Integrin receptors have remained as a key subject of interest in the pharmaceutical industry for the last few years. There are a total of 24 different types of integrin heterodimers. Each of these heterodimers plays i...Integrin receptors have remained as a key subject of interest in the pharmaceutical industry for the last few years. There are a total of 24 different types of integrin heterodimers. Each of these heterodimers plays important role in various biological processes that are inherent to different pathological conditions. As a result, integrin receptors have been extensively evaluated for their role in therapeutic targeting. There are different classes of inhibitors against integrin receptors and this review provides an overview on different classes of integrin inhibitors that are currently available. A number of review articles have been written on the possible application of integrin receptors in therapeutic targeting. Many of these articles have heavily emphasized on the importance of αvβ3 & αvβ5 receptors as major pharmaceutical target in cancer but little emphasis has been given on the importance of other integrin receptors, such as α5β1, αIIbβ3, α4β7, αvβ6 etc. While this review gives due importance to both αvβ3 & αvβ5 receptors and provides an historical perspective on how these two receptors have evolved as a potential target for cancer, significant emphasis has also been given on the other integrin receptors that have started enjoying the status of important drug target over the course of last few years. Effort has been maintained to discuss briefly on the key physiological basis of their importance as drug target. For example, involvement of αvβ3 in angiogenesis has made it a therapeutic target for the treatment of cancer. At the same time expression of this receptor on the surface of osteoclast has made it a target for the treatment of osteoporosis. Thus, emphasis has been given on discussing the role of the integrin receptors in different disease conditions followed by specific examples of drug molecules that have been trialed against these receptors. While hundreds of candidate molecules have been developed against different integrin receptors only a handful of them has been subject to phase-III clinical trial. That necessitates careful consideration of certain concerns that are associated with direct targeting of integrins and thus has also been an important goal of this review. In the last few years application of integrin receptors have extended beyond mere therapeutic targeting. Several integrin receptors are currently are studied for their potential of aiding at diagnostic imaging and drug delivery. In this review a brief overview has also been provided on how integrin are being targeted for diagnostic imaging and drug delivery with relevant examples. Thus the primary aim of this review has been to provide an comprehensive overview on the broad scope of application that integrin receptors have in the field of medical science.展开更多
Objective: To prepare monoclonal antibody (McAb) against the Integrin α6 extracellular domain and identify its biological activities. Methods: Fusion-protein of integrin α6 extracellular domain (GST-IAGED) was expre...Objective: To prepare monoclonal antibody (McAb) against the Integrin α6 extracellular domain and identify its biological activities. Methods: Fusion-protein of integrin α6 extracellular domain (GST-IAGED) was expressed in E.coli. JM109 and used for immunizing BALB/C mice. The spleen cells from immunized mice were fused with SP2/0 cells and selectively cultured with HAT medium. ELISA and immunocytochemistry staining were used to select hybridomas. Results: One strain of hybridoma cells that secreted specific monoclonal antibody against integrin α6 extracellular domain was indentified. The immunoglobulin subclass of the McAb was IgG1. Conclusion: The McAb against the extracellular domain of integrin α6 was successfully prepared by using GST-IA6ED fusion protein expressed by E.Coli. And the McAb had positive reaction with human hepatocarcinoma cells-BEL-7402.展开更多
Axon regeneration in the CNS is largely unsuccessful due to excess inhibitory extrinsic factors within lesion sites together with an intrinsic inability of neurons to regrow following injury. Recent work demonstrates ...Axon regeneration in the CNS is largely unsuccessful due to excess inhibitory extrinsic factors within lesion sites together with an intrinsic inability of neurons to regrow following injury. Recent work demonstrates that forced expression of certain neuronal transmembrane receptors can recapitulate neuronal growth resulting in successful growth within and through inhibitory lesion environments. More specifically, neuronal expression of integrin receptors such as alpha9beta1 integrin which binds the extracellular matrix glycoprotein tenascin-C, trk receptors such as trk B which binds the neurotrophic factor BDNF, and receptor PTPσ which binds chondroitin sulphate proteoglycans, have all been show to significantly enhance regeneration of injured axons. We discuss how reintroduction of these receptors in damaged neurons facilitates signalling from the internal environment of the cell with the external environment of the lesion milieu, effectively resulting in growth and repair following injury. In summary, we suggest an appropriate balance of intrinsic and extrinsic factors are required to obtain substantial axon regeneration.展开更多
Receptor-ligand interactions in blood flow are crucial to initiate such biological processes as inflammatory cascade,platelet thrombosis,as well as tumor metastasis.To mediate cell adhesion,the interacting receptors a...Receptor-ligand interactions in blood flow are crucial to initiate such biological processes as inflammatory cascade,platelet thrombosis,as well as tumor metastasis.To mediate cell adhesion,the interacting receptors and ligands must be anchored onto two apposing surfaces of two cells or a cell and a substratum,i.e.,two-dimensional（2D）binding,which is different from the binding of a soluble ligand in fluid phase to a receptor,i.e.,three-dimensional（3D） binding.While numerous works have been focused on3 D kinetics of receptor-ligand interactions in the immune system,2D kinetics and its regulations have been less understood,since no theoretical framework or experimental assays were established until 1993.Not only does the molecular structure dominate 2D binding kinetics,but the shear force in blood flow also regulates cell adhesion mediated by interacting receptors and ligands.Here,we provide an overview of current progress in 2D binding and regulations,mainly from our group.Relevant issues of theoretical frameworks,experimental measurements,kinetic rates and binding affinities,and force regulations are discussed.展开更多
目的探讨(99)~Tc^m 标记精氨酸-甘氨酸-天冬氨酸(RGD)小分子多肽(GY11)作为肿瘤显像剂的可能性。方法利用 SnCl_2直接还原法进行 GY11的(99)~Tc^m 标记。建立荷人黑色素瘤 A375、肺癌 H460和宫颈癌 HeLa BALB/c 裸鼠肿瘤模型,分别进行...目的探讨(99)~Tc^m 标记精氨酸-甘氨酸-天冬氨酸(RGD)小分子多肽(GY11)作为肿瘤显像剂的可能性。方法利用 SnCl_2直接还原法进行 GY11的(99)~Tc^m 标记。建立荷人黑色素瘤 A375、肺癌 H460和宫颈癌 HeLa BALB/c 裸鼠肿瘤模型,分别进行体内分布和肿瘤显像研究。结果 GY11的(99)~Tc^m 标记率为80%。黑色素瘤 A375荷瘤裸鼠体内分布显示,(99)~Tc^m-GY11主要经肾脏快速从血液中清除,注射后2 h 肿瘤摄取量为3.13%ID/g,肿瘤/血和肿瘤/骨骼肌比值随时间的推移而增加,注射后1和6 h 比值分别为3.0、4.3和8.1、15.1。对于黑色素瘤 A375和肺癌 H460荷瘤裸鼠,(99)~Tc^m-GY11静脉注射后2 h 肿瘤均能清楚显示,24 h 后显像更清晰;2 h 后宫颈癌 HeLa 肿瘤能显影,但6 h后肿瘤放射性基本清除。结论 (99)~Tc^m-GY11有望成为肿瘤α_vβ~3受体显像剂。展开更多
文摘Integrin receptors have remained as a key subject of interest in the pharmaceutical industry for the last few years. There are a total of 24 different types of integrin heterodimers. Each of these heterodimers plays important role in various biological processes that are inherent to different pathological conditions. As a result, integrin receptors have been extensively evaluated for their role in therapeutic targeting. There are different classes of inhibitors against integrin receptors and this review provides an overview on different classes of integrin inhibitors that are currently available. A number of review articles have been written on the possible application of integrin receptors in therapeutic targeting. Many of these articles have heavily emphasized on the importance of αvβ3 & αvβ5 receptors as major pharmaceutical target in cancer but little emphasis has been given on the importance of other integrin receptors, such as α5β1, αIIbβ3, α4β7, αvβ6 etc. While this review gives due importance to both αvβ3 & αvβ5 receptors and provides an historical perspective on how these two receptors have evolved as a potential target for cancer, significant emphasis has also been given on the other integrin receptors that have started enjoying the status of important drug target over the course of last few years. Effort has been maintained to discuss briefly on the key physiological basis of their importance as drug target. For example, involvement of αvβ3 in angiogenesis has made it a therapeutic target for the treatment of cancer. At the same time expression of this receptor on the surface of osteoclast has made it a target for the treatment of osteoporosis. Thus, emphasis has been given on discussing the role of the integrin receptors in different disease conditions followed by specific examples of drug molecules that have been trialed against these receptors. While hundreds of candidate molecules have been developed against different integrin receptors only a handful of them has been subject to phase-III clinical trial. That necessitates careful consideration of certain concerns that are associated with direct targeting of integrins and thus has also been an important goal of this review. In the last few years application of integrin receptors have extended beyond mere therapeutic targeting. Several integrin receptors are currently are studied for their potential of aiding at diagnostic imaging and drug delivery. In this review a brief overview has also been provided on how integrin are being targeted for diagnostic imaging and drug delivery with relevant examples. Thus the primary aim of this review has been to provide an comprehensive overview on the broad scope of application that integrin receptors have in the field of medical science.
基金This work was supported by a grand from the Natural Science Foundation of Beijing (No. 7022006).
文摘Objective: To prepare monoclonal antibody (McAb) against the Integrin α6 extracellular domain and identify its biological activities. Methods: Fusion-protein of integrin α6 extracellular domain (GST-IAGED) was expressed in E.coli. JM109 and used for immunizing BALB/C mice. The spleen cells from immunized mice were fused with SP2/0 cells and selectively cultured with HAT medium. ELISA and immunocytochemistry staining were used to select hybridomas. Results: One strain of hybridoma cells that secreted specific monoclonal antibody against integrin α6 extracellular domain was indentified. The immunoglobulin subclass of the McAb was IgG1. Conclusion: The McAb against the extracellular domain of integrin α6 was successfully prepared by using GST-IA6ED fusion protein expressed by E.Coli. And the McAb had positive reaction with human hepatocarcinoma cells-BEL-7402.
文摘Axon regeneration in the CNS is largely unsuccessful due to excess inhibitory extrinsic factors within lesion sites together with an intrinsic inability of neurons to regrow following injury. Recent work demonstrates that forced expression of certain neuronal transmembrane receptors can recapitulate neuronal growth resulting in successful growth within and through inhibitory lesion environments. More specifically, neuronal expression of integrin receptors such as alpha9beta1 integrin which binds the extracellular matrix glycoprotein tenascin-C, trk receptors such as trk B which binds the neurotrophic factor BDNF, and receptor PTPσ which binds chondroitin sulphate proteoglycans, have all been show to significantly enhance regeneration of injured axons. We discuss how reintroduction of these receptors in damaged neurons facilitates signalling from the internal environment of the cell with the external environment of the lesion milieu, effectively resulting in growth and repair following injury. In summary, we suggest an appropriate balance of intrinsic and extrinsic factors are required to obtain substantial axon regeneration.
基金supported by Natural Science Foundation of China(grants 10042001,10072071,10128205,30225027, 10332060,30730032,11072251,and 31110103918)National Key Basic Research Foundation of China(grants 2006CB910303 and 2011CB710904)+2 种基金National High Technology Research and Development Program of China(grants 2007AA02Z306 and 2011AA020109)Chinese Academy of Sciences(grants KJCX2-L02,KJCX2-SW-L06, 2005-1-16,KJCX2-YW-L08,Y2010030,XDA01030102,XDA04073 801)NIH Fogarty International Research Collaboration Award TW 05774-01
文摘Receptor-ligand interactions in blood flow are crucial to initiate such biological processes as inflammatory cascade,platelet thrombosis,as well as tumor metastasis.To mediate cell adhesion,the interacting receptors and ligands must be anchored onto two apposing surfaces of two cells or a cell and a substratum,i.e.,two-dimensional（2D）binding,which is different from the binding of a soluble ligand in fluid phase to a receptor,i.e.,three-dimensional（3D） binding.While numerous works have been focused on3 D kinetics of receptor-ligand interactions in the immune system,2D kinetics and its regulations have been less understood,since no theoretical framework or experimental assays were established until 1993.Not only does the molecular structure dominate 2D binding kinetics,but the shear force in blood flow also regulates cell adhesion mediated by interacting receptors and ligands.Here,we provide an overview of current progress in 2D binding and regulations,mainly from our group.Relevant issues of theoretical frameworks,experimental measurements,kinetic rates and binding affinities,and force regulations are discussed.
文摘目的探讨(99)~Tc^m 标记精氨酸-甘氨酸-天冬氨酸(RGD)小分子多肽(GY11)作为肿瘤显像剂的可能性。方法利用 SnCl_2直接还原法进行 GY11的(99)~Tc^m 标记。建立荷人黑色素瘤 A375、肺癌 H460和宫颈癌 HeLa BALB/c 裸鼠肿瘤模型,分别进行体内分布和肿瘤显像研究。结果 GY11的(99)~Tc^m 标记率为80%。黑色素瘤 A375荷瘤裸鼠体内分布显示,(99)~Tc^m-GY11主要经肾脏快速从血液中清除,注射后2 h 肿瘤摄取量为3.13%ID/g,肿瘤/血和肿瘤/骨骼肌比值随时间的推移而增加,注射后1和6 h 比值分别为3.0、4.3和8.1、15.1。对于黑色素瘤 A375和肺癌 H460荷瘤裸鼠,(99)~Tc^m-GY11静脉注射后2 h 肿瘤均能清楚显示,24 h 后显像更清晰;2 h 后宫颈癌 HeLa 肿瘤能显影,但6 h后肿瘤放射性基本清除。结论 (99)~Tc^m-GY11有望成为肿瘤α_vβ~3受体显像剂。
