Although there have been improvements in targeted therapy and immunotherapy,the majority of lung adenocarcinoma(LUAD)patients still lack effective therapies.Consequently,it is urgent to screen for new diagno...Objective:Although there have been improvements in targeted therapy and immunotherapy,the majority of lung adenocarcinoma(LUAD)patients still lack effective therapies.Consequently,it is urgent to screen for new diagnosis biomarkers and pharmacological targets.Junctional adhesion molecule-like protein(JAML)was considered to be an oncogenic protein and may be a novel therapeutic target in LUAD.Kaempferol is a natural flavonoid that exhibits antitumor activities in LUAD.However,the effect of kaempferol on JAML is still unknown.Methods:Small interfering RNA was used to knockdown JAML expression.The cell viability was determined using the cell counting kit-8 assay.The proliferation of LUAD cells was evaluated using the 5-ethynyl-2'-deoxyuridine incorporation assay.The migration and invasion of LUAD cells were evaluated by transwell assays.Molecular mechanisms were explored by Western blotting.Results:JAML knockdown suppressed proliferation,migration and invasion of LUAD cells,and JAML deficiency restrained epithelial-mesenchymal transition(EMT)via inactivating the phosphoinositide 3-kinase/protein kinase B/mammalian target of rapamycin(PI3K/AKT/mTOR)pathway.Using a PI3K activator(740Y-P),rescue experiments showed that phenotypes to JAML knockdown in LUAD cells were dependent on the PI3K/AKT/mTOR pathway.Kaempferol also inhibited proliferation,migration and invasion of A549 and H1299 cells and partially suppressed EMT through the PI3K/AKT/mTOR pathway.Knockdown of JAML ameliorated the inhibitory effect of kaempferol on LUAD cells.Kaempferol exerted anticancer effects by targeting JAML.Conclusion:JAML is a novel target for kaempferol against LUAD cells.展开更多
Tight junctions(TJs)are structures between cells where cells appear in the closest possible contact.They are responsible for sealing compartments when epithelial sheets are generated.They regulate the permeability of ...Tight junctions(TJs)are structures between cells where cells appear in the closest possible contact.They are responsible for sealing compartments when epithelial sheets are generated.They regulate the permeability of ions,(macro)molecules and cells via the paracellular pathway.Their structure at the electron microscopic level has been well known since the 1970s;however,only recently has their macromolecular composition been revealed.This review first examines the major macromolecular components of the TJs(occludin,claudins,junctional adhesion molecule and tricellulin)and then the associated macromolecules at the intracellular plaque[zonula occludens(ZO)-1,ZO-2,ZO-3,AF-6,cingulin,7H6].Emphasis is given to their interactions in order to begin to understand the mode of assembly of TJs.The functional significance of TJs is detailed and several mechanisms and factors involved are discussed briefly.Emphasis is given to the role of intestinal TJs and the alterations observed or speculated in diverse disease states.Specifically,intestinal TJs may exert a pathogenetic role in intestinal(inflammatory bowel disease,celiac disease)and extraintestinal diseases (diabetes type 1,food allergies,autoimmune diseases).Additionally,intestinal TJs may be secondarily disrupted during the course of diverse diseases,subsequently allowing the bacterial translocation phenomenon and promoting the systemic inflammatory response,which is often associated with clinical deterioration.The major questions in the field are highlighted.展开更多
文摘The differentiation of cells composing mature human hairs produces layers with different corneous characteristics that would tend to flake away one from another,as in the corneous layer of the epidermis,without anchoring junctions.It is likely that cell junctions established in the forming cells of the hair bulb are not completely degraded like in the corneous layer of the epidermis but instead remain in the hair shaft to bind mature cuticle,cortex,and medulla cells into a compact hair shaft.During cell differentiation in hairs,cell junctions seem to disappear,and little is known about the fate of junctional proteins present in the mature human hair shaft.The present ultrastructural immunogold study has detected some marker proteins of adhesion junction(cadherin and beta-catenin)and tight junctions(occludin and cingulin)that are still present in cornified hairs where numerous isopeptide bonds are detected,especially in the medulla.This qualitative ultrastructural study indicates that aside from the cell membrane complex,a long corneo-desmosome bonding cortex and cuticle cells,also sparse adherens and tight junction remnants are present.It is suggested that the cornification of these junctions with the incorporation of their proteins within the mature corneous material of the hair shaft likely contributes to maintaining the integrity of the mature hair.This information will also allow us to evaluate the effects of different chemical components present in hair formulations and stains on these junctional proteins and the consequent integrity of the hair shaft.
基金Supported by Past and present funding in the senior author’s laboratory as follows--Health Research Board of Ireland(HRA--POR-2014-545HRA/2009/49+6 种基金RP/2006/95,to Hopkins AM)Science Foundation Ireland(13/IA/19942008/RFP/NSC14272008/RFP/NSC1427 TIDA Feasibility 10,to Hopkins AM)Cancer Research Ireland,Breast Cancer IrelandBrazil Science Without Borders(CAPES-13306-13-8)the Beaumont Hospital Cancer Research and Development Trust
文摘Cell-cell and cell-matrix signaling and communication between adhesion sites involve mechanisms which are required for cellular functions during normal development and homeostasis; however these cellular functions and mechanisms are often deregulated in cancer. Aberrant signaling at cell-cell and cell-matrix adhesion sites often involves downstream mediators including Rho GTPases and tyrosine kinases. This review discusses these molecules as putative mediators of cellular crosstalk between cell-cell and cell-matrix adhesion sites, in addition to their attractiveness as therapeutic targets in cancer. Interestingly, inter-junctional crosstalk mechanisms are frequently typified by the way in which bacterial and viral pathogens opportunistically infect or intoxicate mammalian cells. This review therefore also discusses the concept of learning from pathogen-host interaction studies to better understand coordinated communication between cell-cell and cell-matrix adhesion sites, in addition to highlighting the potential therapeutic usefulness of exploiting pathogens or their products to tap into inter-junctional crosstalk. Taken together, we feel that increased knowledge around mechanisms of cell-cell and cell-matrix adhesion site crosstalk and consequently a greater understanding of their therapeutic targeting offers a unique opportunity to contribute to the emerging molecular revolution in cancer biology.
基金supported by the National Natural Science Foundation of China(Grant No.81973630)National Clinical Key Specialty Project Foundation(Grant No.Z155080000004).
文摘Objective:Although there have been improvements in targeted therapy and immunotherapy,the majority of lung adenocarcinoma(LUAD)patients still lack effective therapies.Consequently,it is urgent to screen for new diagnosis biomarkers and pharmacological targets.Junctional adhesion molecule-like protein(JAML)was considered to be an oncogenic protein and may be a novel therapeutic target in LUAD.Kaempferol is a natural flavonoid that exhibits antitumor activities in LUAD.However,the effect of kaempferol on JAML is still unknown.Methods:Small interfering RNA was used to knockdown JAML expression.The cell viability was determined using the cell counting kit-8 assay.The proliferation of LUAD cells was evaluated using the 5-ethynyl-2'-deoxyuridine incorporation assay.The migration and invasion of LUAD cells were evaluated by transwell assays.Molecular mechanisms were explored by Western blotting.Results:JAML knockdown suppressed proliferation,migration and invasion of LUAD cells,and JAML deficiency restrained epithelial-mesenchymal transition(EMT)via inactivating the phosphoinositide 3-kinase/protein kinase B/mammalian target of rapamycin(PI3K/AKT/mTOR)pathway.Using a PI3K activator(740Y-P),rescue experiments showed that phenotypes to JAML knockdown in LUAD cells were dependent on the PI3K/AKT/mTOR pathway.Kaempferol also inhibited proliferation,migration and invasion of A549 and H1299 cells and partially suppressed EMT through the PI3K/AKT/mTOR pathway.Knockdown of JAML ameliorated the inhibitory effect of kaempferol on LUAD cells.Kaempferol exerted anticancer effects by targeting JAML.Conclusion:JAML is a novel target for kaempferol against LUAD cells.
文摘Tight junctions(TJs)are structures between cells where cells appear in the closest possible contact.They are responsible for sealing compartments when epithelial sheets are generated.They regulate the permeability of ions,(macro)molecules and cells via the paracellular pathway.Their structure at the electron microscopic level has been well known since the 1970s;however,only recently has their macromolecular composition been revealed.This review first examines the major macromolecular components of the TJs(occludin,claudins,junctional adhesion molecule and tricellulin)and then the associated macromolecules at the intracellular plaque[zonula occludens(ZO)-1,ZO-2,ZO-3,AF-6,cingulin,7H6].Emphasis is given to their interactions in order to begin to understand the mode of assembly of TJs.The functional significance of TJs is detailed and several mechanisms and factors involved are discussed briefly.Emphasis is given to the role of intestinal TJs and the alterations observed or speculated in diverse disease states.Specifically,intestinal TJs may exert a pathogenetic role in intestinal(inflammatory bowel disease,celiac disease)and extraintestinal diseases (diabetes type 1,food allergies,autoimmune diseases).Additionally,intestinal TJs may be secondarily disrupted during the course of diverse diseases,subsequently allowing the bacterial translocation phenomenon and promoting the systemic inflammatory response,which is often associated with clinical deterioration.The major questions in the field are highlighted.
文摘目的:探讨双歧杆菌三联活菌对葡聚糖硫酸钠(dextran sulfate sodium,DSS)诱导的结肠炎小鼠肠道炎症及紧密连接蛋白连接黏附分子1(junctional adhesion molecule-1,JAM-1)表达与分布的影响.方法:将SPF级♀Balb/c小鼠(8-10周龄)随机分为5组:正常对照NC组、益生菌BB组(正常小鼠予益生菌灌胃14 d)、急性DSS模型组(生理盐水灌胃14 d+第8天起4%DSS溶液自由饮用7 d)、BD组(益生菌灌胃7 d+第8天起4%D S S溶液自由饮用7 d)、B D B组(益生菌灌胃14 d+第8天起4%D S S溶液自由饮用7 d).记录小鼠每日体质量变化.第15天处死小鼠、分离结肠,观察各组肠道损伤情况,以组织病理学积分评估结肠炎的严重程度.采用Western blot法、免疫组织化学法(IHC)检测结肠组织中JAM-1的表达及分布.结果:与D S S模型组相比,益生菌干预组(BD、BDB组)小鼠减轻的体质量得到不同程度恢复(95.17%±3.34%、87.17%±1.83%vs 81.49%±2.16%,P1<0.01,P2=0.08),病变结肠缩短程度、肠黏膜水肿,上皮细胞破坏程度及肠道炎症细胞浸润减轻,且BD组小鼠的改善程度优于BDB组.Western blot结果显示给予益生菌干预,BD、B D B组肠黏膜组织JAM-1蛋白的表达水平较DSS组显著增加(0.725±0.027、0.739±0.033 vs 0.454±0.073,均P<0.05).免疫组织化学结果显示DSS模型组小鼠结肠黏膜JAM-1染色强度明显减弱,染色细胞数减少,分布散乱、中断,益生菌处理后JAM-1染色强度及阳性细胞数减少程度显著改善.仅给予益生菌灌胃的小鼠,体质量、结肠大体、镜下表现以及结肠组织中JAM-1蛋白表达水平及分布,与正常小鼠无显著差异(P>0.05).结论:双歧杆菌三联活菌可能通过影响JAM-1蛋白的表达与分布,改善肠黏膜的屏障功能,从而减轻小鼠急性期肠道炎症反应.
